ProstateCancer 2023.V2 EN

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Prostate Cancer
Version 2.2023 — July 17, 2023
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NCCN Guidelines for Patients® available at www.nccn.org/patients
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Version 2.2023, 07/17/23 © 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
NCCN Guidelines Version 2.2023 NCCN Guidelines Index
Table of Contents
Prostate Cancer Discussion
*Edward M. Schaeffer, MD, PhD/Chair ω James A. Eastham, MD ω George Netto, MD ≠

Robert H. Lurie Comprehensive Cancer Memorial Sloan Kettering Cancer Center O'Neal Comprehensive Cancer Center at UAB
Center of Northwestern University Thomas A. Farrington ¥ Julio M. Pow-Sang, MD ω
*Sandy Srinivas, MD/Vice-Chair † ω Prostate Health Education Network (PHEN) Moffitt Cancer Center
Stanford Cancer Institute Robert Reiter, MD, MBA ω
Xin Gao, MD †
Nabil Adra, MD, MSc † Dana-Farber/Brigham and Women's UCLA Jonsson Comprehensive Cancer Center
Indiana University Melvin and Bren Cancer Center | Massachusetts General Mack Roach, III, MD §
Simon Comprehensive Cancer Center Hospital Cancer Center UCSF Helen Diller Family
Yi An, MD § Shilpa Gupta, MD † Comprehensive Cancer Center
Yale Cancer Center/Smilow Cancer Hospital Case Comprehensive Cancer Center/University Tyler Robin, MD, PhD §
Daniel Barocas, MD, MPH ω Hospitals Seidman Cancer Center and University of Colorado Cancer Center
Vanderbilt-Ingram Cancer Center Cleveland Clinic Taussig Cancer Institute
Stan Rosenfeld ¥
Rhonda Bitting, MD † Thomas Guzzo, MD, MPH ω University of California San Francisco
Duke Cancer Institute Abramson Cancer Center at Patient Services Committee Chair
The University of Pennsylvania
Alan Bryce, MD † Ahmad Shabsigh, MD ω
Mayo Clinic Cancer Center Joseph E. Ippolito, MD, PhD ф The Ohio State University Comprehensive
Siteman Cancer Center at Barnes- Cancer Center - James Cancer Hospital
Brian Chapin, MD ω Jewish Hospital and Washington
The University of Texas and Solove Research Institute
University School of Medicine
MD Anderson Cancer Center Daniel Spratt, MD §
Michael R. Kuettel, MD, MBA, PhD § Case Comprehensive Cancer Center/University
Heather H. Cheng, MD, PhD † Roswell Park Comprehensive Cancer Center Hospitals Seidman Cancer Center and
Fred Hutchinson Cancer Center
Joshua M. Lang, MD, MS † Cleveland Clinic Taussig Cancer Institute
Anthony Victor D’Amico, MD, PhD § University of Wisconsin Carbone Cancer Center Benjamin A. Teply, MD †
Dana-Farber/Brigham and Women’s
Tamara Lotan, MD ≠ Fred & Pamela Buffett Cancer Center
Cancer Center | Massachusetts
General Hospital Cancer Center The Sidney Kimmel Comprehensive Jonathan Tward, MD, PhD §
Cancer Center at Johns Hopkins Huntsman Cancer Institute
Neil Desai, MD, MHS § at the University of Utah
Rana R. McKay, MD †
UT Southwestern Simmons
UC San Diego Moores Cancer Center Richard Valicenti, MD §
Comprehensive Cancer Center
Todd Morgan, MD ω UC Davis Comprehensive Cancer Center
Tanya Dorff, MD †
University of Michigan Rogel Cancer Center Jessica Karen Wong, MD §
City of Hope National Cancer Center
Fox Chase Cancer Center
ф Diagnostic/Interventional ¥ Patient advocate NCCN

Deborah Freedman-Cass, PhD
radiology
Þ Internal medicine
§ Radiotherapy/Radiation oncology
w Urology
Continue Jenna Snedeker, MS, ASCP
† Medical oncology * Discussion Section Writing Dorothy A. Shead, MS
≠ Pathology Committee NCCN Guidelines Panel Disclosures
Table of Contents
NCCN Prostate Cancer Panel Members Principles of Life Expectancy Estimation (PROS-A)
Clinical Trials: NCCN believes
Summary of Guidelines Updates Principles of Quality-of-Life and Shared Decision that the best management for any
Initial Prostate Cancer Diagnosis (PROS-1) -Making (PROS-B)
patient with cancer is in a clinical
Initial Risk Stratification and Staging Workup for Principles of Genetics and Molecular/ Biomarker trial.
Clinically Localized Disease (PROS-2) Analysis (PROS-C) Participation in clinical trials is
Very-Low-Risk Group (PROS-3) Principles of Risk Stratification (PROS-D) especially encouraged.
Low-Risk Group (PROS-4) Principles of Imaging (PROS-E) Find an NCCN Member Institution:
Favorable Intermediate-Risk Group (PROS-5) Principles of Active Surveillance and Observation https://www.nccn.org/home/
(PROS-F) member-institutions.
Unfavorable Intermediate-Risk Group (PROS-6)
Principles of Radiation Therapy (PROS-G)
High- or Very-High-Risk Group (PROS-7)
Principles of Surgery (PROS-H) NCCN Categories of
Regional Risk Group (PROS-8)
Principles of Androgen Deprivation Therapy (PROS-I) Evidence and Consensus: All
Monitoring (PROS-9)
Principles of Non-Hormonal Systemic Therapy recommendations are category 2A
Radical Prostatectomy PSA Persistence/Recurrence (PROS-J) unless otherwise indicated.
(PROS-10)
Staging (ST-1) See NCCN Categories of Evidence
Radiation Therapy Recurrence (PROS-11)
Abbreviations (ABBR-1) and Consensus.
Systemic Therapy for Castration-Sensitive Prostate
Cancer (PROS-12)
Systemic Therapy for M0 Castration-Resistant NCCN Categories of Preference:
Prostate Cancer (CRPC) (PROS-13) All recommendations are
Systemic Therapy for M1 CRPC (PROS-14) considered appropriate.
Systemic Therapy for M1 CRPC: Adenocarcinoma See NCCN Categories of
(PROS-15) Preference.
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2022.
Table of Contents
Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 2.2023 of the NCCN Guidelines for Prostate Cancer from Version 1.2023 include:
PROS-2A
• Footnote j modified: Plain films, CT, MRI, or PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/ MRI with F-18 sodium fluoride, C-11 choline, or
F-18 fluciclovine Ga-68 prostate-specific membrane antigen (PSMA)-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial
bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. mpMRI is
preferred over CT for pelvic staging. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA-PET/CT or PSMA-PET/MRI can be considered for bone
and soft tissue (full body) imaging. See Principles of Imaging (PROS-E).
PROS-9
Footnote II modified: ... Plain films, CT, MRI, or PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, or
F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial bone imaging. Soft tissue imaging of the
pelvis, abdomen, and chest can include chest CT and abdominal/ pelvic CT or abdominal/pelvic MRI. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat
PSMA-PET/CT or PSMA-PET/MRI can be considered for bone and soft tissue (full body) imaging. See Principles of Imaging (PROS-E). (also for PROS-
10, PROS-11A, PROS-12A, and PROS-13)
PROS-10
Footnote oo modified: Ga-68 PSMA-11 or F-18 piflufolastat PSMA-PET/CT or PSMA-PET/MRI are preferred for bone and soft tissue (full body) imaging.
Alternatively, bone imaging can be achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PSMA-PET/CT or PSMA-PET/
MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered
for equivocal results on initial bone imaging. See Principles of Imaging (PROS-E). (also for PROS-11A)
PROS-15
• No prior docetaxel/no prior novel hormone therapy:
Useful in certain circumstances:
◊ Added: Olaparib/abiraterone for BRCA mutation (category 1)
• Prior novel hormone therapy/no prior docetaxel
Other recommended regimens:
◊ Modified: Abiraterone + dexamethasone
PROS-15A
• Added footnote qqq: Olaparib with abiraterone is an option for patients with a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) who
have not yet received a novel hormone therapy or docetaxel.
• Footnote xxx modified: Lu-177–PSMA-617 is a treatment option for patients with ≥1 PSMA-positive lesion and/or metastatic disease that is
predominately PSMA-positive and with no dominant PSMA-negative metastatic lesions who have been treated previously with androgen receptor-
directed therapy and a taxane-based chemotherapy. The panel believes that both Ga-68 PSMA-11 or F-18 piflufolastat PSMA imaging can be used to
determine eligibility. Sartor et al. N Engl J Med 2021; 385:1091-1103. See Principles of Radiation Therapy (PROS-G).
Continued
Version 2.2023, 07/17/23 © 2023 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
PROS-E 2 of 3:
• 5th bullet 1st sub-bullet modified: Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 piflufolastat PSMA, Ga-68 PSMA-11, F-18 flotufolastat
PSMA, F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine can be considered for equivocal results on initial bone scan.
• 5th bullet 2nd sub-bullet modified: Ga-68 PSMA-11, or F-18 piflufolastat PSMA, or F-18 flotufolastat PSMA PET/CT or PET/MRI (full body imaging)
can be considered as an alternative to bone scan.
PROS-E 3 of 3:
• Positron Emission Tomography, first paragraph modified: PSMA-PET refers to a growing body of radiopharmaceuticals that target PSMA on the
surface of prostate cells. There are multiple PSMA radiopharmaceuticals at various stages of investigation. At this time, the NCCN Guidelines only
recommend the currently FDA-approved PSMA agents: F-18 piflufolastat PSMA (also known as F-18 DCFPyL), F-18 flotufolastat PSMA (also
known as rh-PSMA-7.3), and Ga-68 PSMA-11. Throughout these Guidelines, “PSMA-PET” refers to any of these FDA-approved PSMA ligands. See
Table 2 in the Discussion section for more detail.
• 2nd bullet modified: F-18 piflufolastat PSMA or Ga-68 PSMA-11 PSMA-PET/CT or PET/MRI can be considered as an alternative to standard
imaging of bone and soft tissue for initial staging, the detection of biochemically recurrent disease, and as workup for progression.
• 5th bullet modified: Studies suggest that F-18 piflufolastat PSMA or Ga-68 PSMA-11 PSMA-PET imaging have a higher sensitivity than C-11 choline
or F-18 fluciclovine PET imaging, especially at very low PSA levels.
• Added: F-18 flotufolastat PSMA is a PET imaging agent that is part of a novel class of tracers referred to as radiohybrid (rh) ligands. These rh
ligands have the unique advantage of offering two binding sites for radionuclides (i.e., F-18 or Ga-68) which increases its flexibility in imaging. In
addition, the presence of a chelator in these rh ligands also allows for chelation of Lu-177 for its use as a theranostic as well as imaging agent.
The increasing use of PSMA-PET has identified the potential for considerable biological diversity among disease foci within a given individual
with prostate cancer, especially mCRPC, and that this heterogeneity can be detected with a combination of PSMA-PET and FDG-PET. Initial data
suggests that metastases with PSMA-negative/FDG-positive mismatches may exist in mCRPC patients undergoing Lu-PSMA radioligand therapy
and that patients with these mismatches may have worse outcomes. Currently, no robust clinical trial data exists to support the incorporation of
FDG-PET into routine clinical use alongside PSMA-PET. To overcome the limitations of PSMA-PET in PSMA-negative metastatic disease, the
panel currently recommends the use of contrast-enhanced CT or MRI in these patients, as the non-contrast CT component of PSMA PET/CT is
insufficient to detect visceral metastatic disease.
PROS-G 6 of 7:
• Lu-177-PSMA-617
5th bullet modified: Although the FDA has approved Ga-68 PSMA-11 for use with Lu- 177–PSMA-617, the panel believes that F-18 piflufolastat
PSMA and F-18 flotufolastat PSMA can also be used in the same space due to multiple reports describing the equivalency of these imaging
agents.
PROS-J 2 of 3:
• Targeted therapy
3rd bullet added: Olaparib with abiraterone is an option for patients with a pathogenic BRCA1 or BRCA2 mutation (germline and/or somatic) who
have not yet received a novel hormone therapy or docetaxel.
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PROS-1
• Clinically localized prostate cancer, Workup:
3rd bullet modified: Perform and/or collect prostate-specific antigen (PSA) and calculate PSA density and PSA doubling time (PSADT)
8th bullet added: Assess quality-of-life measures
• Regional prostate cancer and metastatic prostate cancer, Workup:
7th bullet added: Assess quality-of-life measures
Footnote d added: See Principles of Quality-of-Life and Shared Decision-Making (PROS-B)
PROS-2
• Risk Group, Additional Evaluation:
Very low, modified: Confirmatory testing can be used to assess the appropriateness of active surveillance (See PROS-F 2 of 5)Consider confirmatory
mpMRI ± prostate biopsy if MRI not performed initially. All patients should undergo a confirmatory prostate biopsy within 1-2 years of their diagnostic
biopsy.
Low, modified: Confirmatory testing can be used to assess the appropriateness of active surveillance (See PROS-F 2 of 5) Consider confirmatory
mpMRI ± prostate biopsy and/or molecular tumor analysis if MRI not performed initially to establish candidacy for active surveillance. All patients
should undergo a confirmatory prostate biopsy within 1-2 years of their diagnostic biopsy.
Intermediate, modified: Confirmatory testing can be used to assess the appropriateness of active surveillance (See PROS-F 2 of 5) Consider
confirmatory mpMRI ± prostate biopsy and/or molecular tumor analysis if MRI not performed initially for those considering active surveillance. All
patients should undergo a confirmatory prostate biopsy within 1-2 years of their diagnostic biopsy.
PROS-3
• Very-Low-Risk Group:
>20 y, Initial Therapy
◊ Added: See Active Surveillance Program (PROS-F 2 of 5)
◊ Removed the following bullets:
– Consider confirmatory mpMRI +/- prostate biopsy if MRI not performed initially
– All patients should undergo a confirmatory prostate biopsy within 1–2 years of their diagnostic biopsy
– PSA no more often than every 6 mo unless clinically indicated
– DRE no more often than every 12 mo unless clinically indicated
– Repeat prostate biopsy no more often than every 12 mo unless clinically indicated
– Repeat mpMRI no more often than every 12 mo unless clinically indicated
10–20 y, Initial Therapy:
– Consider confirmatory mpMRI +/- prostate biopsy if MRI not performed initially
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PROS-4
• Low-Risk Group:
≥10 y, Initial Therapy:
– Consider confirmatory mpMRI +/- prostate biopsy and/or molecular tumor analysis if MRI not performed initially
PROS-5
• Favorable Intermediate-Risk Group:
>10 y, Initial Therapy:
– Consider confirmatory mpMRI +/- prostate biopsy and/or molecular tumor analysis if MRI not performed initially
◊ Modified: RP ± pelvic lymph node dissection (PLND) if predicted probability of lymph node metastasis ≥2%
PROS-6
• Unfavorable Intermediate Risk Group:
>10 y, Initial Therapy, modified: RP ± PLND RP + PLND if predicted probability of lymph node metastasis ≥2%
PROS-7
• High- or Very-High-Risk Group:
>5 y or symptomatic, Initial Therapy, removed: EBRT + ADT (2 y) + docetaxel for 6 cycles (for very-high-risk only)
Footnote ff added: Patients in STAMPEDE had at least two of the following: cT3–4, Grade Group 4 or 5, and PSA >40 ng/mL. (Also on PROS-8A)
PROS-8
• Regional Risk Group (Any T, N1, M0)
>5 y or symptomatic, Initial Therapy:
◊ Modified: EBRT + ADT + abiraterone (preferred)
◊ Modified: EBRT + ADT (preferred)
◊ Modified: RP + PLND in select patients
• Footnote jj added: There is limited evidence that RP + PLND is beneficial in the setting of node-positive disease. Use of this approach should be limited
to patients with >10-year life expectancy and resectable disease and should be used in the context of a clinical trial or planned multimodality approach.
(Also on PROS-8A)
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PROS-8A
• Footnote o modified: If higher grade and/or higher T stage is found during confirmatory testing, see PROS-2.
• Footnote t modified: Decipher molecular assay is recommended should be considered if not previously performed to inform adjuvant treatment if
adverse features are found post-RP.
• Footnote removed: See Principles of Risk Stratification.
• Footnote removed: Repeat molecular tumor analysis is discouraged.
• Footnote z modified: PSA persistence/recurrence after RP is defined as failure of PSA to fall to undetectable levels (PSA persistence) or undetectable
PSA after RP with a subsequent detectable PSA that increases on 2 or more determinations (PSA recurrence) or that increases to PSA >0.1 ng/mL.
(Also on PROS-9 and PROS-10)
PROS-9
• Monitoring, Initial definitive therapy, 2nd bullet modified: DRE if suspicion of recurrence every year, but may be omitted if PSA undetectable.
• Recurrence, Biopsy of metastatic site, modified: See Systemic Therapy for Castration-Naive Sensitive Disease
PROS-10
• The algorithm has been divided into two branches: Life expectancy >5 y and Life expectancy ≤5 y
Life expectancy >5 y
◊ Modified:
– Studies negative for distant metastases and pelvic recurrence
– EBRT ± ADT (preferred) or Observation Monitoring
◊ Added: Studies positive for pelvic recurrence
– Added: EBRT + ADT ± abiraterone
▪ Added: Progression
Life expectancy ≤5 y
◊ Added: Observation
– Added: Progression
• Modified: See Systemic Therapy for Castration Naive Sensitive Disease
• Footnote oo modified: Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI are preferred for bone and soft tissue (full body) imaging.
Alternatively, bone imaging can be achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or PET/MRI with
F-18 sodium fluoride, C-11 choline, F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial
bone imaging. Soft tissue imaging of pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. mpMRI is
preferred over CT for pelvic staging. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft
tissue (full body) imaging. (Also on PROS-11A)
• Footnote pp added: The fine-particle formulation of abiraterone can be used instead of the standard form (category 2B).
PROS-11
• This page has been extensively revised.
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PROS-12
• Page heading has been modified: Systemic Therapy for Castration-Naive Sensitive Prostate Cancer
• M1:
ADT with one of the following, removed: Docetaxel 75 mg/m2 for 6 cycles (category 1)
Added: or ADT with docetaxel and one of the following:
◊ Preferred regimens:
– Abiraterone (category 1)
– Darolutamide (category 1)
Modified: or ADT with EBRT to the primary tumor for low-volume metastatic burden M1
• 3rd bullet modified: Consider periodic imaging Conventional imaging every 3–6 mo to monitor treatment response.
PROS-12A
• Footnote rr modified: The term "castration-naive sensitive" is used to define patients who have not been treated with ADT and those who are not
on ADT at the time of progression. The NCCN Prostate Cancer Panel uses the term "castration-naÏve sensitive" even when patients have had
neoadjuvant, concurrent, or adjuvant ADT as part of radiation therapy provided they have recovered testicular function.
• Footnote zz modified: Routine use of bone antiresorptive therapy is not recommended in the castration-naïve setting unless for elevated fracture risk
Bone antiresorptive therapy is indicated for elevated fracture risk based upon FRAX in the castration-sensitive setting. See PROS-I.
• Footnote removed: High-volume disease is differentiated from low-volume disease by visceral metastases and/or 4 or more bone metastases, with
at least one metastasis beyond the pelvis vertebral column. Patients with low-volume disease have less certain benefit from early treatment with
docetaxel combined with ADT.
• Footnote aaa added: The panel encourages ADT with docetaxel and either darolutamide or abiraterone for patients with high-volume disease who are
fit for chemotherapy. See Principles of Non-Hormonal Systemic Therapy (PROS-J).
• Footnote bbb added: EBRT to the primary tumor is associated with an overall survival benefit in patients with low metastatic burden at the time of
diagnosis of metastatic disease, which is defined by conventional imaging as either non-regional, lymph-node-only disease OR <4 bone metastases
and without visceral/other metastasis (Ali A, et al. JAMA Oncol 2021;7:555-563). See Principles of Radiation Therapy (PROS-G).
• Footnote ccc added: ADT is strongly recommended in combination therapy for metastatic castration-sensitive disease. The use of ADT monotherapy in
metastatic castration-sensitive disease is discouraged unless there are clear contraindications to combination therapy.
• Footnote removed: See Principles of Non-Hormonal Systemic Therapy.
• Footnote ddd modified: Patients who were under monitoring for M0 disease should receive an appropriate therapy for castration-naive sensitive
disease.
PROS-13
• Footnote removed: Observation involves monitoring the course of disease with the expectation to deliver palliative therapy for the development of
symptoms or a change in exam or PSA that suggests symptoms are imminent.
PROS-14
• First-line and subsequent treatment options:
1st bullet, 5th sub-bullet added: For additional options, See NCCN Guidelines for Small Cell Lung Cancer.
• Footnote removed: For additional small cell/NEPC therapy options, see NCCN Guidelines for Small Cell Lung Cancer
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PROS-15
• Prior novel hormonal therapy/no prior docetaxel:
Preferred regimens, removed: Sipuleucel-T
◊ Removed: Pembrolizumab for MSI-H, dMMR, or TMB ≥10 mut/Mb
◊ Added: Sipuleucel-T
• Prior docetaxel/no prior novel hormone therapy:
◊ Removed: Pembrolizumab for MSI-H, dMMR, or TMB ≥10 mut/Mb
◊ Added: Sipuleucel-T
Other recommended regimens, removed: Sipuleucel-T
PROS-15A
• Footnote mmm modified: Novel hormone therapies include abiraterone, enzalutamide, darolutamide, or apalutamide received for metastatic castration-
naÏve sensitive disease, M0 CRPC, or previous lines of therapy for M1 CRPC. Abiraterone given as part of neoadjuvant/concomitant/adjuvant ADT with
EBRT is not considered prior novel hormonal therapy.
• Footnote ttt modified: Olaparib is a treatment option for patients with mCRPC and a pathogenic mutation (germline and/or somatic) in a homologous
recombination repair gene (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or
RAD54L) who have been treated previously with androgen receptor-directed therapy. However, efficacy appears to be driven by the cohort of patients
with at least one alteration in BRCA2, BRCA1, or ATM, and in particular, by patients with BRCA2 or BRCA1 mutations based on exploratory gene-
by-gene analysis. Patients with PPP2R2A mutations in the PROfound trial experienced an unfavorable risk-benefit profile. Therefore, olaparib is not
recommended in patients with a PPP2R2A mutation. There may be heterogeneity of response to olaparib for non-BRCA mutations based on which
gene has a the specific gene mutation.
PROS-B
• A new section has been added to the guidelines: Principles of Quality-of-Life and Shared Decision-Making
PROS-C 1 of 3
• Testing, 1st sub-bullet modified: If criteria are met (see PROS-C, 2 of 3), germline multigene testing that includes at least BRCA1, BRCA2, ATM,
PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2 is recommended.
PROS-C 2 of 3
• By family history and/or ancestry,
1st bullet, 3rd sub-bullet modified: male (sex assigned at birth) breast cancer at any age.
2nd bullet modified: ≥1 first-degree relative (father parent or brother sibling) with:
PROS-C 3 of 3
• Testing, 2nd sub-bullet modified: Tumor testing for microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) is recommended in
patients with metastatic castration-resistant prostate cancer and may be considered in patients with regional or castration-naÏve sensitive metastatic
prostate cancer.
• Post-test Considerations, 1st sub-bullet modified: Post-test genetic counseling is recommended if pathogenic/likely pathogenic variant (mutation)
identified in any gene that has clinical implications if also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2,
MSH6, PMS2).
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PROS-D
• This section has been extensively revised.
PROS-E 3 of 3
• Positron Emission Tomography, 2nd bullet modified: F-18 piflufolastat PSMA or Ga-68 PSMA-11 PET/CT or PET/MRI can be considered as an
alternative to standard imaging of bone and soft tissue for initial staging, the detection of biochemically recurrent disease, and as workup for
progression. with bone scan plus CT or MRI for the evaluation of bone, pelvis, and abdomen.
• Positron Emission Tomography, 8th bullet added: PSMA imaging should be done before initiation of ADT because ADT may affect detection sensitivity.
PROS-F 1 of 5
• Candidacy for Active Surveillance, 2nd bullet modified: Active surveillance is preferred for most patients with low-risk prostate cancer (See Risk Group
Criteria [PROS-2]) and a life expectancy ≥10 years. The panel recognizes that there is heterogeneity across this risk group, and that some factors
may be associated with an increased probability of near-term grade reclassification including high PSA density, a high number of positive cores (eg,
≥3), and high genomic risk (from tissue-based molecular tumor analysis), and/or a known BRCA2 germline mutation…
PROS-F 2 of 5
• Active Surveillance Program, 1st bullet, 4th sub-bullet modified: Consider repeat mpMRI no more often than every 12 months unless clinically
indicated.
PROS-F 3 of 5
• Observation, 3rd bullet modified: Observation may be considered for is preferred for: Asymptomatic patients with favorable and unfavorable
intermediate-risk prostate cancer and a life expectancy between 5–10 years.
PROS-F 5 of 5
• Reference removed: Carter HB, Helfand B, Mamawala M, et al. Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in
men on active surveillance for prostate cancer. Eur Urol 2019;75:743-749.
PROS-G 2 of 7
• Definitive Radiation Therapy by Risk Group
6th bullet, 1st sub-bullet modified: Nodal radiation should be performed. Clinically positive nodes should be dose-escalated as dose-volume
histogram parameters allow. ADT is required unless medically contraindicated, and the addition of abiraterone or fine-particle abiraterone (category
2B) to ADT can be considered is preferred.
7th bullet modified: Low-volume metastatic burden, castration-naive sensitive disease
◊ 1st sub-bullet modified: Radiation therapy to the prostate is an option in patients with low-volume metastatic burden castration-naÏve sensitive
metastatic disease, without contraindications to radiotherapy. ADT is required unless medically contraindicated.
8th bullet and subsequent bullets added: Low metastatic burden is defined as either non-regional, lymph-node-only disease OR <4 bone metastases
and without visceral/other metastasis.
◊ Number and location of lesions is defined by conventional imaging.
◊ At this time, metastases defined only by PET imaging should not be used to exclude a patient from treatment of the primary tumor.
9th bullet modified: This recommendation is based on the STAMPEDE phase 3 randomized trial, which randomized 2061 patients to standard
systemic therapy with or without radiotherapy to the primary. The overall cohort had a significant improvement from the addition of radiotherapy to
the primary in failure-free survival, but not overall survival. The prespecified low-volume subset had a significant improvement in both failure-free
survival and overall survival. A meta-analysis with two other studies confirmed this benefit for primary RT to the primary tumor in lower volume
disease.
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PROS-G 3 of 7
• Principles of Radiation Therapy, 1st bullet added: STAMPEDE Arm H has now distinguished the CHAARTED definition of low metastatic disease
to one that more granularly quantifies who benefits from treatment of the primary based on number of bone metastases. This is relevant because a
patient can have 12 spine metastases and be classified as low volume by CHAARTED, but would not derive benefit in overall survival or failure-free
survival when quantifying number of bone metastases. Thus, the number of bone metastases may be preferred to define candidacy for treatment of
the primary tumor.
• Footnote a added: Micro-boost to MRI-dominant disease improved biochemical control in patients with intermediate- and high-risk prostate cancer
in a randomized phase III study in the setting of conventionally fractionated EBRT. If using micro-boost, it is critical to restrict dose to OARs to meet
constraints that would normally have been achieved without such boost, sacrificing dose coverage of the boost as needed. Further, careful IGRT and
delivery procedures should be developed in line with the technical demands of this approach.
• References added:
Parker CC, James ND, Brawley CD, et al. Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE)
investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3
trial. Lancet 2018;392:2353-2366.
Burdett S, Boevé LM, Ingleby FC, et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review
and Meta-analysis. Eur Urol 2019;76:115-124.
Ali A, Hoyle A, Haran ÁM, et al. Association of bone metastatic burden with survival benefit from prostate radiotherapy in patients with newly
diagnosed metastatic prostate cancer: A secondary analysis of a randomized clinical trial. JAMA Oncol 2021;7:555-563.
PROS-G 4 of 7
• Table 1, Conventional Fractionation, Preferred Dose/Fractionation added: 2.2 Gy x 35 fx + micro-boost to MRI-dominant lesion to up to 95 Gy
(fractions up to 2.7 Gy)
• Regimen, EBRT, added: SBRT
Preferred Dose/Fractionation added: 9.5 Gy x 4x
PROS-G 5 of 7
• Post-Prostatectomy Radiation Therapy:
Sub-bullet removed: The ongoing SPPORT trial (NCT00567580) of patients with PSA levels between 0.1 and 2.0 ng/mL at least 6 weeks after RP
has reported preliminary results on clinicaltrials.gov. The primary outcome measure of percentage of participants free from progression at 5 years
was 70.3 (95% CI, 66.2–74.3) for those who received EBRT to the prostate bed and 81.3 (95% CI, 77.9–84.6) for those who also received 4–6
months of ADT (LHRH agonist plus antiandrogen).
1st bullet, 3rd sub-bullet added: The SPPORT trial included patients with PSA levels between 0.1 and 2.0 ng/mL after RP. The primary outcome
measure of freedom from progression was 70.9% at 5 years (95% CI, 67.0–74.9) for those who received RT to the prostate bed and 81.3% (95%
CI, 78.0–84.6) for those who also received 4–6 months of ADT (LHRH agonist plus antiandrogen). In a group that received RT to pelvic lymphs and
the prostate bed and 4–6 months of ADT, freedom from progression at 5 years was 87.4% (95% CI, 84.7–90.2). Pollack A, Karrison TG, et al. Lancet
2022;399:1886-1901.
Continued
® ® ®
UPDATES
Table of Contents
PROS-G 7 of 7
• Palliative Radiotherapy, 3rd bullet modified: 20 Gy in 5 fractions, 30 Gy in 10 fractions or 37.5 Gy in 15 fractions may be used as alternative palliative
dosing depending on clinical scenario (both category 2B).
PROS-H 1 of 2
• Pelvic Lymph Node Dissection:
Bullet removed: A PLND can be excluded in patients with <2% predicated probability of nodal metastases by nomograms, although some patients
with lymph node metastases will be missed.
4th bullet added: While PLND at the time of RP has not been shown to improve oncologic outcomes, it can provide staging and prognostic
information.
5th bullet added: A PLND can be excluded in patients with low predicated probability of nodal metastases by nomograms, although some patients
with lymph node metastases will be missed. There is no single evidence-based threshold for performing PLND. Based on the risk of complications
with PLND and extra time to perform the procedure, the published thresholds range from 2% to 7%.
6th bullet added: A patient who is above the threshold for performing a PLND, but has a negative PSMA PET scan should still undergo PLND. In two
studies, the sensitivity of PSMA PET for pelvic lymph node involvement among patients undergoing RP and PLND was low (about 40%), and the
negative predictive value was about 81%.Thus, basing the decision to perform PLND on a negative PSMA PET scan could result in missing 19% of
patients with positive lymph nodes.
• Radical Prostatectomy:
3rd bullet modified: Blood loss can be substantial with RP, but can be reduced by using laparoscopic or robotic assistance or by careful control of the
dorsal vein complex and periprostatic vessels when performed as open surgery.
PROS-H 2 of 2
• References have been updated.
PROS-I 1 of 5
• ADT for Clinically Localized (N0,M0) Disease
3rd bullet, 1st sub-bullet, 1st tertiary bullet modified: Goserelin, histrelin, leuprolide, or triptorelin
3rd bullet, sub-bullet removed: LHRH agonist, LHRH agonist plus first-generation antiandrogen, or degarelix with docetaxel (very high risk only)
• ADT for Regional (N1, M0) Disease:
3rd bullet, 2nd sub-bullet, 1st tertiary bullet modified: Goserelin, histrelin, leuprolide, or triptorelin
Continued
® ® ®
UPDATES
Table of Contents
PROS-I 2 of 5
• Heading modified: ADT for M0 PSA Persistence/Recurrence After RP or EBRT (ADT for M0 Castration-NaÏve Sensitive Disease)
• 7th bullet, 1st sub-bullet, 2nd tertiary bullet added: EBRT + LHRH agonist or degarelix with abiraterone (studies positive for pelvic recurrence only)
• 7th bullet, 2nd sub-bullet modified: M0 radiation therapy recurrence, TRUS biopsy negative or M0 PSA recurrence after progression on salvage EBRT
7th bullet, 2nd sub-bullet, 2nd tertiary bullet, 1st quaternary bullet modified: Goserelin, histrelin, leuprolide, or triptorelin
8th bullet added: Abiraterone should be given with concurrent steroid [see ADT for Regional (N1,M0) Disease].
• Heading modified: ADT for Metastatic Castration-NaÏve Sensitive Disease
2nd bullet modified: Treatment options for patients with M1 castration-naÏve sensitive disease are:
◊ 1st sub-bullet, 2 subsequent bullets added:
– LHRH agonists: Goserelin, leuprolide, or triptorelin
– First-generation antiandrogens: Nilutamide, flutamide, or bicalutamide
◊ The following sub-bullets have been removed:
– Orchiectomy plus docetaxel
– LHRH agonist alone plus docetaxel
▪ Goserelin, histrelin, leuprolide, or triptorelin
▪ A first-generation antiandrogen must be given with LHRH agonist for ≥7 days to prevent testosterone flare if metastases are present in weight-
bearing bone
– LHRH agonist (as above) plus first-generation antiandrogen plus docetaxel
▪ Nilutamide, flutamide, or bicalutamide
– Degarelix plus docetaxel
◊ The following sub-bullets have been added:
– Orchiectomy plus docetaxel and abiraterone or daralutamide
– LHRH agonist (as above) plus docetaxel and abiraterone or daralutamide
– Degarelix plus docetaxel and abiraterone or daralutamide
PROS-I 3 of 5
• 1st bullet modified: When EBRT to primary is given with ADT in low-volume metastatic burden M1, the options are LHRH agonist, LHRH antagonist,
and orchiectomy.
• 2nd bullet modified: Two randomized phase 3 clinical trials of abiraterone with prednisone plus ADT in patients with castration-naÏve sensitive
metastatic prostate cancer...
• 3rd bullet modified: A double-blind randomized phase 3 clinical trial of apalutamide plus ADT in patients with castration-naÏve sensitive metastatic
prostate cancer demonstrated improved overall survival over ADT alone...
• 4th bullet modified: An open-label randomized phase 3 clinical trial of enzalutamide plus ADT in patients with castration-naÏve sensitive metastatic
prostate cancer demonstrated improved overall survival over ADT alone. In a separate double-blind randomized phase 3 clinical trial, enzalutamide
reduced the risk of metastatic progression or death compared with placebo and showed an overall survival benefit. Adverse events associated with
enzalutamide included fatigue, seizures, and hypertension.
PROS-I 4 of 5
• 3rd bullet modified: A phase 3 study of docetaxel-naÏve sensitive patients
Continued
® ® ®
UPDATES
Table of Contents
PROS-J 1 of 3
• Heading has been removed: Non-Hormonal Systemic Therapy for Very-High-Risk Prostate Cancer
Bullet removed: Docetaxel can be added to EBRT and 2 years of ADT in patients with very-high-risk prostate cancer. In the STAMPEDE trial, the
hazard ratio for OS in 96 randomized patients with nonmetastatic disease was 0.93 (95% CI, 0.60–1.43) with the addition of docetaxel to EBRT and
ADT.
• Heading has been modified: Non-Hormonal Systemic Therapy for M1 Castration-NaÏve Sensitive Prostate Cancer
Bullet removed: Patients with high-volume, ADT-naïve, metastatic disease should be considered for ADT (See PROS-H) and docetaxel based on
the results of the ECOG 3805 (CHAARTED) trial. In this study, 790 patients were randomized to 6 cycles of docetaxel at 75 mg/m2 every 3 weeks
with dexamethasone with ADT vs. ADT alone. In the majority subset of patients with high-volume disease, defined as 4 or more bone metastases
including one extra-axial bone lesion or visceral metastases, a 17-month improvement in overall survival was observed (HR, 0.60; P = .0006).
Improvements in PSA response, time to clinical progression, and time to recurrence were observed with use of docetaxel. Toxicities of 6 cycles of
docetaxel included fatigue, neuropathy, stomatitis, diarrhea, and neutropenia with or without fever.
• 1st bullet added: Patients with high-volume castration-sensitive metastatic prostate cancer who are fit for chemotherapy should be considered for ADT
plus docetaxel and either abiraterone or daralutamide based on phase 3 studies:
1st sub-bullet added: ADT plus docetaxel and abiraterone improved overall survival and radiographic progression-free survival rPFS in the open-
label PEACE-1 study. A modest increase in toxicity was seen.
2nd sub-bullet added: ADT plus docetaxel and darolutamide improved overall survival in the ARASENS trial. Adverse events were similar between
arms.
3rd sub-bullet modified: The use of myeloid growth factors should follow the NCCN Guidelines for Hematopoietic Growth Factors, based on risk of
neutropenic fever. Docetaxel should not be offered to patients with low-volume metastatic prostate cancer, since this subgroup was not shown to
have improved survival in either the ECOG study or a similar European (GETUG-AFU 15) trial.
• Non-Hormonal Systemic Therapy for M1 CRPC Chemotherapy, 3rd bullet modified: Cabazitaxel/carboplatin with concurrent prednisone steroid twice
daily
PROS-J 2 of 3
• 1st bullet modified: Cabazitaxel at 25 mg/m² with concurrent steroid has been shown in a randomized phase 3 study (TROPIC) to prolong overall
survival, PFS, and PSA response, and radiologic responses when compared with mitoxantrone with and prednisone and is FDA approved in the post-
docetaxel secondline setting.
• 4th bullet modified: Docetaxel retreatment can be attempted after progression on a novel hormone therapy in patients with metastatic CRPC whose
cancer has have not demonstrated definitive evidence of progression on prior docetaxel therapy in the castration-naÏve sensitive setting.
• Targeted Therapy, 1st bullet modified: Consider inclusion of olaparib in patients who have an HRR mutation and have whose cancer has progressed
on prior treatment with androgen receptor-directed therapy regardless of prior docetaxel therapy. Olaparib is a treatment option for patients with
mCRPC and a pathogenic mutation (germline and/or somatic) in a homologous recombination repair gene (BRCA1, BRCA2, ATM, BARD1, BRIP1,
CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L) who have been treated previously with androgen receptor-
directed therapy. However, efficacy appears to be driven by the cohort of patients with at least one alteration in BRCA2, BRCA1, or ATM, and in
particular, by patients with BRCA2 or BRCA1 mutations based on exploratory gene-by-gene analysis. There may be heterogeneity of response to
olaparib for non-BRCA mutations based on which gene has a the specific gene mutation.
• Immunotherapy, 3rd bullet, 1st sub-bullet modified: Pembrolizumab is recommended only as subsequent systemic therapy for patients with metastatic
CRPC who have whose cancer has progressed through prior docetaxel and/or a novel hormone therapy.
UPDATES
Table of Contents
INITIAL PROSTATE CANCER DIAGNOSISa,b,c WORKUP
• Perform physical exam

• Perform digital rectal exam (DRE)
to confirm clinical stage
• Perform and/or collect prostate-
specific antigen (PSA) and
calculate PSA density See Initial Risk
Clinically localized • Obtain and review diagnostic
Stratification and Staging
prostate cancer (Any T, prostate biopsies
• Estimate life expectancy (See Workup for Clinically
N0, M0 or Any T, NX, MX)
Principles of Life Expectancy Localized Disease (PROS-2)
Estimation [PROS-A])
• Inquire about known high-risk
germline mutationsc
• Obtain family historyc
• Assess quality-of-life measuresd
• Perform physical exam

• Perform DRE to confirm clinical stage
Regional prostate • Perform and/or collect PSA and See Regional Prostate Cancer
cancer (Any T, N1, M0) calculate PSA doubling time (PSADT) (PROS-8)
• Estimate life expectancy (See
Principles of Life Expectancy
Estimation [PROS-A])
Metastatic prostate
• Inquire about known high-risk
cancer (Any T, Any N, M1)
germline mutationsc See Metastatic Prostate Cancer
• Obtain family historyc (PROS-12)
• Assess quality-of-life measuresd
a See NCCN Guidelines for Older Adult Oncology for tools to aid optimal
assessment and management of disease in older adults. c See Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).
b See NCCN Guidelines for Prostate Cancer Early Detection. d See Principles of Quality-of-Life and Shared Decision-Making (PROS-B).
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PROS-1
Table of Contents
INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASEe
Clinical/Pathologic Features
Risk Group Additional Evaluationh,i Initial Therapy
See Staging (ST-1)
Has all of the following:
• cT1c
• Grade Group 1 • Confirmatory testing can be used to assess the
Very lowf • PSA <10 ng/mL appropriateness of active surveillance (See PROS-F 2 of 5) See PROS-3
• Fewer than 3 prostate biopsy fragments/cores positive, ≤50%
cancer in each fragment/coreg
• PSA density <0.15 ng/mL/g
Has all of the following but does not qualify for very low risk: • Confirmatory testing can be used to assess the
Lowf • cT1–cT2a appropriateness of active surveillance (See PROS-F 2 of 5) See PROS-4
• Grade Group 1
• PSA <10 ng/mL
Has all of the Has all of the following:
following: • 1 IRF
Favorable • Grade Group 1 or 2 • Confirmatory testing can be used to assess the
• No high-risk group appropriateness of active surveillance (See PROS-F 2 of 5) See PROS-5
features intermediate • <50% biopsy cores
• No very-high-risk positive (eg, <6 of 12
group features cores)g
Intermediatef • Has one or more Has one or more of the
intermediate risk following:
factors (IRFs): • 2 or 3 IRFs Bone and soft tissue imagingj,k
Unfavorable
cT2b–cT2c • Grade Group 3 • If regional or distant metastases are found, see PROS-8 or See PROS-6
Grade Group 2 intermediate • ≥ 50% biopsy cores PROS-12
or 3 positive (eg, ≥ 6 of 12
PSA 10–20 ng/mL cores)g
Has no very-high-risk features and has exactly one high-risk
feature: Bone and soft tissue imagingj,k
High • cT3a OR • If regional or distant metastases are found, see PROS-8 or See PROS-7
• Grade Group 4 or Grade Group 5 OR PROS-12
• PSA >20 ng/mL
Has at least one of the following:
• cT3b–cT4 Bone and soft tissue imagingj,k
Very high • Primary Gleason pattern 5 • If regional or distant metastases are found, see PROS-8 or See PROS-7
• 2 or 3 high-risk features PROS-12
• >4 cores with Grade Group 4 or 5
See Footnotes for Initial Risk Stratification and Staging Workup for Clinically Localized Disease (PROS-2A).
PROS-2
Table of Contents
INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASE
e Tumor-based molecular assays and germline genetic testing are other tools that can assist with risk stratification. See Principles of Genetics and Molecular/Biomarker
Analysis (PROS-C) to determine if a patient is an appropriate candidate for germline genetic testing, and see Principles of Risk Stratification (PROS-D) to determine if
a patient is an appropriate candidate for tumor-based molecular assays. to determine if a patient is an appropriate candidate for tumor-based molecular assays.
f For asymptomatic patients in very-low-, low-, and intermediate-risk groups with life expectancy ≤5 years, no imaging or treatment is indicated until the patient becomes
symptomatic, at which time imaging can be performed and androgen deprivation therapy (ADT) should be given (See PROS-I).
g An ultrasound- or MRI- or DRE-targeted lesion that is biopsied more than once and demonstrates cancer (regardless of percentage core involvement or number of
cores involved) can be considered as a single positive core.
h See Principles of Imaging (PROS-E).
i Bone imaging should be performed for any patient with symptoms consistent with bone metastases.
j Bone imaging can be achieved by conventional technetium-99m-methylene diphosphonate (MDP) bone scan. Plain films, CT, MRI, PSMA-PET/CT or PSMA-PET/MRI,
or PET/CT or PET/ MRI with F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine can be considered for equivocal results on initial bone imaging. Soft tissue imaging
of the pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. mpMRI is preferred over CT for pelvic staging. Alternatively,
PSMA-PET/CT or PSMA-PET/MRI can be considered for bone and soft tissue (full body) imaging. See Principles of Imaging (PROS-E).
k Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease compared to conventional imaging (CT, MRI) at both
initial staging and biochemical recurrence, the panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or
PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients.

PROS-2A
Table of Contents
VERY-LOW-RISK GROUP
EXPECTED INITIAL THERAPY ADJUVANT THERAPY
PATIENT
SURVIVALl
Progressive diseasev
See Initial Risk Stratification
Active surveillance (preferred)n,o
and Staging Workup for
See Active Surveillance Program (PROS-F 2 of 5)
Clinically Localized Disease
(PROS-2)
>20 y External Beam Radiation Therapy (EBRT)p or brachytherapyp
Adverse feature(s):s,t
EBRTp ± androgen deprivation therapy (ADT)u
or
Monitoring, with consideration of early radiation See Monitoring for Initial
Radical prostatectomy (RP)q therapy (RT) for a detectable and rising PSA or Definitive Therapy (PROS-9)
PSA >0.1 ng/mL (See PROS-9)
No adverse features
Progressive diseasev
See Initial Risk
Active surveillancen,o
10–20 ym Stratification and Staging
Workup for Clinically
Localized Disease (PROS-2)
<10 yf Observation r See Monitoring (PROS-9)
See Footnotes for Risk Groups (PROS-8A).

PROS-3
Table of Contents
LOW-RISK GROUP
PATIENT
SURVIVALl Progressive diseasev
See Initial Risk Stratification
Active surveillance (preferred for most patients)n,o,w
and Staging Workup for
Clinically Localized Disease
(PROS-2)
≥10 y EBRTp or brachytherapyp
Adverse feature(s):s,t
EBRT p ± ADTu
or See Monitoring for Initial
Monitoring, with consideration of early RT for Definitive Therapy (PROS-9)
a detectable and rising PSA or PSA >0.1 ng/mL
RPq (See PROS-9)
No adverse features
<10 yf Observation r See Monitoring (PROS-9)

PROS-4
Table of Contents
FAVORABLE INTERMEDIATE-RISK GROUP

PATIENT
SURVIVALl
Progressive
diseasev
See Initial Risk
Active surveillancen,o,x
Stratification and
Staging Workup for
Clinically Localized
Disease (PROS-2)
>10 y EBRTp or brachytherapyp
Adverse feature(s) and no lymph node
metastases:s,t Undetectable PSA See Monitoring for
EBRTp ± ADTu after RP or PSA Initial Definitive
or nadiry after RT Therapy (PROS-9)
Monitoring, with consideration of early
RT for a detectable and rising PSA or PSA
>0.1 ng/mL (See PROS-9) See Radical
Prostatectomy
RPq ± pelvic lymph node No adverse features or lymph node PSA Persistence/
dissection (PLND) metastases Recurrence
(PROS-10)
Lymph node metastasis:bb PSA persistence/
ADTu,cc (category 1) ± EBRTp (category recurrencez,aa
2B) See Radiation
or Therapy
Monitoring, with consideration of early Recurrence
treatment for a detectable and rising PSA (PROS-11)
or PSA >0.1 ng/mL (See PROS-9)
EBRTp or brachytherapyp
5–10 yf See Monitoring
Observation (preferred)r
(PROS-9)

PROS-5
Table of Contents
UNFAVORABLE INTERMEDIATE-RISK GROUP

PATIENT
SURVIVALl
Adverse feature(s) and no lymph node metastases:s,t
EBRT p ± ADTu
or Undetectable PSA See Monitoring for
Monitoring, with consideration of early RT for a after RP or PSA Initial Definitive
detectable and rising PSA or PSA >0.1 ng/mL (See nadiry after RT Therapy (PROS-9)
PROS-9)
RPq + PLND No adverse features or lymph node metastases
See Radical
Prostatectomy
Lymph node metastasis:bb PSA Persistence/
>10 ydd ADTu,cc (category 1) ± EBRT p (category 2B) Recurrence
or (PROS-10)
Monitoring, with consideration of early treatment for PSA persistence/
a detectable and rising PSA or PSA >0.1 ng/mL (See recurrencez,aa
PROS-9) See Radiation
EBRTp + ADTu (4–6 mo) Therapy
or Recurrence
EBRTp + brachytherapyp ± ADTu (4–6 mo) (PROS-11)
5–10 yf
See Monitoring
Observation r
(PROS-9)

PROS-6
Table of Contents
HIGH- OR VERY-HIGH-RISK GROUP

PATIENT
SURVIVALl
EBRTp + ADTu (1.5–3 y; category 1) See Monitoring
or Undetectable
for Initial
EBRTp + brachytherapyp + ADTu (1–3 y; category 1 for ADT) PSA after RP
Definitive
or or PSA nadiry
Therapy
EBRTp + ADTu (2 y) + abirateroneee (for very-high-risk onlyff) after RT
(PROS-9)
>5 y or
Adverse feature(s) and no lymph node metastases:s,t
symptomaticdd See Radical
EBRT p ± ADTu
or Prostatectomy
Monitoring, with consideration of early RT for PSA
detectable and rising PSA or PSA >0.1 ng/mL (See Persistence/
PROS-9) Recurrence
(PROS-10)
RPq + PLNDgg No adverse features or lymph node metastases PSA persistence/
recurrencez,aa
Lymph node metastasis:bb
See Radiation
ADTu,cc (category 1) ± EBRT p (category 2B)
Therapy
or
Recurrence
Monitoring, with consideration of early
(PROS-11)
treatment for detectable and rising PSA or
PSA >0.1 ng/mL (See PROS-9)
Observationr See Monitoring (PROS-9)

or
≤5 y and
ADTu,hh Best supportive care
asymptomatic
or
EBRTp,hh

PROS-7
Table of Contents
REGIONAL RISK GROUP (ANY T, N1, M0)

PATIENT
SURVIVALl
EBRTp + ADTu + abirateroneee,ii (preferred)
or Undetectable
EBRTp + ADTu PSA after RP or See Monitoring
PSA nadiry (PROS-9)
after RT
ADTu ± abirateroneee,ii
>5 y or Adverse feature(s) and no lymph node metastases:s,t
symptomatic EBRT p ± ADTu
or See Radical
Monitoring, with consideration of early RT for a detectable Prostatectomy
and rising PSA or PSA >0.1 ng/mL (See PROS-9) PSA Persistence/
RPq + PLND Recurrence
in select No adverse features or lymph node metastases (PROS-10)
patientsjj
Lymph node metastases:bb
PSA persistence/
ADTu,cc (category 1) ± EBRT p (category 2B) recurrencez,aa
or
Monitoring, with consideration of early treatment for a
detectable and rising PSA or PSA >0.1 ng/mL (See PROS-9) See Radiation
Therapy
Recurrence
Observationr (PROS-11)
≤5 y and
or
asymptomatic Best supportive care
ADTu

PROS-8
Table of Contents
FOOTNOTES
f For asymptomatic patients in very-low-, low-, and intermediate-risk groups with life y PSA nadir is the lowest value reached after EBRT or brachytherapy.
expectancy ≤5 years, no imaging or treatment is indicated until the patient becomes z PSA persistence/recurrence after RP is defined as failure of PSA to fall to undetectable
symptomatic, at which time imaging can be performed and ADT should be given (See levels (PSA persistence) or undetectable PSA after RP with a subsequent detectable
PROS-I). PSA that increases on 2 or more determinations (PSA recurrence) or that increases to
l See Principles of Life Expectancy Estimation (PROS-A). PSA >0.1 ng/mL.
m The panel remains concerned about the problems of overtreatment related to the aa RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for Therapeutic
increased diagnosis of early prostate cancer from PSA testing. See NCCN Guidelines for Radiology and Oncology) Phoenix Consensus: 1) PSA increase by 2 ng/mL or more
Prostate Cancer Early Detection. Active surveillance is recommended for this subset of above the nadir PSA is the standard definition for PSA recurrence after EBRT with or
patients. without HT; and 2) A recurrence evaluation should be considered when PSA has been
n Active surveillance involves actively monitoring the course of disease with the expectation confirmed to be increasing after radiation even if the increase above nadir is not yet 2
to intervene with potentially curative therapy if the cancer progresses. See Principles of ng/mL, especially in candidates for local therapy who are young and healthy. Retaining
Active Surveillance and Observation (PROS-F). a strict version of the ASTRO definition allows comparison with a large existing body
o If higher grade and/or higher T stage is found during confirmatory testing, see PROS-2.
of literature. Rapid increase of PSA may warrant evaluation (prostate biopsy) prior to
meeting the Phoenix definition, especially in younger or healthier patients.
p See Principles of Radiation Therapy (PROS-G). bb For patients with pN1 disease and PSA persistence, see PROS-10.
q See Principles of Surgery (PROS-H). cc See monitoring for N1 on ADT (PROS-9).
r Observation involves monitoring the course of disease with the expectation to deliver dd Active surveillance of unfavorable intermediate and high-risk clinically localized cancers
palliative therapy for the development of symptoms or a change in exam or PSA that is not recommended in patients with a life expectancy >10 years (category 1).
suggests symptoms are imminent. See Principles of Active Surveillance and Observation ee The fine-particle formulation of abiraterone can be used instead of the standard form
(PROS-F).
s Adverse laboratory/pathologic features include: positive margin(s); seminal vesicle
(category 2B; other recommended option).
ff Patients in STAMPEDE had at least two of the following: cT3–4, Grade Group 4 or 5, and
invasion; extracapsular extension; or detectable PSA.
t Decipher molecular assay should be considered if not previously performed to inform
PSA >40 ng/mL.
+ PLND can be considered in younger, healthier patients without tumor fixation to
gg RP
adjuvant treatment if adverse features are found post-RP.
u See Principles of Androgen Deprivation Therapy (PROS-I).
the pelvic sidewall.
hh ADT or EBRT may be considered in selected patients with high- or very-high-risk
v Criteria for progression are not well-defined and require physician judgment; however, a
disease, where complications, such as hydronephrosis or metastasis, can be expected
change in risk group strongly implies disease progression. See Discussion. within 5 years.
w The panel recognizes that there is heterogeneity across the low-risk group, and that
ii Abiraterone with ADT should be considered for a total of 2 years for those patients
some factors may be associated with an increased probability of near-term grade with N1 disease who are treated with radiation to the prostate and pelvic nodes. (See
reclassification, including high PSA density, a high number of positive cores (eg, ≥3), PROS-I).
high genomic risk (from tissue-based molecular tumor analysis), and/or a known BRCA2 jj There is limited evidence that RP + PLND is beneficial in the setting of node-positive
germline mutation. In some of these cases, upfront treatment with radical prostatectomy
or prostate RT may be preferred based on shared decision-making with the patient. See disease. Use of this approach should be limited to patients with >10-year life expectancy
Principles of Active Surveillance and Observation (PROS-F). and resectable disease and should be used in the context of a clinical trial or planned
x Particular consideration to active surveillance may be appropriate for those patients in
multimodality approach.
the favorable intermediate-risk group with a low percentage of Gleason pattern 4 cancer,
low tumor volume, low PSA density, and/or low genomic risk (from tissue-based molecular
tumor analysis). See Principles of Active Surveillance and Observation (PROS-F).

PROS-8A
Table of Contents
MONITORING RECURRENCE See Radical

See NCCN Guidelines for Survivorship Prostatectomy PSA
Post-RP PSA persistence/recurrencez
Persistence/Recurrence
(PROS-10)
• PSA every 6–12 mo
for 5 y,kk then every PSA recurrenceaa See Radiation
Initial definitive therapy year Post-RT or Therapy Recurrence
• DRE if suspicion of Positive DRE (PROS-11)
recurrence
Radiographic evidence of Biopsy of See Systemic Therapy
metastatic disease without metastatic for Castration-Sensitive
PSA persistence/recurrence site Disease (PROS-12)
• Physical exam + PSA N1,M0 Systemic Therapy for

N1 on ADT M0 CRPC (PROS-13)
every 3–6 mo
or Progressionk,ll,mm
• Imaging for symptoms
Localized on observation See Systemic Therapy for
or increasing PSAh M1
M1 CRPC (PROS-14)
h See Principles of Imaging (PROS-E).

k Because of the increased sensitivity and specificity of PSMA-PET tracers for Retaining a strict version of the ASTRO definition allows comparison with a
detecting micrometastatic disease compared to conventional imaging (CT, MRI) large existing body of literature. Rapid increase of PSA may warrant evaluation
at both initial staging and biochemical recurrence, the panel does not feel that (prostate biopsy) prior to meeting the Phoenix definition, especially in younger or
conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA- healthier patients.
PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective kk PSA as frequently as every 3 mo may be necessary to clarify disease status,
front-line imaging tool for these patients. especially in high-risk patients.
z PSA persistence/recurrence after RP is defined as failure of PSA to fall to ll Document castrate levels of testosterone if clinically indicated. Workup for
undetectable levels (PSA persistence) or undetectable PSA after RP with a progression should include bone and soft tissue evaluation. Bone imaging can be
subsequent detectable PSA that increases on 2 or more determinations (PSA achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI,
recurrence) or that increases to PSA >0.1 ng/mL. PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/MRI with F-18 sodium
aa RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for fluoride, C-11 choline, or F-18 fluciclovine can be considered for equivocal results
Therapeutic Radiology and Oncology) Phoenix Consensus: 1) PSA increase by 2 on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can
ng/mL or more above the nadir PSA is the standard definition for PSA recurrence include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively,
after EBRT with or without HT; and 2) A recurrence evaluation should be PSMA-PET/CT or PSMA-PET/MRI can be considered for bone and soft tissue
considered when PSA has been confirmed to be increasing after radiation even if (full body) imaging. See Principles of Imaging (PROS-E).
the increase above nadir is not yet 2 ng/mL, especially in candidates for salvage mm Treatment for patients whose cancer progressed on observation of localized
local therapy who are young and healthy. disease is ADT. See Principles of Androgen Deprivation Therapy (PROS-I).

PROS-9
Table of Contents
RADICAL PROSTATECTOMY PSA PERSISTENCE/RECURRENCE

Studies negative for
distant metastases EBRTp ± ADTu
and pelvic recurrence (preferred)
Progressionk,ll
• Risk stratificationnn or or
Life PSADT Imaging not Monitoringr
PSA expectancy Consider: performed
persistence/ >5 y • Bone and soft tissue See Systemic
recurrencez imagingoo,k Therapy for
Studies positive for EBRTp + ADTu ±
• Prostate bed biopsy Progressionk,ll Castration-
pelvic recurrence abirateronepp
(especially if imaging Sensitive Disease
suggests local (PROS-12)
recurrence)
Studies positive for
distant metastases
Life
expectancy Observationr Progressionk,ll
≤5 y
k Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting
micrometastatic disease compared to conventional imaging (CT, MRI) at both initial staging
and biochemical recurrence, the panel does not feel that conventional imaging is a necessary
prerequisite to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally
effective, if not more effective front-line imaging tool for these patients.
p See Principles of Radiation Therapy (PROS-G).
r Observation involves monitoring the course of disease with the expectation to deliver palliative
therapy for the development of symptoms or a change in exam or PSA that suggests symptoms are
imminent. See Principles of Active Surveillance and Observation (PROS-F).
nn PSADT can be calculated to inform nomogram use and counseling and/or
z PSA persistence/recurrence after RP is defined as failure of PSA to fall to undetectable levels (PSA oo
Decipher molecular assay (category 2B) can be considered to inform counseling.
PSMA-PET/CT or PSMA-PET/MRI are preferred for bone and soft tissue (full
persistence) or undetectable PSA after RP with a subsequent detectable PSA that increases on 2 or
body) imaging. Alternatively, bone imaging can be achieved by conventional
more determinations (PSA recurrence) or that increases to PSA >0.1 ng/mL.
ll Document castrate levels of testosterone if clinically indicated. Workup for progression should technetium-99m-MDP bone scan. Plain films, CT, MRI, PSMA-PET/CT or PSMA-
include bone and soft tissue evaluation. Bone imaging can be achieved by conventional technetium- PET/MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, or
99m-MDP bone scan. Plain films, CT, MRI, PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/ F-18 fluciclovine, can be considered for equivocal results on initial bone imaging.
MRI with F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine can be considered for equivocal Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT and
results on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can include abdominal/pelvic CT or abdominal/pelvic MRI. mpMRI is preferred over CT for
chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively, PSMA-PET/CT or PSMA- pelvic staging. See Principles of Imaging (PROS-E).

PET/MRI can be considered for bone and soft tissue (full body) imaging. See Principles of Imaging pp The fine-particle formulation of abiraterone can be used instead of the standard
(PROS-E). form (category 2B).

PROS-10
Table of Contents
RADIATION THERAPY RECURRENCE Biopsy

negative or Monitoringr
not performed, or Progressionk,ll
studies negative ADTu
for distant
metastases Monitoringr
or
RP + PLNDq See Systemic
• Risk stratificationqq Therapy for
or
PSADT Biopsy positive, Castration-
Life Brachytherapyp
• Bone and soft tissue studies negative Sensitive
expectancy or Progressionk,ll
imagingk,oo for distant Disease
>5 y Cryotherapy
• Consider prostate biopsy metastases (PROS-12)
or
if negative imaging
High-intensity focused
PSA ultrasound (HIFU) or
recurrenceaa (category 2B)
or See Systemic
Monitoringr Therapy for M0
Positive DRE
or CRPC (PROS-
ADTu 13)
Studies positive or
for pelvic Consider pelvic lymph Progressionk,ll or
recurrence node radiation (if not
previously done) See Systemic
or Therapy for M1
Consider PLND CRPC (PROS-
Studies positive 14)
for distant
metastases
Life
expectancy Observationr Progressionk,ll
≤5 y
See footnotes (PROS-11A).

PROS-11
Table of Contents
FOOTNOTES
k Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease compared to conventional imaging (CT, MRI) at both
initial staging and biochemical recurrence, the panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or
PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients.
q See Principles of Surgery (PROS-H).
r Observation involves monitoring the course of disease with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or PSA
that suggests symptoms are imminent. See Principles of Active Surveillance and Observation (PROS-F).
aa RTOG-ASTRO (Radiation Therapy Oncology Group - American Society for Therapeutic Radiology and Oncology) Phoenix Consensus: 1) PSA increase by 2 ng/mL
or more above the nadir PSA is the standard definition for PSA recurrence after EBRT with or without HT; and 2) A recurrence evaluation should be considered when
PSA has been confirmed to be increasing after radiation even if the increase above nadir is not yet 2 ng/mL, especially in candidates for salvage local therapy who are
young and healthy. Retaining a strict version of the ASTRO definition allows comparison with a large existing body of literature. Rapid increase of PSA may warrant
evaluation (prostate biopsy) prior to meeting the Phoenix definition, especially in younger or healthier patients.
ll Document castrate levels of testosterone if clinically indicated. Workup for progression should include bone and soft tissue evaluation. Bone imaging can be achieved
by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11
choline, or F-18 fluciclovine can be considered for equivocal results on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT
and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively, PSMA-PET/CT or PSMA-PET/MRI can be considered for bone and soft tissue (full body) imaging. See
Principles of Imaging (PROS-E).
oo PSMA-PET/CT or PSMA-PET/MRI are preferred for bone and soft tissue (full body) imaging. Alternatively, bone imaging can be achieved by conventional technetium-
99m-MDP bone scan. Plain films, CT, MRI, PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine,
can be considered for equivocal results on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or
abdominal/pelvic MRI. mpMRI is preferred over CT for pelvic staging. See Principles of Imaging (PROS-E)..
qq PSADT can be calculated to inform nomogram use and counseling.

PROS-11A
Table of Contents
SYSTEMIC THERAPY FOR CASTRATION-SENSITIVE PROSTATE CANCERrr
Monitoring (preferred)
M0ss,tt or
ADTu,uu See
Studies
Systemic
• Physical exam + negative
Therapy for
PSA every 3–6 mo for distant
M0 CRPC
ADTu with one of the following: • Imaging for metastases
(PROS-13)
• Preferred regimens: symptomsh
Abiraterone (category 1)u,ee • Conventional Progressionk,ll,ddd
Apalutamide (category 1)u imaging every
Enzalutamide (category 1)u 3–6 mo to See
Studies
or monitor treatment Systemic
M1vv,ww,xx,yy,zz positive
ADTu with docetaxel and one of the followingaaa: responseh Therapy for
for distant
• Preferred regimens: M1 CRPC
metastases
Abiraterone (category 1)u,ee (PROS-14)
Darolutamide (category 1)u
or
ADTu with EBRTp to the primary tumor for low
metastatic burden M1bbb
or
ADTu,uu,ccc
See footnotes on PROS-12A

PROS-12
Table of Contents
FOOTNOTES
h See Principles of Imaging (PROS-E). xx Tumor
and germline testing for homologous recombination repair gene
k Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting mutations (HRRm) is recommended and tumor testing for microsatellite
micrometastatic disease compared to conventional imaging (CT, MRI) at both initial instability (MSI) or deficient mismatch repair (dMMR) can be considered.
staging and biochemical recurrence, the panel does not feel that conventional imaging See Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).
is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI yy Stereotactic body RT (SBRT) to metastases can be considered in
can serve as an equally effective, if not more effective front-line imaging tool for these patients with oligometastatic progression where progression-free survival
patients. (PFS) is the goal.
p See Principles of Radiation Therapy (PROS-G). zz Bone
antiresorptive therapy is indicated for elevated fracture risk based
u See Principles of Androgen Deprivation Therapy (PROS-I). upon FRAX in the castration-sensitive setting. See PROS-I.
ee The fine-particle formulation of abiraterone can be used instead of the standard form aaa The panel encourages ADT with docetaxel and either darolutamide
(category 2B; other recommended option). or abiraterone for patients with high-volume disease who are fit for
ll Document castrate levels of testosterone if clinically indicated. Workup for progression chemotherapy. See Principles of Non-Hormonal Systemic Therapy
should include bone and soft tissue evaluation. Bone imaging can be achieved by (PROS-J).
conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, PSMA-PET/CT bbb EBRT to the primary tumor is associated with an overall survival
or PSMA-PET/MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, or benefit in patients with low metastatic burden at the time of diagnosis of
F-18 fluciclovine can be considered for equivocal results on initial bone imaging. Soft
tissue imaging of the pelvis, abdomen, and chest can include chest CT and abdominal/ metastatic disease, which is defined by conventional imaging as either
pelvic CT or abdominal/pelvic MRI. Alternatively, PSMA-PET/CT or PSMA-PET/MRI non-regional, lymph-node-only disease OR <4 bone metastases and
can be considered for bone and soft tissue (full body) imaging. See Principles of without visceral/other metastasis (Ali A, et al. JAMA Oncol 2021;7:555-
Imaging (PROS-E). 563). See Principles of Radiation Therapy (PROS-G).
rr T he term "castration-sensitive" is used to define patients who have not been treated ccc ADT is strongly recommended in combination therapy for metastatic
with ADT and those who are not on ADT at the time of progression. The NCCN castration-sensitive disease. The use of ADT monotherapy in metastatic
Prostate Cancer Panel uses the term "castration-sensitive" even when patients have castration-sensitive disease is discouraged unless there are clear
had neoadjuvant, concurrent, or adjuvant ADT as part of RT provided they have contraindications to combination therapy.
recovered testicular function. ddd Patients who were under monitoring for M0 disease should receive an
ss PSADT and Grade Group should be considered when deciding whether to begin ADT
appropriate therapy for castration-sensitive disease.
for patients with M0 disease.
tt Patients with a life expectancy ≤5 years can consider observation. See Principles of
Active Surveillance and Observation (PROS-F).
uu Intermittent ADT can be considered for patients with M0 or M1 disease to reduce
toxicity. See Principles of Androgen Deprivation Therapy (PROS-I).
vv EBRT
to sites of bone metastases can be considered if metastases are in weight-
bearing bones or if the patient is symptomatic.
ww ADT alone (see PROS-I) or observation are recommended for asymptomatic patients
with metastatic disease and life expectancy ≤5 years.

PROS-12A
Table of Contents
SYSTEMIC THERAPY FOR M0 CASTRATION-RESISTANT PROSTATE CANCER (CRPC)eee

Change or
No maintain
metastases current
Monitoring PSA (M0) treatment
(preferred) increasing or and continue
PSADT
or radiographic monitoring
>10 mo
Other secondary evidence of Imagingk,ll
hormone therapyu metastases
Continue See Systemic
CRPC, ADTu to Consider Metastases Therapy for
imaging maintain periodic (M1) M1 CRPC
studies castrate disease (PROS-14)
negative serum Preferred regimens: assessment
for distant levels of • Apalutamideu (PSA and
metastases testosterone (category 1) imaging)h
(<50 ng/dL) • Darolutamideu
(category 1) Stable PSA and Maintain current treatment
PSADT
• Enzalutamideu no evidence of and consider periodic disease
≤10 mo
(category 1) metastases assessment (PSA and imaging)h
Other recommended
regimens:
• Other secondary
hormone therapyu
ll Document castrate levels of testosterone if clinically indicated. Workup for

progression should include bone and soft tissue evaluation. Bone imaging can be
achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI,
PSMA-PET/CT or PSMA-PET/MRI, or PET/CT or PET/MRI with F-18 sodium
h See Principles of Imaging (PROS-E). fluoride, C-11 choline, or F-18 fluciclovine can be considered for equivocal results
k Because of the increased sensitivity and specificity of PSMA-PET tracers for on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can
detecting micrometastatic disease compared to conventional imaging (CT, include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively,
MRI) at both initial staging and biochemical recurrence, the panel does not feel PSMA-PET/CT or PSMA-PET/MRI can be considered for bone and soft tissue
that conventional imaging is a necessary prerequisite to PSMA-PET and that (full body) imaging. See Principles of Imaging (PROS-E).
PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more eee CRPC is prostate cancer that progresses clinically, radiographically, or
effective front-line imaging tool for these patients. biochemically despite castrate levels of serum testosterone (<50 ng/dL). Scher
u See Principles of Androgen Deprivation Therapy (PROS-I). HI, et al. J Clin Oncol 2008;26:1148-1159.

PROS-13
Table of Contents
SYSTEMIC THERAPY FOR M1 CRPCeee
• Continue ADTu to maintain

• Metastatic lesion castrate levels of serum
biopsyggg testosterone (<50 ng/dL) Adenocarcinomaggg See PROS-15
• Tumor testing • Additional treatment
for microsatellite options:
CRPC, imaging instability-high Bone antiresorptive
studies (MSI-H) or dMMR therapy with denosumab
positive and HRRm, if (category 1, preferred)
for metastases not previously or zoledronic acid First-line and subsequent treatment
performedc,hhh if bone metastases optionsiii
• Consider tumor present • Chemotherapyfff
mutational burden Palliative RTp for painful Small cell/
Cisplatin/etoposide
(TMB) testingc bone metastases neuroendocrine
Carboplatin/etoposide
Best supportive care Docetaxel/carboplatin
prostate cancer
Cabazitaxel/carboplatinjjj
(NEPC)ggg
For additional options, see NCCN
Guidelines for Small Cell Lung
Cancer
• Best supportive care
c See Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).

u See Principles of Androgen Deprivation Therapy (PROS-I). iii Document castrate levels of testosterone if progression occurs on ADT. Workup
eee CRPC is prostate cancer that progresses clinically, radiographically, or for progression should include chest CT, bone imaging, and abdominal/pelvic CT
biochemically despite castrate levels of serum testosterone (<50 ng/dL). Scher with contrast or abdominal/pelvic MRI with and without contrast. See Principles
HI, et al. J Clin Oncol 2008;26:1148-1159. of Imaging (PROS-E) and Discussion.
fff See Principles of Non-Hormonal Systemic Therapy (PROS-J). jjj Cabazitaxel 20 mg/m² plus carboplatin area under the curve [AUC] 4 mg/mL per
ggg Histologic
evidence of both adenocarcinoma and small cell carcinoma may min with growth factor support can be considered for fit patients with aggressive
be present, in which case treatment can follow either pathway. Treat as variant prostate cancer (ie, visceral metastases, low PSA and bulky disease,
adenocarcinoma if biopsy is not feasible or not performed. high lactate dehydrogenase [LDH], high carcinoembryonic antigen [CEA], lytic
hhh Germline testing for HRRm is recommended if not performed previously. See bone metastases, NEPC histology) or unfavorable genomics (defects in at least
Principles of Genetics and Molecular/Biomarker Analysis (PROS-C). 2 of PTEN, TP53, and RB1). Corn PG, et al. Lancet Oncol 2019;20:1432-1443.

PROS-14
Table of Contents
SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMAiii,kkk,lll

No prior docetaxel/no prior novel hormone therapymmm Prior novel hormone therapy/no prior docetaxelmmm,ttt
• Preferred regimens • Preferred regimens
Docetaxel (category 1)fff
Abirateroneu,nnn (category 1ooo) • Useful in certain circumstances
Docetaxelfff,ppp (category 1) Cabazitaxel/carboplatinfff,jjj
Enzalutamideu (category 1) Olaparib for HRRm (category 1)uuu
• Useful in certain circumstances Radium-223rrr for symptomatic bone metastases (category 1)
�Olaparib/abirateroneu,fff for BRCA mutation (category 1)nnn,qqq Rucaparib for BRCA mutationvvv
Radium-223rrr for symptomatic bone metastases (category 1) Sipuleucel-Tfff,sss
Sipuleucel-Tfff,sss (category 1) • Other recommended regimens
• Other recommended regimens Abirateroneu,nnn
Other secondary hormone therapyu Abirateroneu + dexamethasonennn,www
Enzalutamideu
Other secondary hormone therapyu
Prior docetaxel/no prior novel hormone therapymmm Prior docetaxel and prior novel hormone therapymmm,ttt
• Preferred regimens • Useful in certain circumstances
Lutetium Lu 177 vipivotide tetraxetan (Lu-177–PSMA-617) for PSMA-
Abirateroneu,nnn (category 1) positive metastases (category 1)xxx
Cabazitaxelfff (The following systemic therapies are category 2B if visceral metastases
Enzalutamideu (category 1) are present)
• Useful in certain circumstances • Preferred regimens
Cabazitaxel/carboplatinfff,jjj Cabazitaxelfff (category 1ooo)
Mitoxantrone for palliation in symptomatic patients who Docetaxel rechallengefff
cannot tolerate other therapiesfff • Useful in certain circumstances
Radium-223rrr for symptomatic bone metastases (category 1) Cabazitaxel/carboplatinfff,jjj
Sipuleucel-Tfff,sss Mitoxantrone for palliation in symptomatic patients who cannot
• Other recommended regimens tolerate other therapiesfff
Other secondary hormone therapyu Olaparib for HRRm (category 1ooo)uuu
Pembrolizumab for MSI-H, dMMR, or TMB ≥10 mut/Mbfff
Radium-223rrr for symptomatic bone metastases (category 1ooo)
Rucaparib for BRCA mutationvvv
• Other recommended regimens
Abirateroneu,nnn
Enzalutamideu
Other secondary hormone therapyu
See Footnotes for Systemic Therapy M1 CRPC (PROS-15A).

PROS-15
Table of Contents
FOOTNOTES
u See sss Sipuleucel-T is recommended only for asymptomatic or minimally
Principles of Androgen Deprivation Therapy (PROS-I).
fff See Principles of Non-Hormonal Systemic Therapy (PROS-J). symptomatic, no liver metastases, life expectancy >6 mo, and ECOG
performance status 0–1. Benefit with sipuleucel-T has not been reported in
iii Document castrate levels of testosterone if progression occurs on ADT. Workup
patients with visceral metastases and is not recommended if visceral metastases
for progression should include chest CT, bone imaging, and abdominal/pelvic are present. Sipuleucel-T also is not recommended for patients with small cell/
CT with contrast or abdominal/pelvic MRI with and without contrast. Consider NEPC.
metastatic lesion biopsy. If small cell neuroendocrine is found, see PROS-15. ttt Consider
AR-V7 testing to help guide selection of therapy (See Discussion).
See Principles of Imaging (PROS-E) and Discussion.
uuu Olaparib is a treatment option for patients with metastatic castration-resistant
jjj Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per min with growth
prostate cancer (mCRPC) and a pathogenic mutation (germline and/or
factor support can be considered for fit patients with aggressive variant prostate somatic) in a homologous recombination repair gene (BRCA1, BRCA2, ATM,
cancer (visceral metastases, low PSA and bulky disease, high LDH, high CEA, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C,
lytic bone metastases, NEPC histology) or unfavorable genomics (defects in at RAD51D, or RAD54L) who have been treated previously with androgen
least 2 of PTEN, TP53, and RB1). Corn PG, et al. Lancet Oncol 2019;20:1432- receptor-directed therapy. However, efficacy appears to be driven by the cohort
1443. of patients with at least one alteration in BRCA2, BRCA1, or ATM, and in
kkk Visceral
metastases refers to liver, lung, adrenal, peritoneal, and brain particular by patients with BRCA2 or BRCA1 mutations based on exploratory
metastases. Soft tissue/lymph node sites are not considered visceral gene-by-gene analysis. There may be heterogeneity of response to olaparib for
metastases. non-BRCA mutations based on the specific gene mutation. (See Discussion).
lll Patients
can continue through all treatment options listed. Best supportive care vvv Rucaparib
is a treatment option for patients with mCRPC and a pathogenic
is always an appropriate option. BRCA1 or BRCA2 mutation (germline and/or somatic) who have been treated
mmm Novel hormone therapies include abiraterone, enzalutamide, darolutamide, with androgen receptor-directed therapy and a taxane-based chemotherapy.
or apalutamide. Abiraterone given as part of neoadjuvant/concomitant/ If the patient is not fit for chemotherapy, rucaparib can be considered even if
adjuvant ADT with EBRT is not considered prior novel hormonal therapy. taxane-based therapy has not been given.
nnn The fine-particle formulation of abiraterone can be used instead of the www Switching from prednisone to dexamethasone 1 mg/day can be considered
standard form (other recommended option). for patients with disease progression on either formulation of abiraterone.
ooo The noted category applies only if there are no visceral metastases. Trials show improved PSA responses and PFS and acceptable safety using
this strategy. Romero-Laorden N, et al. Br J Cancer 2018;119:1052-1059 and
ppp Although most patients without symptoms are not treated with chemotherapy, the Fenioux C, et al. BJU Int 2019;123:300-306.
survival benefit reported for docetaxel applies to those with or without symptoms. xxx Lu-177–PSMA-617 is a treatment option for patients with ≥1 PSMA-positive
Docetaxel may be considered for patients with signs of rapid progression or lesion and/or metastatic disease that is predominately PSMA-positive and with no
visceral metastases despite lack of symptoms. dominant PSMA-negative metastatic lesions who have been treated previously
qqq Olaparib with abiraterone is an option for patients with a pathogenic BRCA1 or with androgen receptor-directed therapy and a taxane-based chemotherapy.
BRCA2 mutation (germline and/or somatic) who have not yet received a novel Sartor et al. N Engl J Med 2021; 385:1091-1103. See Principles of Radiation
hormone therapy or docetaxel. Therapy (PROS-G).
rrr Radium-223
is not recommended for use in combination with docetaxel or any
other systemic therapy except ADT and should not be used in patients with
visceral metastases. Concomitant use of denosumab or zoledronic acid is
recommended. See Principles of Radiation Therapy (PROS-G).

PROS-15A
Table of Contents
PRINCIPLES OF LIFE EXPECTANCY ESTIMATION

• Life expectancy estimation is critical to informed decision-making in prostate cancer early detection and treatment.
• Estimation of life expectancy is possible for groups of patients but challenging for individuals.
• Life expectancy can be estimated using:

The Social Security Administration tables (www.ssa.gov/OACT/STATS/table4c6.html)
The WHO’s Life Tables by country (http://apps.who.int/gho/data/view.main.60000?lang=en)
The Memorial Sloan Kettering Male Life Expectancy tool https://www.mskcc.org/nomograms/prostate
• If using a life expectancy table, life expectancy should be adjusted using the clinician’s assessment of overall health as follows:
Best quartile of health - add 50%
Worst quartile of health - subtract 50%
Middle two quartiles of health - no adjustment
• Example of upper, middle, and lower quartiles of life expectancy at selected ages are included in the NCCN Guidelines for Older Adult
Oncology for life expectancy estimation.

PROS-A
Table of Contents
PRINCIPLES OF QUALITY-OF-LIFE AND SHARED DECISION-MAKING

• Treatments for patients with localized prostate cancer have risks and side effects that must be considered in the context of the risk posed
by the disease.1-4
• Baseline urinary, sexual, and bowel function are strongly associated with functional outcomes among patients undergoing treatment.1-4
• Thus, it is important to measure baseline disease specific function (urinary, sexual, and bowel function), preferably using a standardized
patient-reported outcomes instrument (eg, EPIC-265).
• Shared decision-making regarding initial management of localized prostate cancer should include an explanation of the potential benefits
and potential harms of each option. The provider should explain the likelihood of cure, recurrence, disease progression, and disease-
specific mortality with each management option, taking into account disease severity and competing risks. In addition to the primary
intended effects of treatment, the clinician should discuss the side effects of each treatment and predicted impact on quality of life,
including urinary, sexual, and bowel function. Patient preferences should be elicited and should be incorporated into the management
decision.6
References
1 Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-1261.
2 Chen RC, Basak R, Meyer AM, et al. Association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and
patient-reported quality of life among men with localized prostate cancer. JAMA 2017;317:1141-1150.
3 Hoffman KE, Penson DF, Zhao Z, et al. Patient-reported outcomes through 5 years for active surveillance, surgery, brachytherapy, or external beam radiation with or
without androgen deprivation therapy for localized prostate cancer. JAMA 2020;323:149-163.
4 Donovan JL, Hamdy FC, Lane JA, et al; ProtecT Study Group. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med
2016;375:1425-1437.
5 Szymanski KM, Wei JT, Dunn RL, Sanda MG. Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for
measuring health-related quality of life among prostate cancer survivors. Urology 2010;76:1245-1250.
6 Makarov D, Fagerlin A, Finkelstein J et al. AUA White Paper on Implementation of Shared Decision Making into Urological Practice. American Urological Association
2022. Available at: https://www.auanet.org//guidelines-and-quality/guidelines/best-practice-statements-and-whitepapers/shared-decision-making

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PRINCIPLES OF GENETICS AND MOLECULAR/BIOMARKER ANALYSIS

GERMLINE TESTING
For details regarding the nuances of genetic counseling and testing, see Principles of Cancer Risk Assessment and Counseling (EVAL-A) in
the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.
• Pre-test Considerations
The panel recommends inquiring about family and personal history of cancer, and known germline variants at time of initial diagnosis.
Criteria for germline testing (see PROS-C, 2 of 3) should be reviewed at time of initial diagnosis and, if relevant, at recurrence.
Germline testing should be considered in appropriate individuals where it is likely to impact the prostate cancer treatment and clinical trial
options, management of risk of other cancers, and/or potential risk of cancer in family members.
• Testing
If criteria are met (see PROS-C, 2 of 3), germline multigene testing that includes at least BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13,
MLH1, MSH2, MSH6, and PMS2 is recommended.
Additional genes may be appropriate depending on clinical context. For example, HOXB13 is a prostate cancer risk gene that does not
have therapeutic implications in advanced disease, but testing may have utility for family counseling.
• Post-test Considerations
Post-test genetic counseling is strongly recommended if a germline mutation (pathogenic/likely pathogenic variant) is identified. Cascade
testing for relatives is critical to inform the risk for familial cancers in all relatives.
Post-test genetic counseling is recommended if positive family history but no pathogenic variant OR if only germline variants of unknown
significance (VUS) are identified. This is to ensure accurate understanding of family implications and review indications for additional
testing and/or follow-up (including clinical trials of reclassification).
Resources are available to review the available data supporting pathogenic consequences of specific variants (eg, https://www.ncbi.nlm.
nih.gov/clinvar/; https://brcaexchange.org/about/app).
Individuals should be counseled to inform providers of any updates to family cancer history.

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Germline testing is recommended in patients with a personal history of prostate cancer in the following scenarios:
• By prostate cancer stage or risk group (diagnosed at any age)
Metastatic, regional (node positive), very-high-risk localized, or high-risk localized prostate cancer
• By family historya and/or ancestry
≥1 first-, second-, or third-degree relative with:
◊ breast cancer at age ≤50 y
◊ colorectal or endometrial cancer at age ≤50 y
◊ male (sex assigned at birth) breast cancer at any age
◊ ovarian cancer at any age
◊ exocrine pancreatic cancer at any age
◊ metastatic, regional, very-high-risk, or high-risk prostate cancer at any age
≥1 first-degree relative (parent or sibling) with:
◊ prostate cancerb at age ≤60 y
≥2 first-, second-, or third-degree relatives with:
◊ breast cancer at any age
◊ prostate cancerb at any age
≥3 first- or second-degree relatives with:
◊ Lynch syndrome-related cancers, especially if diagnosed <50 y: colorectal, endometrial, gastric, ovarian, exocrine pancreas, upper
tract urothelial, glioblastoma, biliary tract, and small intestinal cancer
A known family history of familial cancer risk mutation (pathogenic/likely pathogenic variants), especially in: BRCA1, BRCA2, ATM,
PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, and EPCAM
Ashkenazi Jewish ancestry
• Personal history of breast cancer
Germline testing may be considered in patients with a personal history of prostate cancer in the following scenarios:
• By prostate cancer tumor characteristics (diagnosed at any age)
◊ intermediate-risk prostate cancer with intraductal/cribriform histologyc
• By prostate cancerb AND a prior personal history of any of the following cancers:
◊ exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal
a Close blood relatives include first-, second-, and third-degree relatives on the same side of the family. See Pedigree: First-, Second-, and Third-Degree Relatives of
Proband (EVAL-B) in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.
b Family history of prostate cancer should not include relatives with clinically localized Grade Group 1 disease.
c Acinar prostate adenocarcinoma with invasive cribriform pattern, intraductal carcinoma of prostate, or ductal adenocarcinoma component have increased genomic
instability, and germline testing may be considered.

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SOMATIC TUMOR TESTING
• Pre-test Considerations
At present, tumor molecular and biomarker analysis may be used for treatment decision-making, including understanding eligibility for
biomarker-directed treatments, genetic counseling, early use of platinum chemotherapy, and eligibility for clinical trials. Clinical trials may
include established and/or candidate molecular biomarkers for eligibility.
Tumor molecular profiles may change with subsequent treatments and re-evaluation may be considered at time of cancer progression for
treatment decision-making.
Patients should be informed that tumor molecular analysis by DNA sequencing has the potential to uncover germline findings.
Confirmatory germline testing may be recommended [see Post-test Considerations, below, and see Tumor Testing: Potential Implications
for Germline Testing in the Principles of Cancer Risk Assessment and Counseling (EVAL-A) in the NCCN Guidelines for Genetic/Familial
High-Risk Assessment: Breast, Ovarian, and Pancreatic]
• Testing
Tumor testing for alterations in homologous recombination DNA repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D,
CHEK2, and CDK12, is recommended in patients with metastatic prostate cancer. This testing can be considered in patients with regional
prostate cancer.
Tumor testing for MSI-H or dMMR is recommended in patients with metastatic castration-resistant prostate cancer and may be considered
in patients with regional or castration-sensitive metastatic prostate cancer.
TMB testing may be considered in patients with metastatic castration-resistant prostate cancer.
• Tumor Specimen and Assay Considerations
The panel strongly recommends a metastatic biopsy for histologic and molecular evaluation. When unsafe or unfeasible, plasma
ciculating tumor (ctDNA) assay is an option, preferably collected during biochemical (PSA) and/or radiographic progression in order to
maximize diagnostic yield.
Caution is needed when interpreting ctDNA-only evaluation due to potential interference from clonal hematopoiesis of indeterminate
potential (CHIP), which can result in a false-positive biomarker signal.
DNA analysis for MSI and immunohistochemistry for MMR are different assays measuring different biological effects caused by dMMR
function. If MSI is used, testing using an a next-generation sequencing assay validated for prostate cancer is preferred.
• Post-test Considerations
Post-test genetic counseling is recommended if pathogenic/likely pathogenic variant (mutation) identified in any gene that has clinical
implications if also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, PMS2).
Post-test genetic counseling to assess for the possibility of Lynch syndrome is recommended if MSI-H or dMMR is found.

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PRINCIPLES OF RISK STRATIFICATION

• The purpose of NCCN risk groups is to provide a method for risk stratification to allow standardized treatment recommendations to be
provided.
It is acknowledged that there are methods of risk stratification that have been designed with superior performance, but have not been
routinely reported in clinical trials. This limits the ability to provide evidence-based guideline treatment recommendations using these
methods.
Thus, the NCCN Guidelines continue to use NCCN risk groups as a framework. However, the panel acknowledges the ability to personalize
treatment decisions through improved tools for risk stratification and have created this section to assist.
• Current treatment recommendations for localized through recurrent prostate cancer are based on prognosis, rather than use of predictive
biomarkers. Prognosis is estimated through risk stratification.
The only identified exception to this, from a routine clinical or pathologic variable with randomized clinical trial validation, is pre-salvage
radiotherapy PSA level, which has been shown to be both prognostic and predictive of benefit from hormone therapy with salvage
radiotherapy in a phase III randomized trial.1,2
• Clinical trials that have established the benefit of various treatments in localized and recurrent prostate cancer often enroll patients
across a spectrum of risk. Subgroup analyses, absolute benefit estimates, and expert opinion are used to provide simplified treatment
recommendations for each NCCN risk group.
Given the moderate performance of NCCN risk groups to risk stratify localized prostate cancer, there is intrinsic heterogeneity in prognosis
within a given NCCN risk group. Thus, treatment recommendations for adjacent risk groups may be appropriate when using more accurate
risk stratification methods.
• Multivariable models should be used for risk stratification.
Multivariable risk stratification models, such as NCCN and STAR-CAP,3 incorporate routine clinical (ie, PSA, T stage) and pathologic
variables (ie, Grade Group, percent positive cores), and outperform a single clinical or pathologic feature for risk stratification.
Multivariable models, such as gene expression classifiers or artificial intelligence (AI)-derived digital histopathology biomarkers, can
combine clinical, pathologic, and other biomarkers to further improve risk stratification.
• There are newer risk classification models that have been shown to outperform NCCN risk groups.3,4 There are also common histopathology
variables that are prognostic (ie, cribriform, intraductal carcinoma, percent Gleason pattern 4); however, they have been rarely reported in
the context of clinical trials.
• Imaging (ie, MRI and PET/CT) can also aid in risk stratification. See Principles of Imaging (PROS-E).

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• There are advanced risk stratification tools (ie, gene expression biomarkers, AI digital pathology5) that independently improve risk
stratification. See Table 1: Initial Risk Stratification for Clinically Localized Disease.
These tools are recommended to be used when they will have the potential ability to change management. These tools should not be
ordered reflexively.
There are an extensive number of these tools created with substantial variability in quality of reporting and model design, endpoint
selection, and quality and caliber of validation. It is recommended to use models that have high-quality and robust validation, ideally with
randomized clinical trial data across multiple clinical trials.
These tools are not recommended for patients with very-low-risk prostate cancer.
Patients with NCCN low, favorable intermediate, unfavorable intermediate, or high-risk disease and life expectancy ≥10 y may consider the
use of the following tumor-based molecular assays: Decipher, Oncotype DX Prostate, and Prolaris.
AI digital pathology can be used for patients with localized prostate cancer with life expectancy ≥10 years if the results will impact
management (category 2B).5
The data are limited and inconsistent regarding the prognostic impact of germline testing results for localized prostate cancer, and thus
there is poor quality evidence to use this information to change treatment recommendations. The current evidence in localized prostate
cancer is limited to small retrospective series with inconsistent results, and none has assessed the independent prognostic effect of
germline mutation in complete multivariable clinical and pathologic models.6-9 The prognostic impact of germline testing results should be
viewed as distinct from the purposes for cascade testing, see PROS-C.

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Table 1. Initial Risk Stratification for Clinically Localized Disease
Category Tool Predictive Prognostic Endpoint Trained Fora Level of Evidence
for Validationb
NCCN No Yes See notec 1
STAR-CAP2 No Yes PCSM 3
Clinical
CAPRA11,d No Yes BCR 3
MSKCC12 No Yes BCR and PCSMf 3
ArteraAI Prostate No Yes BCR, DM, PCSMg 1
AI
(category 2B)5,e
Decipher13 No Yes DM 1
Gene Expression Testing Prolaris14 No Yes See noteh 3
Oncotype15 No Yes Adverse pathology 3
Germline HRR No Uncertain See notei 4
_ BCR, biochemical recurrence; DM, distant metastases; PCSM, prostate cancer-specific mortality
a "Endpoint trained for" specifically relates to what the biomarker or model was designed and optimized to predict. This is distinct from endpoints for which the biomarker has been shown
to be prognostic in validation.
b Levels of evidence for biomarkers in this section are based on modified Simon et al criteria:10
1: Validation in the context of multiple clinical trials with consistent results. Randomized trials are necessary for predictive biomarkers for validation.
2: Validation in multiple independent prospective registry/observational cohorts with consistent results.
3: Validation in multiple independent retrospective studies with consistent results.
4: Validation in a single retrospective study, or multiple independent retrospective studies with inconsistent results.
c NCCN risk groups were not trained for a specific endpoint. They were a modification of the original D’Amico risk groups trained for BCR. Subsequently, NCCN risk groups were
subdivided into seven risk groups (very low, low, favorable intermediate, unfavorable intermediate, high, very high, and regional disease).
d CAPRA does not include cT3b–T4 or cN+ patients.
e ArteraAI Prostate, also known as a multi-modal AI biomarker, has trained and validated multiple AI-derived digital histopathology-based biomarkers from five phase III randomized
radiation-based trials.5
f These are two separate models developed and trained for different endpoints.
g ArteraAI Prostate trained three distinct prognostic models, one for each endpoint (BCR, DM, and PCSM).
h Prolaris is a composite of CAPRA and cell cycle progression (CCP) score. The derivation of CCP was based on genes involved in the cell cycle that were highly correlated and provided
highly reproducible measurements of cell proliferation. Like other biomarkers it has been validated for multiple endpoints, but the test was not specifically trained for an endpoint a
priori.16
i Studies have inconsistent results in the setting of small biomarker-positive sample sizes. In addition, studies commonly do not adjust for standard clinical and pathologic factors and have
variable follow-up and heterogeneous reporting quality.
See References on PROS-D 4 of 4.

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1 Dess RT, Sun Y, Jackson WC, et al. Association of presalvage radiotherapy PSA levels after prostatectomy with outcomes of long-term antiandrogen therapy in men
with prostate cancer. JAMA Oncol 2020;6:735-743.
2 Pollack A, Karrison TG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/
RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial. Lancet 2022;399:1886-1901.
3 Dess RT, Suresh K, Zelefsky MJ, et al. Development and validation of a clinical prognostic stage group system for nonmetastatic prostate cancer using disease-
specific mortality results from the international staging collaboration for cancer of the prostate. JAMA Oncol 2020;6:1912-1920.
4 Zelic R, Garmo H, Zugna D, et al. Predicting prostate cancer death with different pretreatment risk stratification tools: A head-to-head comparison in a nationwide
cohort study. Eur Urol 2020;77:180-188.
5 Esteva A, Feng J, van der Wal D, et al. Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials. NPJ Digit Med
2022;5:71.
6 Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in
prostate cancer. J Clin Oncol 2013;31:1748-1757.
7 Berchuck JE, Zhang Z, Silver R, et al. Impact of pathogenic germline DNA damage repair alterations on response to intense neoadjuvant androgen deprivation therapy
in high-risk localized prostate cancer. Eur Urol 2021;80:295-303.
8 Halstuch D, Ber Y, Kedar D, Golan S, Baniel J, Margel D. Short-term outcomes of active surveillance for low risk prostate cancer among men with germline DNA repair
gene mutations. J Urol 2020;204:707-713.
9 Carter HB, Helfand B, Mamawala M, et al. Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for
prostate cancer. Eur Urol 2019;75:743-749.
10 Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009;101:1446-1452.
11 Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable
preoperative predictor of disease recurrence after radical prostatectomy. J Urol 2005;173:1938-1942.
12 Graefen M, Karakiewicz PI, Cagiannos I, et al. International validation of a preoperative nomogram for prostate cancer recurrence after radical prostatectomy. J Clin
Oncol 2002;20:3206-3212.
13 Jairath NK, Dal Pra A, Vince R Jr, et al. A systematic review of the evidence for the Decipher Genomic Classifier in prostate cancer. Eur Urol 2021;79:374-383.
14 Sommariva S, Tarricone R, Lazzeri M, et al. Prognostic value of the cell cycle progression score in patients with prostate cancer: A systematic review and meta-
analysis. Eur Urol 2016;69:107-115.
15 Covas Moschovas M, Chew C, Bhat S, et al. Association between Oncotype DX Genomic Prostate Score and adverse tumor pathology after radical prostatectomy.
Eur Urol Focus 2022;8:418-424.
16 Cuzick J, Swanson GP, Fisher G, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a
retrospective study. Lancet Oncol 2011;12:245-255.

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PRINCIPLES OF IMAGING
Goals of Imaging Ultrasound
• Imaging is performed for the detection and characterization of disease • Ultrasound uses high-frequency sound waves to image small
to select treatment or guide change in management. regions of the body.
• Imaging techniques can evaluate anatomic or functional parameters. Standard ultrasound imaging provides anatomic information.
Anatomic imaging techniques include plain film radiographs, Vascular flow can be assessed using Doppler ultrasound
ultrasound, CT, and MRI. techniques.
Functional imaging techniques include radionuclide bone scan, • Endorectal ultrasound is used to guide transrectal biopsies of the
PET/CT, and advanced MRI techniques, such as spectroscopy and prostate. Endorectal ultrasound can be considered for patients
diffusion-weighted imaging (DWI). with suspected recurrence after RP to guide prostate bed biopsy.
Efficacy of Imaging • Advanced ultrasound techniques for imaging of the prostate and
• The utility of imaging for patients with early PSA persistence/ for differentiation between prostate cancer and prostatitis are
recurrence after RP depends on risk group prior to operation, under evaluation.
pathologic Gleason grade and stage, PSA, and PSADT after Bone Imaging
recurrence. Low- and intermediate-risk groups with low serum PSAs • The use of the term “bone scan” refers to the conventional
postoperatively have a very low risk of positive bone scans or CT technetium-99m-MDP bone scan in which technetium is taken up
scans. by bone that is turning over and imaged with a gamma camera
• Frequency of imaging should be based on individual risk, age, PSADT, using planar imaging or 3-D imaging with single-photon emission
Gleason score, and overall health. CT (SPECT).
• Conventional bone scans are rarely positive in asymptomatic patients Sites of increased uptake imply accelerated bone turnover and
with PSA <10 ng/mL. The relative risk for bone metastasis or death may indicate metastatic disease.
increases as PSADT shortens. Bone imaging should be performed Osseous metastatic disease may be diagnosed based on the
more frequently when PSADT ≤8 months, where there appears to be an overall pattern of activity, or in conjunction with anatomic
inflection point. imaging.
Plain Radiography • Bone imaging is indicated in the initial evaluation of patients at
• Plain radiography can be used to evaluate symptomatic regions in the high risk for skeletal metastases.
skeleton. However, conventional plain x-rays will not detect a bone • Bone imaging can be considered for the evaluation of the
lesion until nearly 50% of the mineral content of the bone is lost or patient post-prostatectomy when there is failure of PSA to fall to
gained. undetectable levels, or when there is undetectable PSA after RP
• CT or MRI may be more useful to assess fracture risk as these with a subsequent detectable PSA that increases on 2 or more
modalities permit more accurate assessment of cortical involvement subsequent determinations.
than plain films where osteoblastic lesions may obscure cortical • Bone imaging can be considered for the evaluation of patients
involvement. with an increasing PSA or positive DRE after RT if the patient is a
candidate for additional local therapy or systemic therapy.

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• Bone scans are helpful to monitor metastatic prostate cancer to optimized to maximize diagnostic utility while minimizing radiation
determine the clinical benefit of systemic therapy. However, new lesions dose.
seen on an initial post-treatment bone scan, compared to the pre- • CT can be used for examination of the pelvis and/or abdomen for
treatment baseline scan, may not indicate disease progression. initial evaluation (see PROS-2) and as part of workup for recurrence or
• New lesions in the setting of a falling PSA or soft tissue response and progression (see PROS-11 through PROS-15).
in the absence of pain progression at that site may indicate bone scan Magnetic Resonance Imaging
flare or an osteoblastic healing reaction. For this reason, a confirmatory • The strengths of MRI include high soft tissue contrast and
bone scan 8–12 weeks later is warranted to determine true progression characterization, multiparametric image acquisition, multiplanar
from flare reaction. Additional new lesions favor progression. Stable imaging capability, and advanced computational methods to assess
scans make continuation of treatment reasonable. Bone scan flare is function.
common, particularly on initiation of new hormonal therapy, and may MRI can be performed with and without the administration of IV
be observed in nearly half of patients treated with the newer agents, contrast material.
enzalutamide and abiraterone. Similar flare phenomena may exist with Resolution of MRI images in the pelvis can be augmented using an
other imaging modalities, such as CT or PET/CT imaging. endorectal coil.
• Bone scans and soft tissue imaging (CT or MRI) in patients with • Standard MRI techniques can be used for examination of the pelvis and/
metastatic or non-metastatic prostate cancer may be obtained regularly or abdomen for initial evaluation (see PROS-2) and as part of workup
during systemic therapy to assess clinical benefit. for recurrence or progression (see PROS-11 through PROS-15).
• Bone scans should be performed for symptoms and as often as every • MRI may be considered in patients after RP when PSA fails to fall to
6–12 mo to monitor ADT. The need for soft tissue images remains undetectable levels or when an undetectable PSA becomes detectable
unclear. In CRPC, 8- to 12-week imaging intervals appear reasonable. and increases on 2 or more subsequent determinations, or after RT
• PET imaging for detection of bone metastatic disease for increasing PSA or positive DRE if the patient is a candidate for
Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 piflufolastat additional local therapy. MRI-ultrasound fusion biopsy may improve the
PSMA, Ga-68 PSMA-11, F-18 flotufolastat PSMA, F-18 sodium fluoride, detection of higher grade (Grade Group ≥2) cancers.
C-11 choline, or F-18 fluciclovine can be considered for equivocal • mpMRI can be used in the staging and characterization of prostate
results on initial bone scan. cancer. mpMRI images are defined as images acquired with at least
Ga-68 PSMA-11, F-18 piflufolastat PSMA, or F-18 flotufolastat PSMA one more sequence in addition to the anatomical T2-weighted images,
PET/CT or PET/MRI (full body imaging) can be considered as an such as DWI or dynamic contrast-enhanced (DCE) images.mpMRI
alternative to bone scan. may be used to better risk stratify patients who are considering
Computed Tomography active surveillance. Additionally, mpMRI may detect large and
• CT provides a high level of anatomic detail, and may detect gross poorly differentiated prostate cancer (Grade Group ≥2) and detect
extracapsular disease, nodal metastatic disease, and/or visceral extracapsular extension (T staging) and is preferred over CT for
metastatic disease. abdominal/pelvic staging. mpMRI has been shown to be equivalent to
• CT is generally not sufficient to evaluate the prostate gland. CT scan for pelvic lymph node evaluation.
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Positron Emission Tomography
recurrence.
• PSMA-PET refers to a growing body of radiopharmaceuticals that target PSMA on the
• PET/CT or PET/MRI results may change treatment but may not change oncologic
surface of prostate cells. There are multiple PSMA radiopharmaceuticals at various
outcome.
stages of investigation. At this time, the NCCN Guidelines only recommend the currently
• When patients with the worst prognosis move from one risk group to the higher risk
FDA-approved PSMA agents: F-18 piflufolastat PSMA (also known as F-18 DCFPyL), F-18
group, the average outcome of both risk groups will improve even if treatment has
flotufolastat PSMA (also known as rh-PSMA-7.3), and Ga-68 PSMA-11. Throughout these
no impact on disease. This phenomenon is known as the Will Rogers effect, in which
Guidelines, “PSMA-PET” refers to any of these FDA-approved PSMA ligands. See Table 2
the improved outcomes of both groups could be falsely attributed to improvement in
in the Discussion section for more detail.
treatment, but would be due only to improved risk group assignment. As an example,
• PSMA-PET/CT or PET/MRI can be considered as an alternative to standard imaging of
F-18 sodium fluoride PET/CT may categorize some patients as M1b who would have
bone and soft tissue for initial staging, the detection of biochemically recurrent disease,
been categorized previously as M0 using a bone scan (stage migration). Absent any
and as workup for progression.
change in the effectiveness of therapy, the overall survival of both M1b and M0 groups
• Synthesis of Ga-68 PSMA-11 requires that the PSMA-11 ligand is labeled with Ga-68 from
would improve. The definition of M0 and M1 disease for randomized clinical trials that
a generator or cyclotron. Two commercial kits to perform this in nuclear pharmacies have
added docetaxel or abiraterone to ADT was based on CT and conventional radionuclide
been approved by the FDA.
bone scans. Results suggest that overall survival of M1 disease is improved, whereas
• C-11 choline or F-18 fluciclovine PET/CT or PET/MRI may be used to detect small-volume
progression-free but not overall survival of M0 disease is improved. Therefore, a subset
recurrent disease in soft tissues and in bone.
of patients now diagnosed with M1 disease using F-18 sodium fluoride PET/CT might
• Studies suggest that PSMA-PET imaging have a higher sensitivity than C-11 choline or
not benefit from the more intensive therapy used in these trials and could achieve
F-18 fluciclovine PET imaging, especially at very low PSA levels.
equivalent overall survival from less intensive therapy aimed at M0 disease. Carefully
• Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting
designed clinical trials using proper staging will be necessary to prove therapeutic
micrometastatic disease compared to conventional imaging (CT, MRI) at both initial
benefit, rather than making assumptions compromised by stage migration.
staging and biochemical recurrence, the panel does not feel that conventional imaging
• F-18 fluorodeoxyglucose (FDG) PET/CT should not be used routinely for staging
is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI
prostate cancer since data are limited in patients with prostate cancer.
can serve as an equally effective, if not more effective front-line imaging tool for these
• F-18 flotufolastat PSMA is a PET imaging agent that is part of a novel class of tracers
patients.
referred to as radiohybrid (rh) ligands. These rh ligands have the unique advantage
• Histologic or radiographic confirmation of involvement detected by PET imaging is
of offering two binding sites for radionuclides (i.e., F-18 or Ga-68) which increases its
recommended whenever feasible due to the presence of false positives. Although false
flexibility in imaging. In addition, the presence of a chelator in these rh ligands also
positives exist, literature suggests that these are outweighed by the increase in true
allows for chelation of Lu-177 for its use as a theranostic as well as imaging agent.
positives detected by PET relative to conventional imaging. To reduce the false-positive
• The increasing use of PSMA-PET has identified the potential for considerable biological
rate, physicians should consider the intensity of PSMA-PET uptake and correlative CT
diversity among disease foci within a given individual with prostate cancer, especially
findings in the interpretation of scans. Several reporting sytems have been proposed but
mCRPC, and that this heterogeneity can be detected with a combination of PSMA-PET
will not have been validated or widely used.
and FDG-PET. Initial data suggests that metastases with PSMA-negative/FDG-positive
• PSMA imaging should be done before initiation of ADT because ADT may affect detection
mismatches may exist in mCRPC patients undergoing Lu-PSMA radioligand therapy
sensitivity.
and that patients with these mismatches may have worse outcomes. Currently, no
• High variability among PET/CT or PET/MRI equipment, protocols, interpretation, and
robust clinical trial data exists to support the incorporation of FDG-PET into routine
institutions provides challenges for application and interpretation of the utility of PET/CT
clinical use alongside PSMA-PET. To overcome the limitations of PSMA-PET in PSMA-
or PET/MRI.
negative metastatic disease, the panel currently recommends the use of contrast-
• Table 2 in the Discussion section provides a summary of the main PET/CT or PET/MRI
enhanced CT or MRI in these patients, as the non-contrast CT component of PSMA-
imaging tracers utilized for study in prostate cancer both before definitive therapy and at
PET/CT is insufficient to detect visceral metastatic disease.

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PRINCIPLES OF ACTIVE SURVEILLANCE AND OBSERVATION

• The NCCN Prostate Cancer Panel and the NCCN Prostate Cancer Early Detection Panel (See NCCN Guidelines for Prostate Cancer
Early Detection) remain concerned about overdiagnosis and overtreatment of prostate cancer. The Prostate Cancer Panel recommends that
patients and their physicians carefully consider active surveillance based on the patient’s prostate cancer risk profile and estimated life
expectancy. In settings where the patient’s age and comorbidities suggest a shorter life expectancy, observation may be more appropriate.
Shared decision-making, after appropriate counseling on the risks and benefits of the various options, is critical.
ACTIVE SURVEILLANCE1
• Active surveillance involves actively monitoring the course of disease with the expectation to intervene with curative intent if the cancer
progresses.
• Life Expectancy:
Life expectancy is a key determinant for the choice between observation, active surveillance, and definitive treatment.
Consider incorporating a validated metric of comorbidity such as the Adult Comorbidity Evaluation-27 Index (ACE-27)2 to differentiate
between recommendations for observation versus active surveillance. Prior studies did not incorporate a validated metric of comorbidity
to estimate life expectancy (See Table 1 on PROS-F 4 of 5), which is a potential limitation when interpreting the data for a patient who is in
excellent health.
Life expectancy can be challenging to estimate for individual patients (see Principles of Life Expectancy Estimation, PROS-A).
• Candidacy for Active Surveillance:

Active surveillance is preferred for patients with very-low-risk prostate cancer (See Risk Group Criteria [PROS-2]) and a life expectancy ≥10
years. (Observation is preferred for patients with a life expectancy <10 years and very-low-risk disease.)
Active surveillance is preferred for most patients with low-risk prostate cancer (See Risk Group Criteria [PROS-2]) and a life expectancy ≥10
years. The panel recognizes that there is heterogeneity across this risk group, and that some factors may be associated with an increased
probability of near-term grade reclassification including high PSA density, a high number of positive cores (eg, ≥3), and high genomic risk
(from tissue-based molecular tumor analysis).3 In some of these cases, upfront treatment with RP or prostate RT may be preferred based
on shared decision-making with the patient.
Patients with favorable intermediate-risk prostate cancer (See Risk Group Criteria [PROS-2]) and a life expectancy >10 years may also
consider active surveillance. Particular consideration for active surveillance may be appropriate for those patients with a low percentage
of Gleason pattern 4 cancer, low tumor volume, low PSA density, and/or low genomic risk (from tissue-based molecular tumor analysis).
See Discussion.
Please see Table 1 (PROS-F 4 of 5) below for a summary of major active surveillance cohorts, including their inclusion criteria.

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• Confirmatory Testing to Establish Appropriateness of Active Surveillance:
Goals of confirmatory testing are to help facilitate early identification of those patients who may be at a higher risk of future grade
reclassification or cancer progression.
Since an initial prostate biopsy may underestimate tumor grade or volume, confirmatory testing is strongly recommended within the first 6
to 12 months of diagnosis for patients who are considering active surveillance.
Options for confirmatory testing include prostate biopsy, mpMRI with calculation of PSA density (and repeat biopsy as indicated), and/or
molecular tumor analysis, see Principles of Risk Stratification (PROS-D).
Early confirmatory testing may not be necessary in patients who have had an mpMRI prior to diagnostic biopsy.
All patients should undergo a confirmatory prostate biopsy within 1–2 years of their diagnostic biopsy.
• Active Surveillance Program:

Patients who choose active surveillance should have regular follow-up, and key principles include:
◊ PSA no more often than every 6 months unless clinically indicated.
◊ DRE no more often than every 12 months unless clinically indicated.
◊ Repeat prostate biopsy no more often than every 12 months unless clinically indicated. While the intensity of surveillance may be
tailored on an individual basis, most patients should have prostate biopsies incorporated as part of their monitoring.
◊ Consider repeat mpMRI no more often than every 12 months unless clinically indicated.
◊ In patients with a suspicious lesion on mpMRI, MRI-ultrasound fusion biopsy improves the detection of higher grade (Grade Group ≥2)
cancers.
◊ Patients should be transitioned to observation when life expectancy is <10 years.
◊ Repeat molecular tumor analysis is discouraged.
◊ The intensity of surveillance may be tailored based on patient life expectancy and risk of reclassification.
• Considerations for Treatment of Patients on Active Surveillance:

Grade reclassification on repeat biopsy is the most common factor influencing a change in management from active surveillance to
treatment.
Other factors affecting decisions to actively treat include: increase in tumor volume, a rise in PSA density, and patient anxiety.
Considerations for a change in management strategy should be made in the context of the patient’s life expectancy.

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• Advantages of active surveillance:
Between 50% and 68% of those eligible for active surveillance may safely avoid treatment for at least 10 years.4-6
Patients will avoid possible side effects of definitive therapy that may be unnecessary while on active surveillance.
Quality of life/normal activities will be less affected while on active surveillance.
Risk of unnecessary treatment of small, indolent cancers will be reduced.
• Limitations of active surveillance:

Between 32% and 50% of patients will undergo treatment by 10 years,4-6 although treatment delays do not seem to impact cure rate.
Although the risk is very low (<0.5% in most series), it is possible for a cancer to progress to a regional or metastatic stage.4-6
OBSERVATION
• Observation involves monitoring with a history and physical exam no more often than every 12 months (without surveillance biopsies) until
symptoms develop or are thought to be imminent.
• Observation is recommended for:
Asymptomatic patients in very-low-, low-, and intermediate-risk groups with life a expectancy ≤5 years.
Asymptomatic patients with very-low- and low-risk prostate cancer with a life expectancy 5–10 years.
• Observation is preferred for:
Asymptomatic patients with favorable and unfavorable intermediate-risk prostate cancer and a life expectancy between 5–10 years.
• Observation may be considered for:
Asymptomatic patients with high-risk, very-high-risk, regional, and metastatic prostate cancer and life expectancy ≤5 years.
• Life expectancy can be challenging to estimate for individual patients (see Principles of Life Expectancy Estimation, PROS-A). Consider
incorporating a validated metric of comorbidity (see Life Expectancy, above).
• If patients under observation become symptomatic, an assessment of disease burden can be performed, and treatment or palliation can be
considered (see PROS-12).
• Advantages of observation:
Patients will avoid possible side effects of unnecessary confirmatory testing and definitive therapy.
• Limitation of observation:
There may be a risk of local or systemic symptoms (eg, urinary retention, pathologic fracture), without prior symptoms or concerning PSA
levels.

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Table 1: Selected Active Surveillace Experiences with Large Patient Cohorts
Johns UCSF
Cohort Toronto5,7,8 Hopkins4,9-11 Canary PASS14 Cooley/Catalona PRIAS15
Initial Cohort12 Newer
Cohort13 Meta-Dataset6
No. patients 993 1298 321 810 905 6775 5302
Median age (y) 68 66 63 62 63 64 66
Core involvement % of cohort with ≤2 Median # Mean % positive Not % of cohort with % of cohort % of cohort
positive cores, 69 positive cores, 1 cores, 20.3% available ≤10% positive with ≤2 positive with ≤2 positive
cores, 53 cores, 77.6 cores, 99
25% IR (D'Amico
criteria) 13% NCCN IR/HR
Median follow-up (months) 77 60 43 60 28 80 120
Conversion to treatment* 36.5% (10-y) 50% (10-y) 24% (3-y) 40% (5-y) 19% (28-mo) 33% (6.7-y) 52% (5-y)
73% (10-y)
Systemic progression 3.1% 0.15% distant 0% distant 0.1% 0% distant 0.4% 0.2%
(1.8% distant metastases metastases metastases
Lymph node involvement metastases; 1.3%
and/or metastasis positive lymph 0.08% positive 0.2% positive 0.2% positive
nodes) lymph nodes lymph nodes lymph nodes
6.6% systemic
progression in IR
group
Cancer-specific survival 98% (10-y) 99.9% (10-y) 100% (5-y) 100% (5-y) 100% (28-m) 99.8% (6.7-y) >99% (10-y)
Overall survival 80% (10-y) 93% (10-y) 98% (10-y) 98% (5-y) - - -
*Reason for conversion to treatment (% of entire cohort)
Gleason grade change 9.5% 15.1% 38% - - 49% 34% (5-y) / 41%
(20-y)a
PSA increase 11.7% - 26% - - 8.5% -
Tumor volume increase - - - - - 7.2% -
Personal choice -1.6% 8% 8% - - 5% (anxiety) 5%
IR = intermediate risk; HR = high risk.
a Protocol-based reclassification (included change in Gleason grade, number of positive cores, or cT stage).

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REFERENCES
1 Ganz PA, Barry JM, Burke W, et al. NIH State-of-the-Science Conference Statement: Role of active surveillance in the management of men with localized prostate
cancer. NIH Consens State Sci Statements 2011;28:1-27.
2 Ng SP, Duchesne G, Tai KH, et al. Support for the use of objective comorbidity indices in the assessment of noncancer death risk in prostate cancer patients. Prostate
Int 2017;5:8-12.
3 Cooperberg MR, Zheng Y, Faino AV, et al. Tailoring intensity of active surveillance for low-risk prostate cancer based on individualized prediction of risk stability. JAMA
Oncol 2020;6:e203187.
4 Tosoian JJ, Mamawala M, Epstein JI, et al. Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer.
J Clin Oncol 2015;33:3379-3385.
5 Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015;33:272-277.
6 Cooley LF, Emeka AA, Meyers TJ, et al. Factors associated with time to conversion from active surveillance to treatment for prostate cancer in a multi-institutional
cohort. J Urol 2021;206:1147-1156.
7 Klotz L, Zhang L, Lam A, et al. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010;28:126-131.
8 Yamamoto T, Musunuru HB, Vesprini D, et al. Metastatic prostate cancer in men initially treated with active surveillance. J Urol 2016;195:1409-1414.
9 Carter HB, Kettermann A, Warlick C, et al. Expectant management of prostate cancer with curative intent: an update of the Johns Hopkins experience. J Urol
2007;178:2359-2364; discussion 2364-2365.
10 Sheridan TB, Carter HB, Wang W, et al. Change in prostate cancer grade over time in men followed expectantly for stage T1c disease. J Urol 2008;179:901-904;
discussion 904-905.
11 Tosoian JJ, Trock BJ, Landis P, et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol 2011;29:2185-2190.
12 Dall'Era MA, Konety BR, Cowan JE, et al. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer 2008;112:2664-2670.
13 Welty CJ, Cowan JE, Nguyen H, et al. Extended followup and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer.
J Urol 2015;193:807-811.
14 Newcomb LF, Thompson IM, Jr., Boyer HD, et al. Outcomes of active surveillance for the management of clinically localized prostate cancer in the prospective, multi-
institutional Canary PASS cohort. J Urol 2015;195:313-320.
15 Bokhorst LP, Valdagni R, Rannikko A, et al. A decade of active surveillance in the PRIAS Study: An update and evaluation of the criteria used to recommend a switch
to active treatment. Eur Urol 2016;70:954-960.

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PRINCIPLES OF RADIATION THERAPY

Definitive Radiation Therapy General Principles • Biologically effective dose (BED) modeling with the linear-quadratic
• Highly conformal RT techniques should be used to treat localized equation may not be accurate for extremely hypofractionated
prostate cancer. (SBRT/stereotactic ablative radiotherapy [SABR]) radiation.
• Photon or proton EBRT are both effective at achieving highly • Brachytherapy:
conformal radiotherapy with acceptable and similar biochemical Interstitial implantation of prostate +/- proximal seminal vesicles
control and long-term side effect profiles (See Discussion). with temporary (high dose-rate, HDR) or permanent (low dose-rate,
• Ideally, the accuracy of treatment should be verified by daily LDR) radioactive sources for monotherapy or as "boost" when
prostate localization, with any of the following: techniques of added to EBRT should be performed in practices with adequate
image-guided RT (IGRT) using CT, ultrasound, implanted fiducials, training, experience, and quality assurance measures.
or electromagnetic targeting/tracking. Endorectal balloons may Patient selection should consider aspects of gland size, baseline
be used to improve prostate immobilization. Biocompatible and urinary symptoms, and prior procedures (ie, transurethral
biodegradable perirectal spacer materials may be implanted resection of prostate) that may increase risk of adverse effects.
between the prostate and rectum in patients undergoing external Neoadjuvant ADT to shrink a gland to allow treatment should
radiotherapy with organ-confined prostate cancer in order to balance its additional toxicity with this benefit.
displace the rectum from high radiation dose regions. A randomized Post-implant dosimetry must be performed for LDR implants to
phase III trial demonstrated reduced rectal bleeding in patients verify dosimetry.
undergoing the procedure compared to controls. Retrospective data Brachytherapy boost, when added to EBRT and ADT, improves
also support its use in similar patients undergoing brachytherapy. biochemical control. To address historical trial data concerns
Patients with obvious rectal invasion or visible T3 and posterior for increased toxicity incidence, careful patient selection and
extension should not undergo perirectal spacer implantation. contemporary planning associated with lesser toxicity, such as
• Various fractionation and dose regimens can be considered use of recognized organ at risk (OAR) dose constraints, use of
depending on the clinical scenario (See Table 1 on PROS-G 4 of 7). high-quality ultrasound and other imaging, and prescription of
Dose escalation has been proven to achieve the best biochemical dose as close as possible to the target without excessive margins
control in patients with intermediate- and high-risk disease. should be implemented.
• Stereotactic body RT (SBRT) is acceptable in practices with
appropriate technology, physics, and clinical expertise. SBRT for
metastases can be considered in the following circumstances:
In a patient with limited metastatic disease to the vertebra or
paravertebral region when ablation is the goal (eg, concern for
impending fracture or tumor encroachment on spinal nerves or
vertebra)
In a patient with oligometastatic progression where progression-
free survival is the goal
In a symptomatic patient where the lesion occurs in or immediately
adjacent to a previously irradiated treatment field.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Continued
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Definitive Radiation Therapy by Risk Group
• Very low risk • Regional disease
Patients with NCCN very-low-risk prostate cancer are encouraged Nodal radiation should be performed. Clinically positive nodes
to pursue active surveillance. should be dose-escalated as dose-volume histogram parameters
• Low risk allow. ADT is required unless medically contraindicated, and the
Patients with NCCN low-risk prostate cancer are encouraged to addition of abiraterone or fine-particle abiraterone (category 2B) to
pursue active surveillance. ADT is preferred.
Prophylactic lymph node radiation should NOT be performed • Low metastatic burden, castration-sensitive disease
routinely. ADT or antiandrogen therapy should NOT be used RT to the prostate is an option in patients with low metastatic
routinely. burden castration-sensitive metastatic disease, without
• Favorable intermediate riska contraindications to radiotherapy. ADT is required unless
Prophylactic lymph node radiation is not performed routinely, and medically contraindicated.
ADT or antiandrogen therapy is not used routinely. Prophylactic • Low metastatic burden is defined as either non-regional, lymph-
lymph node radiation and/or ADT use is reasonable if additional node-only disease OR <4 bone metastases and without visceral/
risk assessments suggest aggressive tumor behavior. other metastasis.
• Unfavorable intermediate riska ◊ Number and location of lesions is defined by conventional
Prophylactic nodal radiation can be considered if additional risk imaging.
assessments suggest aggressive tumor behavior. ADT should ◊ At this time, metastases defined only by PET imaging should
be used unless additional risk assessments suggest less- not be used to exclude a patient from treatment of the primary
aggressive tumor behavior or if medically contraindicated. The tumor.
duration of ADT can be reduced when combined with EBRT and • This recommendation is based on the STAMPEDE phase 3
brachytherapy. Brachytherapy combined with ADT (without EBRT), randomized trial, which randomized 2061 patients to standard
or SBRT combined with ADT can be considered if delivering systemic therapy with or without radiotherapy to the primary. The
longer courses of EBRT would present medical or social hardship. overall cohort had a significant improvement from the addition of
• High and very high riska radiotherapy to the primary in failure-free survival, but not overall
Prophylactic nodal radiation should be considered. ADT is survival. The prespecified low-volume subset had a significant
required unless medically contraindicated. Brachytherapy improvement in both failure-free survival and overall survival.1
combined with ADT (without EBRT), or SBRT combined with ADT, A meta-analysis with two other studies confirmed this benefit for
can be considered if delivering longer courses of EBRT would primary RT to the primary tumor in lower volume disease.2
present a medical or social hardship.
See References (PROS-G 3 of 7)

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STAMPEDE Arm H has now distinguished the CHAARTED • High-volume metastatic disease
definition of low metastatic disease to one that more granularly RT to the prostate should NOT be performed in patients with high-
quantifies who benefits from treatment of the primary based on volume metastatic disease outside the context of a clinical trial
number of bone metastases. This is relevant because a patient unless for palliative intent.
can have 12 spine metastases and be classified as low volume This recommendation is based on two randomized trials, HORRAD
by CHAARTED, but would not derive benefit in overall survival or and STAMPEDE, neither of which showed an improvement in
failure-free survival when quantifying number of bone metastases. overall survival from the addition of radiotherapy to the primary
Thus, the number of bone metastases may be preferred to define when combined with standard systemic therapy.
candidacy for treatment of the primary tumor. 3
Minimizing toxicity is paramount when delivering RT to the
primary in patients with metastatic disease.
It remains uncertain whether treatment of regional nodes in
addition to the primary improves outcomes; nodal treatment
should be performed in the context of a clinical trial.
Dose escalation beyond BED equivalents of the two-dose
prescriptions used in STAMPEDE (55 Gy in 20 fractions or 6 Gy
x 6 fractions) is not recommended given the known increase
in toxicity from dose intensification without overall survival
improvement in localized disease.
Brachytherapy is not recommended outside of a clinical trial,
as safety and efficacy have not been established in this patient
population.
a Micro-boost to MRI-dominant disease improved biochemical control in patients with intermediate- and high-risk prostate cancer in a randomized phase III study in
the setting of conventionally fractionated EBRT. If using micro-boost, it is critical to restrict dose to OARs to meet constraints that would normally have been achieved
without such boost, sacrificing dose coverage of the boost as needed. Further, careful IGRT and delivery procedures should be developed in line with the technical
demands of this approach.
References
1 Parker CC, James ND, Brawley CD, et al. Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators.
Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 2018;392:2353-2366.
2 Burdett S, Boevé LM, Ingleby FC, et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis.
Eur Urol 2019;76:115-124.
3 Ali A, Hoyle A, Haran ÁM, et al. Association of bone metastatic burden with survival benefit from prostate radiotherapy in patients with newly diagnosed metastatic
prostate cancer: A secondary analysis of a randomized clinical trial. JAMA Oncol 2021;7:555-563.

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Table 1: Below are examples of regimens that have shown acceptable efficacy and toxicity. The optimal regimen for an individual patient warrants evaluation of comorbid conditions, voiding
symptoms and toxicity of therapy. Additional fractionation schemes may be used as long as sound oncologic principles and appropriate estimate of BED are considered.
See PROS-3, PROS-4, PROS-5, PROS-6, PROS-7, PROS-8, PROS-12, and PROS-I for other recommendations, including recommendations for neoadjuvant/concomitant/adjuvant ADT.
NCCN Risk Group

( indicates an appropriate regimen option if RT is given)
Regimen Preferred Dose/Fractionation
Very Low Favorable Unfavorable High and
Intermediate Intermediate Regional N1 Low Volume M1a
and Low Very High
EBRT
3 Gy x 20 fx
Moderate Hypofractionation 2.7 Gy x 26 fx     
(Preferred) 2.5 Gy x 28 fx
2.75 Gy x 20 fx 
1.8–2 Gy x 37–45 fx     
Conventional Fractionation 2.2 Gy x 35 fx + micro-boost to
MRI-dominant lesion to up to 95   
Gy (fractions up to 2.7 Gy)
9.5 Gy x 4 fx
SBRT 7.25–8 Gy x 5 fx  
 
Ultra-Hypofractionation 6.1 Gy x 7 fx
6 Gy x 6 fx 
Brachytherapy Monotherapy
LDR
Iodine 125 145 Gy
Palladium 103 125 Gy  
Cesium 131 115 Gy
HDR
13.5 Gy x 2 implants  
Iridium-192
9.5 Gy BID x 2 implants
EBRT and Brachytherapy (combined with 45–50.4 Gy x 25–28 fx or 37.5 Gy x 15 fx)
LDR
Iodine 125 110–115 Gy  
Palladium 103 90–100 Gy
Cesium 131 85 Gy
HDR 15 Gy x 1 fx  
Iridium-192 10.75 Gy x 2 fx
a High-volume disease is differentiated from low-volume disease by visceral metastases and/or 4 or more bone metastases, with at least one metastasis beyond the pelvis vertebral column. Patients with low-
volume disease have less certain benefit from early treatment with docetaxel combined with ADT.

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Salvage Brachytherapy
• Permanent LDR or temporary HDR brachytherapy is a treatment The SPPORT trial included patients with PSA levels between 0.1
option for pathologically confirmed local recurrence after EBRT or and 2.0 ng/mL after RP. The primary outcome measure of freedom
brachytherapy. Subjects should have restaging imaging according from progression was 70.9% at 5 years (95% CI, 67.0–74.9) for
to the NCCN high-risk stratification group to rule out regional nodal those who received RT to the prostate bed and 81.3% (95% CI,
or metastatic disease. Patients should be counseled that salvage 78.0–84.6) for those who also received 4–6 months of ADT (LHRH
brachytherapy significantly increases the probability of urologic, agonist plus antiandrogen). In a group that received RT to pelvic
sexual, and bowel toxicity compared to primary brachytherapy. lymph nodes and the prostate bed and 4–6 months of ADT, freedom
Post-Prostatectomy Radiation Therapy from progression at 5 years was 87.4% (95% CI, 84.7–90.2). Pollack
• The panel recommends use of nomograms and consideration of age A, Karrison TG, et al. Lancet 2022;399:1886-1901.
and comorbidities, clinical and pathologic information, PSA levels, • The panel recommends consultation with the American Society
PSADT, and Decipher molecular assay to individualize treatment for Radiation Oncology (ASTRO)/American Urological Association
discussion. Patients with high Decipher genomic classifier scores (AUA) Guidelines. Evidence supports offering adjuvant/salvage RT
(GC >0.6) should be strongly considered for EBRT and addition of in most patients with adverse pathologic features or detectable PSA
ADT when the opportunity for early EBRT has been missed. and no evidence of disseminated disease.
EBRT with 2 years of 150 mg/day of bicalutamide demonstrated • Indications for adjuvant RT include pT3a disease, positive margin(s),
improved overall and metastasis-free survival on a prospective or seminal vesicle involvement. Adjuvant RT is usually given within
randomized trial (RTOG 9601) versus radiation alone in the salvage 1 year after RP and after operative side effects have improved/
setting. A secondary analysis of RTOG 9601 found that patients stabilized. Patients with positive surgical margins may benefit the
with PSA ≤0.6 ng/mL had no overall survival improvement with most.
the addition of the antiandrogen to EBRT. In addition, results of • Indications for salvage RT include an undetectable PSA
a retrospective analysis of RP specimens from patients in RTOG that becomes subsequently detectable and increases on 2
9601 suggest that those with low PSA and a low Decipher score measurements or a PSA that remains persistently detectable after
derived less benefit (development of distant metastases, overall RP. Treatment is more effective when pre-treatment PSA is low and
survival) from bicalutamide than those with a high Decipher score. PSADT is long.
EBRT with 6 months of ADT (luteinizing hormone-releasing • The recommended prescribed doses for adjuvant/salvage post-
hormone [LHRH] agonist) improved biochemical or clinical prostatectomy RT are 64–72 Gy in standard fractionation. Biopsy-
progression at 5 years on a prospective randomized trial proven gross recurrence may require higher doses.
(GETUG-16) versus radiation alone in patients with rising PSA • Nuclear medicine advanced imaging techniques can be useful
levels between 0.2 and 2.0 ng/mL after RP. for localizing disease with PSA levels as low as 0.5 ng/mL (see
Discussion).
• Nomograms, and tumor-based molecular assays, can be used
to prognosticate risk of metastasis and prostate cancer-specific
mortality in patients with adverse risk features after RP.
• Target volumes include the prostate bed and may include the whole
pelvis according to physician discretion.

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Radiopharmaceutical Therapy • Lu-177–PSMA-617
• Radium-223 is an alpha-emitting radiopharmaceutical that has Lu-177–PSMA-617 is a beta-emitting radiopharmaceutical that
been shown to extend survival in patients who have CRPC with selectively binds to PSMA receptors on prostate cancer cells. In
symptomatic bone metastases, but no visceral metastases. patients with PSMA-positive disease, Lu-177–PSMA-617 has been
Radium-223 alone has not been shown to extend survival in shown to improve overall survival in patients with progressive
patients with visceral metastases or bulky nodal disease (>3–4 mCRPC previously treated with androgen receptor inhibitors and
cm). Radium-223 differs from beta-emitting agents, such as taxane chemotherapy. Sartor O, et al. N Engl J Med 2021;385:1091-
samarium-153 and strontium-89, which are palliative and have no 1103.
survival advantage. Radium-223 causes double-strand DNA breaks Lu-177–PSMA-617 is not recommended in patients with dominant
and has a short radius of activity. Grade 3–4 hematologic toxicity (ie, PSMA-negative lesions. PSMA-negative lesions are defined as
2% neutropenia, 3% thrombocytopenia, 6% anemia) occurs at low metastatic disease that lacks PSMA uptake including bone with soft
frequency. tissue components ≥1.0 cm, lymph nodes ≥2.5 cm in short axis, and
• Radium-223 is administered IV once a month for 6 months by an solid organ metastases ≥1.0 cm in size.
appropriately licensed facility, usually in nuclear medicine or RT Lu-177–PSMA-617 is typically administered IV 200 mCi (7.4 GBq)
departments. every 6 weeks for a total of 6 treatments by an appropriately
• Prior to the initial dose, patients must have absolute neutrophil count licensed facility, usually in nuclear medicine or RT departments.
(ANC) ≥1.5 x 10⁹/L, platelet count ≥100 x 10⁹/L, and hemoglobin ≥10 g/ Patients should be well-hydrated during treatment. Because Lu-
dL. 177 also emits gamma radiation, appropriate precautions should
• Prior to subsequent doses, patients must have ANC ≥1 x 10⁹/L be taken to minimize exposure to personnel administering the
and platelet count ≥50 x 10⁹/L (per label). Radium-223 should be radiopharmaceutical. Treatment rooms should be monitored
discontinued if a delay of 6–8 weeks does not result in the return of for potential contamination following treatments, and patients
blood counts to these levels. should be provided written instructions regarding radiation safety
• Non-hematologic side effects are generally mild, and include nausea, precautions following treatment.
diarrhea, and vomiting. These symptoms may occur because The most frequently reported side effects from Lu-177–PSMA-617
radium-223 is eliminated predominantly by fecal excretion. include fatigue (43%), dry mouth (39%), nausea (35%), and anemia
• Radium-223 is not intended to be used in combination with (32%).
chemotherapy due to the potential for additive myelosuppression, Although the FDA has approved Ga-68 PSMA-11 for use with Lu-
except in a clinical trial. 177–PSMA-617, the panel believes that F-18 piflufolastat PSMA and
• Radium-223 may increase fracture risk when given concomitantly F-18 flotufolastat PSMA can also be used in the same space due to
with abiraterone. multiple reports describing the equivalency of these imaging agents
• Radium-223 is not recommended for use in combination with in:
docetaxel or any other systemic therapy except ADT. ◊ PSMA molecular recognition motifs,
• Concomitant use of denosumab or zoledronic acid is recommended; ◊ normal organ biodistribution, and
it does not interfere with the beneficial effects of radium-223 on ◊ detection accuracy of prostate cancer lesions.
survival.

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Palliative Radiotherapy
• 8 Gy as a single dose is as effective for pain palliation at any bony
site as longer courses of radiation, but re-treatment rates are higher.
• Widespread bone metastases can be palliated using strontium-89 or
samarium-153 with or without focal EBRT.
• 20 Gy in 5 fractions, 30 Gy in 10 fractions, or 37.5 Gy in 15 fractions
may be used as alternative palliative dosing depending on clinical
scenario.

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PRINCIPLES OF SURGERY
Pelvic Lymph Node Dissection Radical Prostatectomy
• Extended PLND provides more complete staging and may cure • RP is an appropriate therapy for any patient with clinically localized
some patients with microscopic metastases; therefore, an extended prostate cancer that can be completely excised surgically, who has
PLND is preferred when PLND is performed. a life expectancy of ≥10 years, and who has no serious comorbid
• An extended PLND includes removal of all node-bearing tissue conditions that would contraindicate an elective operation.
from an area bound by the external iliac vein anteriorly, the pelvic • High-volume surgeons in high-volume centers generally provide
sidewall laterally, the bladder wall medially, the floor of the pelvis better outcomes.
posteriorly, Cooper's ligament distally, and the internal iliac artery • Blood loss can be substantial with RP, but can be reduced by using
proximally. laparoscopic or robotic assistance or by careful control of the
• While PLND at the time of RP has not been shown to improve dorsal vein complex and periprostatic vessels when performed as
oncologic outcomes, it can provide staging and prognostic open surgery.
information.1 • Urinary incontinence can be reduced by preservation of urethral
• A PLND can be excluded in patients with low predicated probability length beyond the apex of the prostate and avoiding damage to
of nodal metastases by nomograms, although some patients the distal sphincter mechanism. Bladder neck preservation may
with lymph node metastases will be missed. There is no single decrease the risk of incontinence. Anastomotic strictures increase
evidence-based threshold for performing PLND. Based on the risk of the risk of long-term incontinence.
complications with PLND and extra time to perform the procedure, • Recovery of erectile function is directly related to age at RP,
the published thresholds range from 2% to 7%.2-5 preoperative erectile function, and the degree of preservation of the
• A patient who is above the threshold for performing a PLND, but cavernous nerves. Replacement of resected nerves with nerve grafts
has a negative PSMA PET scan should still undergo PLND. In has not been shown to be beneficial. Early restoration of erections
two studies, the sensitivity of PSMA PET for pelvic lymph node may improve late recovery.
involvement among patients undergoing RP and PLND was low
(about 40%), and the negative predictive value was about 81%.6,7 Salvage Radical Prostatectomy
Thus, basing the decision to perform PLND on a negative PSMA PET • Salvage RP is an option for highly selected patients with local
scan could result in missing 19% of patients with positive lymph recurrence after EBRT, brachytherapy, or cryotherapy in the
nodes. absence of metastases, but the morbidity (ie, incontinence, loss of
• PLND can be performed using an open, laparoscopic, or robotic erection, anastomotic stricture) is high and the operation should be
technique. performed by surgeons who are experienced with salvage RP.
See References (PROS-H 2 of 2)

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PRINCIPLES OF SURGERY
References
1 Fossati N, Willemse PPM, Van den Broeck T, et al. The benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate
cancer: A systematic review. Eur Urol 2017;72:84-109.
2 Cagiannos I, Karakiewicz P, Eastham JA, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J
Urol 2003;170:1798-803.
3 Briganti A, Larcher A, Abdollah F, et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node
dissection: the essential importance of percentage of positive cores. Eur Urol 2012;61:480-487.
4 Gandaglia G, Ploussard G, Valerio M, et al. A novel nomogram to identify candidates for extended pelvic lymph node dissection among patients with clinically localized
prostate cancer diagnosed with magnetic resonance imaging-targeted and systematic biopsies. Eur Urol 2019;75:506-514.
5 Gandaglia G, Martini A, Ploussard G, et al; EAU-YAU Prostate Cancer Working Group. External validation of the 2019 Briganti nomogram for the identification of
Pprostate cancer patients who should be considered for an extended pelvic lymph node dissection. Eur Urol 2020;78:138-142.
6 Hope TA, Eiber M, Armstrong WR, et al. Diagnostic accuracy of 68Ga-PSMA-11 PET for pelvic nodal metastasis detection prior to radical prostatectomy and pelvic
lymph node dissection: A multicenter prospective phase 3 imaging trial. JAMA Oncol 2021;7:1635-1642.
7 Pienta KJ, Gorin MA, Rowe SP, et al. A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with
18F-DCFPyL in prostate cancer patients (OSPREY). J Urol 2021;206:52-61.

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PRINCIPLES OF ANDROGEN DEPRIVATION THERAPY

ADT for Clinically Localized (N0,M0) Disease ADT for Regional (N1,M0) Disease
• Neoadjuvant ADT for RP is strongly discouraged outside of a clinical trial. • Patients with N1,M0 prostate cancer and a life expectancy >5 years can be
• ADT should not be used as monotherapy in clinically localized prostate treated with:
cancer unless there is a contraindication to definitive local therapy such EBRT and neoadjuvant, concurrent, and/or adjuvant ADT as for patients
as life expectancy ≤5 years and comorbidities. Under those circumstances, with N0,M0 disease (see above) without abiraterone
ADT may be used [see ADT for Patients on Observation Who Require EBRT and neoadjuvant, concurrent, and/or adjuvant LHRH agonist or
Treatment and Those with Life Expectancy ≤5 Years (PROS-I, 4 of 5)]. degarelix with abiraterone
• Giving ADT before, during, and/or after radiation (neoadjuvant, concurrent, ADT alone or with abiraterone (see below)
and/or adjuvant ADT) prolongs survival in selected radiation-managed • Abiraterone should be given with concurrent steroid:
patients. Options are: Prednisone 5 mg PO once daily for the standard formulation
LHRH agonist alone Methylprednisolone 4 mg PO twice daily for the fine-particle formulation
◊ Goserelin, leuprolide, or triptorelin (category 2B)
LHRH agonist (as above) plus first-generation antiandrogen
Abiraterone with ADT should be considered for a total of 2 years for those
◊ Nilutamide, flutamide, or bicalutamide
patients with N1 disease who are treated with radiation to the prostate
LHRH antagonist
and pelvic nodes.
◊ Degarelix or relugolix
LHRH agonist or degarelix with abiraterone (very high risk only) • Options for ADT are:
• Studies of short-term (4–6 mo) and long-term (2–3 y) neoadjuvant, Orchiectomy
concurrent, and/or adjuvant ADT all have used combined androgen LHRH agonist alone
blockade. Whether the addition of an antiandrogen is necessary requires ◊ Goserelin, leuprolide, or triptorelin
further study. LHRH agonist (as above) plus first-generation antiandrogen
• The largest randomized trial to date using the antiandrogen bicalutamide ◊ Nilutamide, flutamide, or bicalutamide
alone at high dose (150 mg) showed a delay in recurrence of disease but LHRH antagonist
no improvement in survival; however, longer follow-up is needed. ◊ Degarelix or relugolix
• Abiraterone can be added to EBRT and 2 years of ADT in patients with Orchiectomy plus abiraterone
very-high-risk prostate cancer. In the STAMPEDE trial, the hazard ratios LHRH agonist (as above) plus abiraterone
for overall survival with the addition of abiraterone to EBRT and ADT in Degarelix plus abiraterone
patients with node-negative disease was 0.69 (95% CI, 0.49–0.96). Patients with regional disease and life expectancy <5 years who chose
ADT can receive LHRH agonist, LHRH antagonist, or orchiectomy.
Abiraterone should be given with concurrent steroid:
◊ Prednisone 5 mg PO once daily for the standard formulation ADT for pN1 Disease
◊ Methylprednisolone 4 mg PO twice daily for the fine-particle • In one randomized trial, immediate and continuous use of ADT in patients
with positive nodes following RP resulted in significantly improved overall
formulation (category 2B).
survival compared to patients who received delayed ADT. Therefore,
such patients should be considered for immediate LHRH agonist, LHRH
antagonist, or orchiectomy. EBRT may be added (category 2B), in which
case the ADT options are as for neoadjuvant, concurrent, and/or adjuvant
ADT for clinically localized disease (see above). Many of the side effects of
continuous ADT are cumulative over time on ADT.

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ADT for M0 PSA Persistence/Recurrence After RP or EBRT (ADT for M0 ◊ LHRH agonist alone
Castration-Sensitive Disease) – Goserelin, leuprolide, or triptorelin
• The timing of ADT for patients whose only evidence of cancer after ◊ LHRH agonist (as above) plus first-generation antiandrogen
definitive treatment is an increasing PSA is influenced by PSA velocity, – Nilutamide, flutamide, or bicalutamide
patient anxiety, the short- and long-term side effects of ADT, and the ◊ LHRH antagonist
underlying comorbidities of the patient. – Degarelix or relugolix
• Most patients will have a good 15-year prognosis, but their prognosis is Abiraterone should be given with concurrent steroid [see ADT for
best approximated by the absolute level of PSA, the rate of change in the Regional (N1,M0) Disease].
PSA level (PSADT), and the initial stage, grade, and PSA level at the time of ADT for Metastatic Castration-Sensitive Disease
definitive therapy. • ADT with treatment intensification is preferred for most patients with
• Earlier ADT may be better than delayed ADT, although the definitions of metastatic prostate cancer. ADT alone is appropriate for some patients.
early and late (what level of PSA) are controversial. Since the benefit of • Treatment options for patients with M1 castration-sensitive disease are:
early ADT is not clear, treatment should be individualized until definitive ADT alone (orchiectomy, LHRH agonist, LHRH agonist plus first-
studies are done. Patients with a shorter PSADT (or a rapid PSA velocity) generation antiandrogen, or LHRH antagonist)
and an otherwise long life expectancy should be encouraged to consider ◊ LHRH agonists: Goserelin, leuprolide, or triptorelin
ADT earlier. ◊ First-generation antiandrogens: Nilutamide, flutamide, or bicalutamide
• Some patients are candidates for salvage therapy after PSA persistence/
◊ A first-generation antiandrogen must be given with LHRH agonist
recurrence. See PROS-10 and PROS-11.
for ≥7 days to prevent testosterone flare if metastases are present in
• Patients with prolonged PSADTs (>12 months) and who are older are
candidates for observation. weight-bearing bone
• Patients who choose ADT should consider intermittent ADT. A phase 3 trial Orchiectomy plus abiraterone, enzalutamide, or apalutamide
that compared intermittent to continuous ADT showed that intermittent Orchiectomy plus docetaxel and abiraterone or darolutamide
ADT was not inferior to continuous ADT with respect to survival, and LHRH agonist (as above) plus abiraterone, enzalutamide, or apalutamide
quality of life was better for the intermittent ADT arm. The 7% increase in LHRH agonist (as above) plus docetaxel and abiraterone or darolutamide
prostate cancer deaths in the intermittent ADT arm was balanced by more Degarelix plus abiraterone, enzalutamide, or apalutamide
non-prostate cancer deaths in the continuous ADT arm. An unplanned Degarelix plus docetaxel and abiraterone or darolutamide
subset analysis showed that patients with Grade Group 4 or 5 prostate • Abiraterone should be given with concurrent steroid [see ADT for Regional
cancer in the continuous arm had a median overall survival that was 14 (N1,M0) Disease].
months longer (8 years) than those in the intermittent arm (6.8 years). • When EBRT to primary is given with ADT in low metastatic burden M1, the
• ADT options are: options are LHRH agonist, LHRH antagonist, and orchiectomy.
M0 RP PSA persistence/recurrence: • Two randomized phase 3 clinical trials of abiraterone with prednisone
◊ EBRT +/- neoadjuvant, concurrent, and/or adjuvant ADT [See ADT for plus ADT in patients with castration-sensitive metastatic prostate
Clinically Localized (N0,M0) Disease] cancer demonstrated improved overall survival over ADT alone. Adverse
◊ EBRT + LHRH agonist or degarelix with abiraterone (studies positive events were higher with abiraterone and prednisone but were generally
for pelvic recurrence only) mild in nature and were largely related to mineralocorticoid excess (ie,
M0 RT recurrence, biopsy negative or M0 PSA recurrence after hypertension, hypokalemia, edema), hormonal effects (ie, fatigue, hot
progression on salvage EBRT: flushes), and liver toxicity. Cardiac events, severe hypertension, and liver
◊ Orchiectomy toxicity were increased with abiraterone.
Note: All recommendations are category 2A unless otherwise indicated. Continued

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• A double-blind randomized phase 3 clinical trial of apalutamide plus • Administration of secondary hormonal therapy can include:
ADT in patients with castration-sensitive metastatic prostate cancer Second-generation antiandrogen
demonstrated improved overall survival over ADT alone. Adverse events ◊ Apalutamide (for M0 and PSADT ≤10 months)
that were more common with apalutamide than with placebo included rash, ◊ Darolutamide (for M0 and PSADT ≤10 months)
hypothyroidism, and ischemic heart disease. ◊ Enzalutamide (for M0 and PSADT ≤10 months or M1)
• An open-label randomized phase 3 clinical trial of enzalutamide plus Androgen metabolism inhibitor
ADT in patients with castration-sensitive metastatic prostate cancer ◊ Abiraterone + prednisone (for M1 only)
demonstrated improved overall survival over ADT alone. In a separate ◊ Fine-particle abiraterone + methylprednisolone (for M1 only)
double-blind randomized phase 3 clinical trial, enzalutamide reduced Other secondary hormone therapy (for M0 or M1)
the risk of metastatic progression or death compared with placebo and ◊ First-generation antiandrogen (nilutamide, flutamide, or bicalutamide)
showed an overall survival benefit. Adverse events associated with ◊ Corticosteroids (hydrocortisone, prednisone, or dexamethasone)
enzalutamide included fatigue, seizures, and hypertension. ◊ Antiandrogen withdrawal
• A phase 3 trial compared continuous ADT to intermittent ADT, but the ◊ Ketoconazole plus hydrocortisone
study could not demonstrate non-inferiority for survival. However, quality- • Abiraterone should be given with concurrent steroid, either prednisone 5
of-life measures for erectile function and mental health were better in the mg PO twice daily for the standard formulation or methylprednisolone 4
intermittent ADT arm after 3 months of ADT compared to the continuous mg PO twice daily for the fine-particle formulation.
ADT arm. • A phase 3 study of patients with M0 CRPC and a PSADT ≤10 months
• In addition, three meta-analyses of randomized controlled trials failed to showed apalutamide (240 mg/day) improved the primary endpoint of
show a difference in survival between intermittent and continuous ADT. metastasis-free survival over placebo (40.5 months vs. 16.2 months). After
• Close monitoring of PSA and testosterone levels and possibly imaging a median follow-up of 52 months, final overall survival analysis showed an
is required when using intermittent ADT, especially during off-treatment improved median overall survival with apalutamide versus placebo (73.9
periods, and patients may need to switch to continuous ADT upon signs of months vs. 59.9 months). Adverse events included rash (24% vs. 5.5%),
disease progression. fracture (11% vs. 6.5%), and hypothyroidism (8% vs. 2%). Bone support
should be used in patients receiving apalutamide.
Secondary Hormone Therapy for M0 or M1 CRPC • A phase 3 study of patients with M0 CRPC and a PSADT ≤10 months
• Androgen receptor activation and autocrine/paracrine androgen synthesis showed enzalutamide (160 mg/day) improved the primary endpoint of
are potential mechanisms of recurrence of prostate cancer during ADT metastasis-free survival over placebo (36.6 months vs. 14.7 months).
(CRPC). Thus, castrate levels of testosterone (<50 ng/dL) should be Median overall survival was longer in the enzalutamide group than in the
maintained by continuing LHRH agonist or degarelix while additional placebo group (67.0 months vs. 56.3 months). Adverse events included
therapies are applied. falls and nonpathologic fractures (17% vs. 8%), hypertension (12% vs. 5%),
• Once the tumor becomes resistant to initial ADT, there are a variety of major adverse cardiovascular events (5% vs. 3%), and mental impairment
options that may afford clinical benefit. The available options are based on disorders (5% vs. 2%). Bone support should be used in patients receiving
whether the patient has evidence of metastases by conventional imaging, enzalutamide.
M0 CRPC vs. M1 CRPC, and whether or not the patient is symptomatic.

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• A phase 3 study of patients with M0 CRPC and a PSADT ≤10 months plus prednisone have been shown to extend survival in randomized
showed darolutamide (600 mg twice daily) improved the primary endpoint controlled trials. Therefore, each agent has a category 1 recommendation.
of metastasis-free survival over placebo (40.4 months vs. 18.4 months). • Two randomized clinical trials (STRIVE and TERRAIN) showed that 160 mg/
Overall survival at 3 years was 83% (95% CI, 80–86) in the darolutamide day enzalutamide improved PFS compared to 50 mg/day bicalutamide in
group compared with 77% (95% CI, 72–81) in the placebo group. Adverse patients with treatment-naïve M1 CRPC and, therefore, enzalutamide may
events that occurred more frequently in the treatment arm included fatigue be the preferred option in this setting. However, bicalutamide can still be
(12.1% vs. 8.7%), pain in an extremity (5.8% vs. 3.2%), and rash (2.9% vs. considered in some patients, given the different side effect profiles of the
0.9%). The incidence of fractures was similar between darolutamide and agents and the increased cost of enzalutamide.
placebo (4.2% vs. 3.6%). • Evidence-based guidance on the sequencing of agents in either pre- or
• In a randomized controlled trial in the setting of M1 CRPC prior to post-docetaxel remains limited.
docetaxel chemotherapy, abiraterone and low-dose prednisone (5 mg ADT for Patients on Observation Who Require Treatment and Those with
BID) compared to prednisone alone improved radiographic progression- Life Expectancy ≤5 Years
free survival (rPFS), time to initiation of chemotherapy, time to onset or • Treatment for patients whose cancer progressed on observation of
worsening of pain, and time to deterioration of performance status. An localized disease is LHRH agonist or antagonist or orchiectomy.
improvement in overall survival was demonstrated. Use of abiraterone
and prednisone in this setting is a category 1 recommendation. The Optimal ADT
side effects of abiraterone that require ongoing monitoring include • Medical castration (ie, LHRH agonist or antagonist) and surgical castration
hypertension, hypokalemia, peripheral edema, atrial fibrillation, congestive (ie, bilateral orchiectomy) are equally effective.
heart failure, liver injury, and fatigue, as well as the known side effects of • Combined androgen blockade (medical or surgical castration combined
ADT and long-term corticosteroid use. with an antiandrogen) provides modest to no benefit over castration alone
• A phase 3 study of docetaxel-sensitive patients with M1 CRPC showed that in patients with metastatic disease.
enzalutamide (160 mg daily) resulted in significant improvement in rPFS • Antiandrogen therapy should precede or be coadministered with LHRH
and overall survival. The use of enzalutamide in this setting is category 1. agonist and be continued in combination for at least 7 days for patients
The side effects of enzalutamide that require long-term monitoring include with overt metastases who are at risk of developing symptoms associated
fatigue, diarrhea, hot flashes, headache, and seizures (reported in 0.9% of with the flare in testosterone with initial LHRH agonist alone.
patients on enzalutamide). • Antiandrogen monotherapy appears to be less effective than medical or
• For symptomatic patients with M1 CRPC, all secondary hormone options surgical castration and is not recommended.
listed above are allowed, but initial use of docetaxel may be preferred. • No clinical data support the use of finasteride or dutasteride with combined
Both randomized trials of abiraterone and enzalutamide in the pre- androgen blockade.
docetaxel setting were conducted in patients who had no or minimal • Patients who do not achieve adequate suppression of serum testosterone
symptoms due to M1 CRPC. How these agents compare to docetaxel (<50 ng/dL) with medical or surgical castration can be considered
for pain palliation in this population of patients is not clear. Both drugs for additional hormonal manipulations (with antiandrogens, LHRH
have palliative effects in the post-docetaxel setting. Both abiraterone and antagonists, or steroids), although the clinical benefit remains uncertain.
enzalutamide are approved in this pre-docetaxel setting and have category Consider monitoring testosterone levels 12 weeks after first dose of
1 recommendations. Both drugs are suitable options for patients who are LHRH therapy, then upon increase in PSA. The optimal level of serum
not good candidates to receive docetaxel. testosterone to affect “castration” has yet to be determined.
• In the post-docetaxel M1 CRPC population, enzalutamide and abiraterone • Relugolix has not been adequately studied in combination with potent

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androgen receptor inhibitors such as enzalutamide, apalutamide, • Screening and treatment for osteoporosis are advised according to
darolutamide, or abiraterone acetate, nor has it been studied in guidelines for the general population from the National Osteoporosis
combination with docetaxel or cabazitaxel chemotherapy. Potential drug Foundation (www.nof.org). The National Osteoporosis Foundation guidelines
interactions include induction of cytochrome P450 enzymes and reduced include recommendations for: 1) calcium (1000–1200 mg daily from food
concentration and efficacy of relugolix with enzalutamide or apalutamide and supplements) and vitamin D3 (400–1000 IU daily); and 2) additional
and cardiac QTc interactions with abiraterone. Further studies of relugolix treatment for males aged ≥50 years with low bone mass (T-score between
dosing and drug interactions with commonly used agents in advanced -1.0 and -2.5, osteopenia) at the femoral neck, total hip, or lumbar spine by
prostate cancer are needed to ensure patient safety and proper dosing. dual-energy x-ray absorptiometry (DEXA) scan and a 10-year probability of
• Data are limited on long-term compliance of oral relugolix and the potential hip fracture ≥3% or a 10-year probability of a major osteoporosis-related
effects on optimal ADT. Ongoing monitoring for sustained suppression of fracture ≥20%. Fracture risk can be assessed using FRAX, the algorithm
testosterone (<50 ng/dL) can be considered, and relugolix may not be a released by WHO. ADT should be considered “secondary osteoporosis”
preferred agent if patient compliance is uncertain. when using the FRAX algorithm. Treatment options to increase bone
density, a surrogate for fracture risk in patients without metastases,
Monitor/Surveillance
include denosumab (60 mg SQ every 6 months), zoledronic acid (5 mg IV
• ADT has a variety of adverse effects, including hot flashes, loss of libido,
annually), and alendronate (70 mg PO weekly).
erectile dysfunction, shrinkage of penis and testicles, loss of muscle
• A baseline DEXA scan should be obtained before starting therapy in
mass and strength, fatigue, anemia, breast enlargement and tenderness/
patients at increased risk for fracture based on FRAX screening. A follow-
soreness, depression and mood swings, hair loss, osteoporosis, greater
up DEXA scan after 1 year of therapy is recommended by the International
incidence of clinical fractures, obesity, insulin resistance, alterations
Society for Clinical Densitometry, although there is no consensus on the
in lipids, and greater risk for diabetes and cardiovascular disease. The
optimal approach to monitoring the effectiveness of drug therapy. Use of
intensity and spectrum of these side effects vary greatly, and many are
biochemical markers of bone turnover to monitor response to therapy is
reversible or can be avoided or mitigated. For example, physical activity
not recommended. The serum level of 25-hydroxy vitamin D and average
can counter many of these symptoms and should be recommended
daily dietary intake of vitamin D will assist the nutritionist in making a
(see NCCN Guidelines for Survivorship). Use of statins also should be
patient-specific recommendation for vitamin D supplementation. There are
considered. Patients and their medical providers should be advised about
currently no guidelines on how often to monitor vitamin D levels. However,
these risks prior to treatment.
for those who require monitoring with DEXA scans, it makes sense to
check the serum vitamin D level at the same time.
• Denosumab (60 mg SQ every 6 months), zoledronic acid (5 mg IV annually),
and alendronate (70 mg PO weekly) increase bone mineral density, a
surrogate for fracture risk, during ADT for prostate cancer. Treatment
with either denosumab, zoledronic acid, or alendronate sodium is
recommended when the absolute fracture risk warrants drug therapy.
• Screening for and intervention to prevent/treat diabetes and cardiovascular
disease are recommended in patients receiving ADT. These medical
conditions are common in older individuals and it remains uncertain
whether strategies for screening, prevention, and treatment of diabetes
and cardiovascular disease in patients receiving ADT should differ from the
general population.

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PRINCIPLES OF NON-HORMONAL SYSTEMIC THERAPY

Non-Hormonal Systemic Therapy for M1 Castration-Sensitive Prostate Cancer
• Patients with high-volume castration-sensitive metastatic prostate cancer • Patients who are not candidates for docetaxel or who are intolerant of
who are fit for chemotherapy should be considered for ADT plus docetaxel docetaxel should be considered for cabazitaxel with concurrent steroid,
and either abiraterone or darolutamide based on phase 3 studies: based on recent results that suggest clinical activity of cabazitaxel
ADT plus docetaxel and abiraterone improved overall survival and rPFS in in mCRPC. Cabazitaxel was associated with lower rates of peripheral
the open-label PEACE-1 study. A modest increase in toxicity was seen. neuropathy than docetaxel, particularly at 20 mg/m2 (12% vs. 25%) and may
ADT plus docetaxel and darolutamide improved overall survival in the be appropriate in patients with pre-existing mild peripheral neuropathy.
ARASENS trial. Adverse events were similar between arms. Current data do not support greater efficacy of cabazitaxel over docetaxel.
The use of myeloid growth factors should follow the NCCN Guidelines for • Increasing PSA should not be used as the sole criteria for progression.
Hematopoietic Growth Factors, based on risk of neutropenic fever. Assessment of response should incorporate clinical and radiographic
Non-Hormonal Systemic Therapy for M1 CRPC criteria.
Chemotherapy • Cabazitaxel at 25 mg/m² with concurrent steroid has been shown in a
• Docetaxel with concurrent steroid randomized phase 3 study (TROPIC) to prolong overall survival, PFS, PSA
Concurrent steroids may include: dexamethasone on the day of response, and radiologic response when compared with mitoxantrone and
chemotherapy or daily prednisone. prednisone and is FDA approved in the post-docetaxel second-line setting.
• Cabazitaxel with concurrent steroid Toxicity at this dose was significant and included febrile neutropenia,
Concurrent steroids may include: dexamethasone on the day of severe diarrhea, fatigue, nausea/vomiting, anemia, thrombocytopenia,
chemotherapy or daily prednisone. sepsis, and renal failure. A recent trial, PROSELICA, compared cabazitaxel
• Cabazitaxel/carboplatin with concurrent steroid 25 mg/m² every 3 weeks to 20 mg/m² every 3 weeks. Cabazitaxel 20 mg/
Concurrent steroids may include: dexamethasone on the day of m² had less toxicity; febrile neutropenia, diarrhea, and fatigue were
chemotherapy or daily prednisone. less frequent. Cabazitaxel at 20 mg/m² had a significantly lower PSA
• Mitoxantrone with prednisone response rate but non-significantly lower radiographic response rate and
• Every-3-week docetaxel with concurrent steroid is the preferred first-line non-significantly shorter PFS and overall survival (13.4 months vs. 14.5
chemotherapy treatment based on phase 3 clinical trial data for patients months) compared to 25 mg/m². Cabazitaxel starting dose can be either 20
with symptomatic mCRPC. Radium-223 has been studied in symptomatic mg/m² or 25 mg/m² for patients with mCRPC whose cancer has progressed
patients who are not candidates for docetaxel-based regimens and despite prior docetaxel chemotherapy. Cabazitaxel 25 mg/m² with
resulted in improved overall survival. Abiraterone and enzalutamide have concurrent steroid may be considered for healthy patients who wish to be
been shown to extend survival in patients whose cancer progressed more aggressive. Growth factor support may be needed with either dose.
on docetaxel. (See PROS-I). Mitoxantrone with prednisone may provide • Cabazitaxel at 25 mg/m2 with concurrent steroid improved rPFS and
palliation but has not been shown to extend survival. reduced the risk of death compared with abiraterone or enzalutamide in
• Only regimens utilizing docetaxel on an every-3-week schedule patients with prior docetaxel treatment for mCRPC in the CARD study.
demonstrated beneficial impact on survival. The duration of therapy should • Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per minute with
be based on the assessment of benefit and toxicities. In the pivotal trials growth factor support can be considered for fit patients with aggressive
establishing survival advantage of docetaxel-based chemotherapy, patients variant prostate cancer (ie, visceral metastases, low PSA and bulky
received up to 10 cycles of treatment if no progression and no prohibitive disease, high LDH, high CEA, lytic bone metastases, NEPC histology) or
toxicities were noted. unfavorable genomics (defects in at least 2 of PTEN, TP53, and RB1). Corn
PG, et al. Lancet Oncol 2019;20:1432-1443.

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• Docetaxel retreatment can be attempted after progression on a novel Immunotherapy
hormone therapy in patients with metastatic CRPC whose cancer has not • Patients with asymptomatic or minimally symptomatic mCRPC may
demonstrated definitive evidence of progression on prior docetaxel therapy consider immunotherapy.
in the castration-sensitive setting. • Sipuleucel-T
• No chemotherapy regimen to date has demonstrated improved survival or Sipuleucel-T is only for asymptomatic or minimally symptomatic
quality of life after cabazitaxel, and trial participation should be encouraged. patients with no liver metastases, life expectancy >6 months, and
• Treatment decisions around off-label chemotherapy use in the treatment- ECOG performance status 0–1.
refractory CRPC should be individualized based on comorbidities and Sipuleucel-T is not recommended for patients with small cell/NEPC.
Sipuleucel-T has been shown in a phase 3 clinical trial to extend mean
functional status and after informed consent.
• No benefits of combination approaches over sequential single-agent survival from 21.7 months in the control arm to 25.8 months in the
therapies have been demonstrated, and toxicity is higher with combination treatment arm, which constitutes a 22% reduction in mortality risk.
regimens. See NCCN Guidelines for Hematopoietic Growth Factors for Sipuleucel-T is well-tolerated; common complications include chills,
recommendations on growth factor support. pyrexia, and headache.
• Pembrolizumab (for MSI-H, dMMR, or TMB ≥10 mut/Mb)
Targeted Therapy
Pembrolizumab is recommended only as subsequent systemic therapy
• Consider inclusion of olaparib in patients who have an HRR mutation
for patients with metastatic CRPC whose cancer has progressed
and whose cancer has progressed on prior treatment with androgen
through prior docetaxel and a novel hormone therapy.
receptor-directed therapy regardless of prior docetaxel therapy. Olaparib
is a treatment option for patients with mCRPC and a pathogenic mutation
(germline and/or somatic) in a homologous recombination repair gene
(BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL,
PALB2, RAD51B, RAD51C, RAD51D, or RAD54L) who have been treated
previously with androgen receptor-directed therapy. However, efficacy
appears to be driven by the cohort of patients with at least one alteration
in BRCA2, BRCA1, or ATM, and in particular by patients with BRCA2 or
BRCA1 mutations based on exploratory gene-by-gene analysis. There may
be heterogeneity of response to olaparib for non-BRCA mutations based on
which gene has a the specific gene mutation.
• Consider inclusion of rucaparib for patients with mCRPC and a pathogenic
BRCA1 or BRCA2 mutation (germline and/or somatic) who have been treated
with androgen receptor-directed therapy and a taxane-based chemotherapy.
If the patient is not fit for chemotherapy, rucaparib can be considered even if
taxane-based therapy has not been given.
• Olaparib with abiraterone is an option for patients with a pathogenic BRCA1
or BRCA2 mutation (germline and/or somatic) who have not yet received a
novel hormone therapy or docetaxel.

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Prevention of Skeletal-Related Events

• In patients with CRPC who have bone metastases, denosumab and zoledronic acid have been shown to prevent disease-related skeletal
complications, which include fracture, spinal cord compression, or the need for surgery or RT to bone.
• When compared to zoledronic acid, denosumab was shown to be superior in prevention of skeletal-related events.
• A phase 3 clinical trial that assessed a role for zoledronic acid in patients beginning ADT for bone metastases was negative.
• Choice of agent may depend on underlying comorbidities, whether the patient has been treated with zoledronic acid previously, logistics, and/or cost
considerations.
Denosumab (preferred) is given SQ every 4 weeks. Although renal monitoring is not required, denosumab is not recommended in patients with
creatinine clearance <30 mL/min. When creatinine clearance is <60 mL/min, the risk for severe hypocalcemia increases. Even in patients with normal
renal function, hypocalcemia is seen twice as often with denosumab than zoledronic acid and all patients on denosumab should be treated with
vitamin D and calcium with periodic monitoring of serum calcium levels.
Zoledronic acid is given IV every 3 to 4 weeks or every 12 weeks. The dose is based on the serum creatinine obtained just prior to each dose and
must be adjusted for impaired renal function. Zoledronic acid is not recommended for creatinine clearance <30 mL/min.
• Osteonecrosis of the jaw (ONJ) is seen with both agents; risk is increased in patients who have tooth extractions, poor dental hygiene, or a dental
appliance. Patients should be referred for dental evaluation before starting either zoledronic acid or denosumab. If invasive dental procedures are
required, bone-targeted therapy should be withheld until the dentist indicates that the patient has healed completely from all dental procedure(s).
• The optimal duration of therapy for either denosumab or zoledronic acid remains uncertain.
• The toxicity profile of denosumab when denosumab is used in patients who have been treated with zoledronic acid remains uncertain.

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Table of Contents
American Joint Committee on Cancer (AJCC)

TNM Staging System For Prostate Cancer (8th ed., 2017)
Pathological T (pT)
Table 1. Definitions for T, N, M
Clinical T (cT) T Primary Tumor
T Primary Tumor T2 Organ confined
TX Primary tumor cannot be assessed T3 Extraprostatic extension
T0 No evidence of primary tumor T3a Extraprostatic extension (unilateral or bilateral) or microscopic
T1 Clinically inapparent tumor that is not palpable invasion of bladder neck
T1a Tumor incidental histologic finding in 5% or less of T3b Tumor invades seminal vesicle(s)
tissue resected T4 Tumor is fixed or invades adjacent structures other than seminal
T1b Tumor incidental histologic finding in more than 5% vesicles such as external sphincter, rectum, bladder, levator
of tissue resected muscles, and/or pelvic wall
Note: There is no pathological T1 classification.
T1c Tumor identified by needle biopsy found in one or both sides,
Note: Positive surgical margin should be indicated by an R1 descriptor, indicating
but not palpable residual microscopic disease.
T2 Tumor is palpable and confined within prostate
T2a Tumor involves one-half of one side or less N Regional Lymph Nodes
T2b Tumor involves more than one-half of one side but NX Regional lymph nodes cannot be assessed
not both sides N0 No positive regional nodes
T2c Tumor involves both sides N1 Metastases in regional node(s)
T3 Extraprostatic tumor that is not fixed or does not invade
adjacent structures M Distant Metastasis
T3a Extraprostatic extension (unilateral or bilateral) M0 No distant metastasis
T3b Tumor invades seminal vesicle(s) M1 Distant metastasis
T4 Tumor is fixed or invades adjacent structures other M1a Nonregional lymph node(s)
than seminal vesicles such as external sphincter, rectum, M1b Bone(s)
bladder, levator muscles, and/or pelvic wall.
M1c Other site(s) with or without bone disease

Note: When more than one site of metastasis is present, the most advanced category
is used. M1c is most advanced.
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
ST-1
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Table 2. AJCC Prognostic Groups

Group T N M PSA (ng/mL) Grade Group Histopathologic Type
Stage I cT1a-c N0 M0 PSA <10 1 This classification applies to adenocarcinomas and squamous carcinomas,
cT2a N0 M0 PSA <10 1 but not to sarcoma or transitional cell (urothelial) carcinoma of the prostate.
Adjectives used to describe histologic variants of adenocarcinomas of
pT2 N0 M0 PSA <10 1 prostate include mucinous, signet ring cell, ductal, and neuroendocrine,
Stage IIA cT1a-c N0 M0 PSA ≥10 <20 1 including small cell carcinoma. There should be histologic confirmation of the
cT2a N0 M0 PSA ≥10 <20 1 disease.
pT2 N0 M0 PSA ≥10 <20 1 Definition of Histologic Grade Group (G)
cT2b N0 M0 PSA <20 1 Recently, the Gleason system has been compressed into so-called Grade
cT2c N0 M0 PSA <20 1 Groups.
Stage IIB T1-2 N0 M0 PSA <20 2
Grade Group Gleason Score Gleason Pattern
Stage IIC T1-2 N0 M0 PSA <20 3
1 ≤6 ≤3+3
T1-2 N0 M0 PSA <20 4
2 7 3+4
Stage IIIA T1-2 N0 M0 PSA ≥20 1-4
3 7 4+3
Stage IIIB T3-4 N0 M0 Any PSA 1-4
4 8 4+4, 3+5, 5+3
Stage IIIC Any T N0 M0 Any PSA 5
5 9 or 10 4+5, 5+4, 5+5
Stage IVA Any T N1 M0 Any PSA Any
Stage IVB Any T Any N M1 Any PSA Any
Note: When either PSA or Grade Group is not available, grouping should be
determined by T category and/or either PSA or Grade Group as available.
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition
(2017) published by Springer International Publishing.
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ABBREVIATIONS
ADT androgen deprivation therapy HR high risk OAR organ at risk
AI artificial intelligence HRRm homologous recombination OS overall survival

repair gene mutations
AUC area under the curve PCSM prostate cancer-specific
IGRT image-guided radiation mortality
therapy
BCR biochemical recurrence
PFS progression-free survival
IR intermediate risk
BED biologically effective dose
PLND pelvic lymph node dissection
IRF intermediate risk factor
CCP cell cycle progression
PSA prostate-specific antigen
LDH lactate dehydrogenase
CEA carcinoembryonic antigen
PSADT prostate-specific antigen
LDR low dose-rate doubling time
CRPC castration-resistant prostate
cancer
LHRH luteinizing hormone- PSMA prostate-specific membrane
releasing hormone antigen
ctDNA circulating tumor DNA
mCRPC metastatic castration- RP radical prostatectomy

DM distant metastases resistant prostate cancer
rPFS radiographic progression-free
dMMR mismatch repair deficient MDP methylene diphosphonate survival
DRE digital rectal exam mpMRI multiparametric MRI RT radiation therapy
DWI diffusion-weighted imaging MSI microsatellite instability SBRT stereotactic body radiation
therapy
EBRT external beam radiation therapy MSI-H microsatellite instability-high
TMB tumor mutational burden
HDR high dose-rate NEPC neuroendocrine prostate
cancer
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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 2.2023
Prostate Cancer
Discussion This discussion corresponds to the NCCN Guidelines for Prostate Cancer. Last updated: May 10, 2022.
Table of Contents
Overview ...................................................................................................... MS-2 Adjuvant/Early Treatment for Adverse Features ..................................... MS-38
Literature Search Criteria and Guidelines Update Methodology .................. MS-2 Adjuvant Therapy for pN1 ....................................................................... MS-39
Initial Prostate Cancer Diagnosis ................................................................. MS-3 Biochemical Recurrence After Radical Prostatectomy ............................ MS-40
Estimates of Life Expectancy ....................................................................... MS-3 Post-Radiation Recurrence ........................................................................ MS-41
Prostate Cancer Genetics ............................................................................ MS-3 Androgen Deprivation Therapy ................................................................... MS-42
Homologous DNA Repair Genes ............................................................. MS-4 ADT for Clinically Localized (N0M0) Disease ......................................... MS-42
DNA Mismatch Repair Genes .................................................................. MS-5 ADT for Regional Disease ...................................................................... MS-44
Effect of Intraductal/Cribriform or Ductal Histology .................................. MS-5 Palliative ADT ......................................................................................... MS-45
Risk Stratification for Clinically Localized Disease ....................................... MS-7 ADT for Castration-Naive Disease .......................................................... MS-45
NCCN Risk Groups .................................................................................. MS-7 Intermittent Versus Continuous ADT ...................................................... MS-50
Nomograms ............................................................................................. MS-9 Adverse Effects of Traditional ADT ......................................................... MS-52
Tumor Multigene Molecular Testing ......................................................... MS-9 Progression to and Management of CRPC ................................................. MS-54
Initial Clinical Assessment and Staging Evaluation .................................... MS-10 Secondary Hormone Therapy for CRPC .................................................... MS-55
Imaging Techniques .................................................................................. MS-11 Abiraterone Acetate in M1 CRPC ........................................................... MS-55
Multiparametric MRI (mpMRI) ................................................................ MS-12 Enzalutamide in M0 and M1 CRPC ........................................................ MS-57
PET Imaging .......................................................................................... MS-12 Apalutamide in M0 CRPC ....................................................................... MS-58
Observation ............................................................................................... MS-15 Darolutamide in M0 CRPC ..................................................................... MS-59
Active Surveillance .................................................................................... MS-16 Other Secondary Hormone Therapies .................................................... MS-59
Rationale................................................................................................ MS-17 Chemotherapy, Immunotherapy, and Targeted Therapy in Metastatic Prostate
Patient Selection .................................................................................... MS-18 Cancer ....................................................................................................... MS-59
Confirmatory Testing .............................................................................. MS-20 Docetaxel ............................................................................................... MS-59
Active Surveillance Program .................................................................. MS-20 Cabazitaxel............................................................................................. MS-61
Considerations for Treatment of Patients on Active Surveillance .......... MS-21 Cabazitaxel/Carboplatin ......................................................................... MS-62
Radical Prostatectomy ............................................................................... MS-22 Sipuleucel-T ........................................................................................... MS-62
Pelvic Lymph Node Dissection ............................................................... MS-24 Pembrolizumab ...................................................................................... MS-63
Radiation Therapy ..................................................................................... MS-25 Mitoxantrone ........................................................................................... MS-64
External Beam Radiation Therapy ......................................................... MS-25 Treatment Options for Patients with DNA Repair Gene Mutations .......... MS-64
Stereotactic Body Radiation Therapy ..................................................... MS-28 Small Cell/Neuroendocrine Prostate Cancer .............................................. MS-67
Brachytherapy ........................................................................................ MS-29 Bone Metastases ........................................................................................ MS-67
Proton Therapy ...................................................................................... MS-32 Visceral Metastases ................................................................................... MS-68
Radiation for Distant Metastases ........................................................... MS-33 Sequencing of Therapy in CRPC................................................................ MS-69
Comparison of Treatment Options for Localized Disease .......................... MS-35 AR-V7 Testing ........................................................................................ MS-69
Other Local Therapies ............................................................................... MS-36 Summary .................................................................................................... MS-70
Disease Monitoring .................................................................................... MS-37 Table 1. Available Tissue-Based Tests for Prostate Cancer Risk
Patients After Initial Definitive Therapy .................................................. MS-37 Stratification/Prognosis ............................................................................... MS-71
Patients with Castration-Naïve Disease on ADT .................................... MS-37 Table 2. Summary of FDA-Cleared PET Imaging Tracers Studied in Prostate
Patients with Localized Disease Under Observation .............................. MS-37 Cancer ....................................................................................................... MS-72
Workup for Progression ......................................................................... MS-38 References ................................................................................................. MS-73
Post-Radical Prostatectomy Treatment ..................................................... MS-38
Version 2.2023 © 2023 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1
Prostate Cancer
Overview years.20 These updated recommendations may allow for a more balanced
An estimated 248,530 new cases of prostate cancer will be diagnosed in approach to prostate cancer early detection. Better use of PSA for early
the United States in 2021, accounting for almost 26% of new cancer cases detection of potentially fatal prostate cancer coupled with the use of
in males.1 Researchers further estimate that prostate cancer will account imaging and biomarkers to improve the specificity of screening (see the
for 10.7% of male cancer deaths in the United States in 2021, with an NCCN Guidelines for Prostate Cancer Early Detection, available at
estimated 34,130 deaths.1 Over the past several years, the incidence of www.NCCN.org) should decrease the risk of overdetection. This reduced
prostate cancer has declined, likely in part as a result of decreased overdetection along with the use of active surveillance in appropriate
detection attributed to decreased rates of prostate-specific antigen (PSA) patients should reduce overtreatment AND preserve the decrease in
screening.2-4 The age-adjusted death rate from prostate cancer declined prostate cancer mortality.
by 52% from 1993 to 2017, but the death rate has become stable in recent
Literature Search Criteria and Guidelines Update
years.1 For all stages combined, the 5-year relative survival rate for
Methodology
prostate cancer is 98%.1 The comparatively low death rate suggests that
Prior to the update of the NCCN Guidelines for Prostate Cancer, an
increased public awareness with earlier detection and treatment has
electronic search of the PubMed database was performed to obtain key
affected mortality from this prevalent cancer, but is also complicated by
literature in prostate cancer published since the previous Guidelines
screening-related lead-time bias and detection of indolent cancers.
update, using the search term “prostate cancer.” The PubMed database
Early detection can lead to overtreatment of prostate cancers that do not was chosen because it remains the most widely used resource for medical
threaten life expectancy, which results in unnecessary side effects that literature and indexes peer-reviewed biomedical literature.21
impair quality of life (QOL) and increase health care expenditures. The
The search results were narrowed by selecting studies in humans
U.S. Preventive Services Task Force (USPSTF) recommended against
published in English. Results were confined to the following article types:
PSA testing in 2012.5 The incidence of metastatic disease has increased
Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized
since that time.4,6,7 The rate of prostate cancer mortality, which had been in
Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation
decline for 2 decades, has stabilized.1,4 Prostate cancer incidence and
Studies.
deaths have increased in the past few years for the first time in recent
history, with prostate cancer deaths increasing from an estimated 26,730 The data from key PubMed articles as well as articles from additional
in 2017 to 34,130 in 2021.1,8 Increases in the incidence of metastases at sources deemed as relevant to these guidelines as discussed by the panel
presentation and prostate cancer deaths may be influenced by declines in during the Guidelines update have been included in this version of the
the rates of prostate cancer early detection, biopsies, diagnosis of Discussion section. Recommendations for which high-level evidence is
localized prostate cancers, and radical prostatectomy that followed the lacking are based on the panel’s review of lower-level evidence and expert
2012 USPSTF recommendations.9-19 The USPSTF released updated opinion.
recommendations in 2018 that include individualized, informed decision-
making regarding prostate cancer screening in males aged 55 to 69
MS-2
Prostate Cancer
The complete details of the Development and Update of the NCCN Kettering Male Life Expectancy tool26 and adjusted for individual patients
Guidelines are available at www.NCCN.org. by adding or subtracting 50% based on whether one believes the patient is
in the healthiest quartile or the unhealthiest quartile, respectively.27 As an
Initial Prostate Cancer Diagnosis example, the Social Security Administration Life Expectancy for a 65-year-
Initial suspicion of prostate cancer is based on an abnormal digital rectal old American male is 17.7 years. If judged to be in the upper quartile of
exam (DRE) or an elevated PSA level. A separate NCCN Guidelines health, a life expectancy of 26.5 years is assigned. If judged to be in the
Panel has written guidelines for prostate cancer early detection (see the lower quartile of health, a life expectancy of 8.8 years is assigned. Thus,
NCCN Guidelines for Prostate Early Detection, available at treatment recommendations could change dramatically using the NCCN
www.NCCN.org). Definitive diagnosis requires biopsies of the prostate, Guidelines if a 65-year-old patient was judged to be in either poor or
usually performed by a urologist using a needle under transrectal excellent health.
ultrasound (TRUS) guidance. A pathologist assigns a Gleason primary
and secondary grade to the biopsy specimen. Clinical staging is based on Prostate Cancer Genetics
the TNM (tumor, node, metastasis) classification from the AJCC Staging Family history of prostate cancer raises the risk of prostate cancer.28-31 In
Manual, Eighth Edition.22 NCCN treatment recommendations are based on addition, prostate cancer has been associated with hereditary breast and
risk stratification that includes TNM staging rather than on AJCC ovarian cancer (HBOC) syndrome (due to germline mutations in
prognostic grouping. homologous DNA repair genes) and Lynch syndrome (resulting from
germline mutations in DNA mismatch repair [MMR] genes).31-36 In fact,
Pathology synoptic reports (protocols) are useful for reporting results from approximately 11% of patients with prostate cancer and at least 1
examinations of surgical specimens; these reports assist pathologists in additional primary cancer carry germline mutations associated with
providing clinically useful and relevant information. The NCCN Guidelines increased cancer risk.37 Therefore, the panel recommends a thorough
Panel favors pathology synoptic reports from the College of American review of personal and family history for all patients with prostate
Pathologists (CAP) that comply with the Commission on Cancer (CoC) cancer.38,39
requirements.23
The newfound appreciation of the frequency of germline mutations has
Estimates of Life Expectancy implications for family genetic counseling, cancer risk syndromes, and
Estimates of life expectancy have emerged as a key determinant of assessment of personal risk for subsequent cancers. Some patients with
primary treatment, particularly when considering active surveillance or prostate cancer and their families may be at increased risk for breast and
observation. Life expectancy can be estimated for groups of individuals, ovarian cancer, melanoma, and pancreatic cancer (HBOC); colorectal
but it is difficult to extrapolate these estimates to an individual patient. Life cancers (Lynch syndrome); and other cancer types. Data also suggest that
expectancy can be estimated using the Minnesota Metropolitan Life patients with prostate cancer who have BRCA1/2 germline mutations have
Insurance Tables, the Social Security Administration Life Insurance increased risk of progression on local therapy and decreased overall
Tables,24 the WHO’s Life Tables by Country,25 or the Memorial Sloan survival (OS).40-42 This information should be discussed with such patients
MS-3
Prostate Cancer
if they are considering active surveillance. Finally, there are possible mutation identified was high (28.6%, 2 of 7 patients). Although having a
treatment implications for patients with DNA repair defects (see Treatment relative with breast cancer was associated with germline mutation
Options for Patients with DNA Repair Gene Mutations, below). identification (P = .035), only 45.5% of the mutation carriers in the study
had mutations that were concordant with their personal and family history.
Prostate cancer is often associated with somatic mutations that occur in Another study also found that a family history of breast cancer increased
the tumor but not in the germline. An estimated 89% of metastatic the chances of identifying a germline DNA repair gene mutation in patients
castration-resistant prostate cancer (CRPC) tumors contain a potentially with prostate cancer (OR, 1.89; 95% CI, 1.33–2.68; P = .003).52 In a study
actionable mutation, with only about 9% of these occurring in the of an unselected cohort of 3607 patients with a personal history of prostate
germline.43 Both germline and tumor mutations are discussed herein. cancer who had germline genetic testing based on clinician referral, 11.5%
had germline mutations in BRCA2, CHEK2, ATM, BRCA1, or PALB2.53
Homologous DNA Repair Genes
Somatic mutations in DNA repair pathway genes occur in up to 19% of More than 2% of Ashkenazi Jews carry germline mutations in BRCA1 or
localized prostate tumors and 23% of metastatic CRPC tumors, with most BRCA2, and these carriers have a 16% chance (95% CI, 4%–30%) of
mutations found in BRCA2 and ATM.43,44 These tumor mutations are often developing prostate cancer by the age of 70.54 In a study of 251
associated with germline mutations. For example, 42% of patients with unselected Ashkenazi Jewish patients with prostate cancer, 5.2% had
metastatic CRPC and somatic mutations in BRCA2 were found to carry germline mutations in BRCA1 and BRCA2, compared with 1.9% of control
the mutation in their germlines.43 In localized prostate cancer, that number Ashkenazi Jewish males.55
was 60%.44
Germline BRCA1 or BRCA2 mutations have been associated with an
Overall, germline DNA repair mutations have been reported with the increased risk for prostate cancer in numerous reports.35,36,55-65 In
lowest frequencies seen in patients with lower-risk localized prostate particular, BRCA2 mutations have been associated with a 2- to 6-fold
cancer (1.6%–3.8%), higher frequencies in those with higher-risk localized increase in the risk for prostate cancer, whereas the association of BRCA1
disease (6%–8.9%), and the highest frequencies in those with metastatic mutations and increased risks for prostate cancer are less
disease (7.3%–16.2%).43,45-51 One study found that 11.8% of patients with consistent.35,36,55,57,59,64,66,67 In addition, limited data suggest that germline
metastatic prostate cancer have germline mutations in 1 of 16 DNA repair mutations in ATM, PALB2, and CHEK2 increase the risk of prostate
genes: BRCA2 (5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), cancer.68-71 Furthermore, prostate cancer in individuals with germline
RAD51D (0.4%), PALB2 (0.4%), ATR (0.3%), and NBN, PMS2, GEN1, BRCA mutations appears to occur earlier, has a more aggressive
MSH2, MSH6, RAD51C, MRE11A, BRIP1, or FAM175A.50 phenotype, and is associated with significantly reduced survival times than
in non-carrier patients.41,42,66,72-76
An additional study showed that 9 of 125 patients with high-risk, very-high-
risk, or metastatic prostate cancer (7.2%) had pathogenic germline
mutations in MUTYH (4), ATM (2), BRCA1 (1), BRCA2 (1), and BRIP1
(1).47 In this study, the rate of metastatic disease among those with a
MS-4
Prostate Cancer
DNA Mismatch Repair Genes cribriform component and would be missed without the use of basal cell
Tumor mutations in MLH1, MSH2, MSH6, and PMS2 may result in tumor markers.
microsatellite instability (MSI) and deficient MMR (dMMR; detected by
Limited data suggest that acinar prostate adenocarcinoma with invasive
immunohistochemistry) and are sometimes associated with germline
cribriform pattern, intraductal carcinoma of prostate (IDC-P), or ductal
mutations and Lynch syndrome. Patients with Lynch syndrome may have
adenocarcinoma component y have increased genomic instability.82-85 In
an increased risk for prostate cancer. In particular, studies show an
particular, tumors with these histologies may be more likely to harbor
increased risk for prostate cancer in patients who are older and have
somatic MMR gene alterations than those with adenocarcinoma
germline MSH2 mutations.77,78
histology.85-87 In addition, limited data suggest that germline homologous
In a study of more than 15,000 patients with cancer treated at Memorial DNA repair gene mutations may be more common in prostate tumors of
Sloan Kettering Cancer Center who had their tumor and matched normal ductal or intraductal origin88,89 and that intraductal histology is common in
DNA sequenced and tumor MSI status assessed, approximately 5% of germline BRCA2 mutation carriers with prostate cancer.90 Overall, the
1048 patients with prostate cancer had MSI-high (MSI-H) or MSI- panel believes that the data connecting histology and the presence of
indeterminate tumors, 5.6% of whom were found to have Lynch syndrome genomic alterations are stronger for intraductal than ductal histology at this
(0.29% of patients with prostate cancer).32 In another prospective case time. Therefore, patients with presence of intraductal carcinoma on biopsy
series, the tumors of 3.1% of 1033 patients with prostate cancer should have germline testing as described below.
demonstrated MSI-H/dMMR status, and 21.9% of these patients had
Genetic Testing Recommendations
Lynch syndrome (0.68% of the total population).79 In a study of an
Germline Testing Based on Family History, Histology, and Risk Groups
unselected cohort of 3607 patients with a personal history of prostate
cancer who had germline genetic testing based on clinician referral, 1.7% The panel recommends inquiring about family and personal history of
had germline mutations in PMS2, MLH1, MSH2, or MSH6.53 cancer and known germline variants at time of initial diagnosis. Germline
testing should be considered in appropriate individuals where it is likely to
Effect of Intraductal/Cribriform or Ductal Histology impact the prostate cancer treatment and clinical trial options,
Ductal prostate carcinomas are rare, accounting for approximately 1.3% of management of risk of other cancers, and/or potential risk of cancer in
prostate carcinomas.80 Intraductal prostate cancer may be more common, family members. Based on the data discussed above, the panel
especially in higher risk groups, and may be associated with a poor recommends germline genetic testing for patients with prostate cancer and
prognosis.81 It is important to note that there is significant overlap in any of the following38,39:
diagnostic criteria and that intraductal, ductal, and invasive cribriform • A positive family history (see definition in the guidelines above)
features may coexist in the same biopsy. By definition, intraductal • High-risk, very-high-risk, regional, or metastatic prostate cancer,
carcinoma includes cribriform proliferation of malignant cells as long as regardless of family history
they remain confined to a preexisting gland that is surrounded by basal • Ashkenazi Jewish ancestry
cells. These features are seen frequently with an adjacent invasive • A personal history of breast cancer
MS-5
Prostate Cancer
In addition, germline genetic testing should be considered in patients with CHEK2, CDK12) can be considered in patients with regional (N1)
a personal history of prostate cancer and 1) intermediate-risk prostate prostate cancer and is recommended for those with metastatic
cancer and intraductal/cribriform histology or 2) a personal history of disease.
exocrine pancreatic cancer, breast cancer, colorectal, gastric, melanoma, 2. Tumor testing for MSI or dMMR can be considered in patients with
pancreatic cancer, upper tract urothelial cancer, glioblastoma, biliary tract regional or metastatic castration-naïve prostate cancer and is
cancer, and small intestinal cancer. recommended in the metastatic CRPC setting.
3. Tumor mutational burden (TMB) testing may be considered in
Germline testing, when performed, should include MLH1, MSH2, MSH6, patients with metastatic CRPC.
and PMS2 (for Lynch syndrome) and the homologous recombination 4. Multigene molecular testing can be considered for patients with
genes BRCA1, BRCA2, ATM, PALB2, and CHEK2. Additional genes may low-, intermediate-, and high-risk prostate cancer and life
be appropriate depending on clinical context. For example, HOXB13 is a expectancy ≥10 years (see Tumor Multigene Molecular Testing,
prostate cancer risk gene and, whereas there are not currently clear below).
therapeutic implications in the advanced disease setting, testing may have 5. The Decipher molecular assay is recommended to inform adjuvant
utility for family counseling.91,92 treatment if adverse features are found post-radical prostatectomy,
and can be considered as part of counseling for risk stratification in
Genetic counseling resources and support are critical, and post-test
patients with PSA resistance/recurrence after radical
genetic counseling is recommended if a germline mutation (pathogenic
prostatectomy (category 2B). See Tumor Multigene Molecular
variant) is identified. Cascade testing for relatives is critical to inform the
Testing, below).
risk for familial cancers in all relatives. Post-test genetic counseling is
recommended if positive family history but no pathogenic variant OR if
The panel strongly recommends a metastatic biopsy for histologic and
only germline variants of unknown significance (VUS) are identified. This
molecular evaluation. When unsafe or unfeasible, plasma ctDNA assay is
is to ensure accurate understanding of family implications and review
an option, preferably collected during biochemical (PSA) and/or
indications for additional testing and/or follow up (including clinical trials of
radiographic progression in order to maximize diagnostic yield. Caution is
reclassification). Resources are available to check the known pathologic
needed when interpreting ctDNA-only evaluation due to potential
effects of genomic variants (eg, https://brcaexchange.org/about/app;
interference from clonal hematopoiesis of indeterminate potential (CHIP),
https://www.ncbi.nlm.nih.gov/clinvar/). Information regarding germline
which can result in a false-positive biomarker signal.93
mutations in patients with metastatic disease can be used to inform future
treatments or to determine eligibility for clinical trials. If MSI testing is performed, testing using an NGS assay validated for
prostate cancer is preferred.94-96 If MSI-H or dMMR is found, the patient
Somatic Tumor Testing Based on Risk Groups
should be referred for genetic counseling to assess for the possibility of
Tumor testing recommendations are as follows:
Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab for
1. Tumor testing for somatic homologous recombination gene
certain patients with metastatic CRPC (see Pembrolizumab, below).
mutations (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D,
MS-6
Prostate Cancer
Post-test genetic counseling is recommended if pathogenic/likely There are newer risk classification schemas that have been shown to
pathogenic somatic mutations in any gene that has clinical implications if outperform NCCN risk groups,97,98 as well as tools (ie, imaging, gene
also identified in germline (eg, BRCA1, BRCA2, ATM, PALB2, CHEK2, expression biomarkers, germline testing) that together improve risk
MLH1, MSH2, MSH6, PMS2). Post-test genetic counseling to assess for stratification. These tools should not be ordered reflexively. They are
the possibility of Lynch syndrome is recommended if MSI-H or dMMR is recommended only when they will have the ability to change management
found. Virtually none of the NGS tests is designed or validated for (eg, active surveillance vs. radical treatment). Improved risk stratification
germline assessment. Therefore, over-interpretation of germline findings can better identify patients who may derive greater or lesser absolute
should be avoided. If a germline mutation is suspected, the patient should benefit from a given treatment.
be recommended for genetic counseling and follow-up dedicated germline
testing. NCCN Risk Groups
The NCCN Guidelines have, for many years, incorporated a risk
Additional Testing stratification scheme that uses a minimum of stage, Gleason grade, and
Tumors from a majority of patients with metastatic CRPC harbor mutations PSA to assign patients to risk groups. These risk groups are used to select
in genes involved in the androgen receptor signaling pathway.43 Androgen the appropriate options that should be considered and to predict the
receptor splice variant 7 (AR-V7) testing in circulating tumor cells (CTCs) probability of biochemical recurrence after definitive local therapy.99 Risk
can be considered to help guide selection of therapy in the post- group stratification has been published widely and validated, and provides
abiraterone/enzalutamide metastatic CRPC setting (discussed in more a better basis for treatment recommendations than clinical stage
detail below, under AR-V7 Testing). alone.100,101
Risk Stratification for Clinically Localized Disease A new prostate cancer grading system was developed during the 2014
Optimal treatment of prostate cancer requires estimation of risk: How likely International Society of Urological Pathology (ISUP) Consensus
is a given cancer to be confined to the prostate or spread to the regional Conference.102 Several changes were made to the assignment of Gleason
lymph nodes? How likely is the cancer to progress or metastasize after pattern based on pathology. The new system assigns Grade Groups from
treatment? How likely is adjuvant or post-recurrence radiation to control 1 to 5, derived from the Gleason score.
cancer after an unsuccessful radical prostatectomy? • Grade Group 1: Gleason score ≤6; only individual discrete well-
formed glands
NCCN and other risk classification schemas are prognostic and have not • Grade Group 2: Gleason score 3+4=7; predominantly well-formed
been shown to be predictive of benefit to a specific treatment. Thus,
glands with lesser component of poorly formed/fused/cribriform
recommendations of when to offer conservative management versus
glands
radical therapy and the use of short-term versus long-term ADT are based
• Grade Group 3: Gleason score 4+3=7; predominantly poorly
on expert opinion and estimates of absolute benefit and harm from a given
formed/fused/cribriform glands with lesser component of well-
therapy in the context of NCCN risk groups.
formed glands
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Prostate Cancer
o
For cases with >95% poorly formed/fused/cribriform glands the higher risk groups. In another study of the new ISUP Grade Group
or lack of glands on a core or at radical prostatectomy, the system, all-cause mortality and prostate cancer-specific mortality were
component of <5% well-formed glands is not factored into higher in patients in Grade Group 5 than in those in Grade Group 4.105
the grade. Additional studies have supported the validity of this new system.106-111 The
• Grade Group 4: Gleason score 4+4=8; 3+5=8; 5+3=8 NCCN Panel has accepted the new Grade Group system to inform better
o Only poorly formed/fused/cribriform glands; or treatment discussions compared to those using Gleason score. Patients
o Predominantly well-formed glands and lesser component remain divided into very-low-, low-, intermediate-, high-, and very-high-risk
lacking glands (poorly formed/fused/cribriform glands can groups.
be a more minor component); or
o Predominantly lacking glands and lesser component of The NCCN Guidelines Panel recognized that heterogeneity exists within
well-formed glands (poorly formed/fused/cribriform glands each risk group. For example, an analysis of 12,821 patients showed that
can be a more minor component) those assigned to the intermediate-risk group by clinical stage (T2b–T2c)
• Grade Group 5: Gleason score 9–10; lack gland formation (or with had a lower risk of recurrence than those categorized according to
necrosis) with or without poorly formed/fused/cribriform glands Gleason score (7) or PSA level (10–20 ng/mL).112 A similar trend of
o For cases with >95% poorly formed/fused/cribriform glands superior recurrence-free survival was observed in patients placed in the
or lack of glands on a core or at radical prostatectomy, the high-risk group by clinical stage (T3a) compared to those assigned by
component of <5% well-formed glands is not factored into Gleason score (8–10) or PSA level (>20 ng/mL), although it did not reach
the grade. statistical significance. Other studies have reported differences in
outcomes in the high-risk group depending on risk factors or primary
Many experts believe that ISUP Grade Groups will enable patients to Gleason pattern.113,114 Evidence also shows heterogeneity in the low-risk
better understand their true risk level and thereby limit overtreatment. The group, with PSA levels and percent positive cores affecting pathologic
new Grade Group system was validated in two separate cohorts, one of findings after radical prostatectomy.115,116
>26,000 patients and one of 5880 patients, treated for prostate cancer
with either radical prostatectomy or radiation.103,104 Both studies found that In a retrospective study, 1024 patients with intermediate-risk prostate
Grade Groups predicted the risk of recurrence after primary treatment. For cancer were treated with radiation with or without neoadjuvant and
instance, in the larger study, the 5-year biochemical recurrence-free concurrent ADT.117 Multivariate analysis revealed that primary Gleason
progression probabilities after radical prostatectomy for Grade Groups 1 pattern 4, number of positive biopsy cores ≥50%, and presence of >1
through 5 were 96% (95% CI, 95–96), 88% (95% CI, 85–89), 63% (95% intermediate-risk factors (IRFs; ie, T2b-c, PSA 10–20 ng/mL, Gleason
CI, 61–65), 48% (95% CI, 44–52), and 26% (95% CI, 23–30), respectively. score 7) were significant predictors of increased incidence of distant
The separation between Grade Groups was less pronounced in the metastasis. The authors used these factors to separate the patients into
radiation therapy (RT) cohort, likely because of increased use of unfavorable and favorable intermediate-risk groups and determined that
neoadjuvant/concurrent/adjuvant androgen deprivation therapy (ADT) in the unfavorable intermediate-risk group had worse PSA recurrence-free
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Prostate Cancer
survival and higher rates of distant metastasis and prostate cancer- evidence of distant metastases or to die from prostate cancer. Those with
specific mortality than the favorable intermediate-risk group. The use of a short PSA doubling time (PSADT) are at greatest risk of death. Not all
active surveillance in patients with favorable intermediate-risk prostate PSA recurrences are clinically relevant; thus, PSADT may be a more
cancer is discussed below (see Active Surveillance in Favorable useful measure of risk of death.149 The NCCN Guidelines Panel
Intermediate Risk). The NCCN Panel has included the separation of recommends that NCCN risk groups be used to begin the discussion of
intermediate risk group into favorable and unfavorable subsets in their risk options for the treatment of clinically localized prostate cancer and that
stratification scheme. nomograms be used to provide additional and more individualized
information.
Nomograms
The more clinically relevant information that is used in the calculation of Tumor Multigene Molecular Testing
time to PSA recurrence, the more accurate the result. A nomogram is a Personalized or precision medicine is a goal for many translational and
predictive instrument that takes a set of input data (variables) and makes clinical investigators. Molecular testing of a tumor offers the potential of
predictions about an outcome. Nomograms predict more accurately for the added insight into the “biologic behavior” of a cancer that could thereby aid
individual patient than risk groups, because they combine the relevant in the clinical decision-making. The NCCN Prostate Cancer Guidelines
prognostic variables. The Partin tables were the first to achieve Panel strongly advocates for use of life expectancy estimation,
widespread use for counseling patients with clinically localized prostate nomograms, and other clinical parameters such as PSA density as the
cancer.118-121 The tables give the probability (95% CI) that a patient with a foundations for augmented clinical decision-making. Whereas risk groups,
certain clinical stage, Gleason score, and PSA will have a cancer of each life expectancy estimates, and nomograms help inform decisions,
pathologic stage. Nomograms can be used to inform treatment decision- uncertainty about disease progression persists, and this is where the
making for patients contemplating active surveillance,122-124 radical prognostic multigene molecular testing can have a role.
prostatectomy,125-128 neurovascular bundle preservation129-131 or omission of
pelvic lymph node dissection (PLND) during radical prostatectomy,132-135 Several tissue-based molecular assays have been developed in an effort
brachytherapy,125,136-138 or external beam RT (EBRT).125,139 Biochemical to improve decision-making in newly diagnosed patients considering active
progression-free survival (PFS) can be reassessed postoperatively using surveillance and in treated patients considering adjuvant therapy or
age, diagnostic serum PSA, and pathologic grade and stage.125,140-142 treatment for recurrence. Uncertainty about the risk of disease progression
Potential success of adjuvant or post-recurrence RT after unsuccessful can be reduced if such molecular assays can provide accurate and
radical prostatectomy can be assessed using a nomogram.125,143 reproducible prognostic or predictive information beyond NCCN risk group
assignment and currently available life expectancy tables and nomograms.
None of the current models predicts with perfect accuracy, and only some Retrospective case cohort studies have shown that these assays provide
of these models predict metastasis124,125,140,144,145 and cancer-specific prognostic information independent of NCCN or CAPRA risk groups,
death.126,128,146-148 Given the competing causes of mortality, many patients which include likelihood of death with conservative management,
who sustain PSA recurrence will not live long enough to develop clinical likelihood of biochemical recurrence after radical prostatectomy or EBRT,
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Prostate Cancer
likelihood of adverse pathologic features after radical prostatectomy, and be used to inform adjuvant treatment if adverse features are found post-
likelihood of developing metastasis after operation, definitive EBRT, or radical prostatectomy.
post-recurrence EBRT.150-162 Evaluation of diagnostic biopsy tissue from
patients enrolled in the Canary PASS multicenter active surveillance Several of these assays are available, and four have received positive
cohort suggested that results of a molecular assay were not associated reviews by the Molecular Diagnostic Services Program (MolDX) and are
with adverse pathology either alone or in combination with clinical likely to be covered by CMS (Centers for Medicare & Medicaid Services).
variables.163 Several other tests are under development, and the use of these assays is
likely to increase in the coming years.
Clinical utility studies on the tissue-based molecular assays have also
been performed.164-166 One prospective, clinical utility study of 3966 Table 1 lists these tests in alphabetical order and provides an overview of
patients newly diagnosed with localized prostate cancer found that the each test, populations where each test independently predicts outcome,
rates of active surveillance increased with use of a tissue-based gene and supporting references. These molecular biomarker tests have been
expression classifier.164 Active surveillance rates were 46.2%, 75.9%, and developed with extensive industry support, guidance, and involvement,
57.9% for those whose classifier results were above the specified and have been marketed under the less rigorous FDA regulatory pathway
threshold, those whose classifier results were below the threshold, and for biomarkers. Although full assessment of their clinical utility requires
those who did not undergo genomic testing, respectively (P < .001). The prospective randomized clinical trials, which are unlikely to be done, the
authors estimate that one additional patient may choose active panel believes that patients with low or favorable intermediate disease and
surveillance for every nine patients with favorable-risk prostate cancer who life expectancy greater than or equal to 10 years may consider the use of
undergo genomic testing. Decipher, Oncotype DX Prostate, or Prolaris during initial risk stratification.
Patients with unfavorable intermediate- and high-risk disease and life
Another clinical utility study used two prospective registries of patients with expectancy greater than or equal to 10 years may consider the use of
prostate cancer post-radical prostatectomy (n = 3455).165 Results of Decipher or Prolaris. In addition, Decipher may be considered to inform
molecular testing with Decipher changed management recommendations adjuvant treatment if adverse features are found after radical
for 39% of patients. This study also evaluated clinical benefit in 102 prostatectomy and during workup for radical prostatectomy PSA
patients. Those who were classified as high risk by the assay had persistence or recurrence (category 2B for the latter setting). Future
significantly different 2-year PSA recurrence rates if they received comparative effectiveness research may allow these tests and others like
adjuvant EBRT versus if they did not (3% vs. 25%; hazard ratio [HR], 0.1; them to gain additional evidence regarding their utility for better risk
95% CI, 0.0–0.6; P = .013). No differences in 2-year PSA recurrence were stratification of patients with prostate cancer.
observed between those who did and did not receive adjuvant therapy in
those classified as low or intermediate risk by the assay. Based on these Initial Clinical Assessment and Staging Evaluation
results, the panel recommends that the Decipher molecular assay should For patients with very-low-, low-, and intermediate-risk prostate cancer
and a life expectancy of 5 years or less and without clinical symptoms,
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Prostate Cancer
further imaging and treatment should be delayed until symptoms develop, Retrospective evidence suggests that Gleason score and PSA levels are
at which time imaging can be performed and ADT should be given. Those associated with positive bone scan findings.167 Multivariate analysis of
with a life expectancy less than or equal to 5 years who fall into the high- retrospective data on 643 patients with newly diagnosed prostate cancer
or very-high-risk categories should undergo bone imaging and, if indicated who underwent staging CT found that PSA, Gleason score, and clinical T
by nomogram prediction of lymph node involvement, pelvic +/- abdominal stage were associated independently with a positive finding (P < .05 for
imaging. all).168 mpMRI may detect large and poorly differentiated prostate cancer
(Grade Group ≥2) and detect extracapsular extension (T staging) and is
For symptomatic patients and/or those with a life expectancy of greater preferred over CT for abdominal/pelvic staging. mpMRI has been shown to
than 5 years, bone and soft tissue imaging is appropriate for patients with be equivalent to CT scan for pelvic lymph node evaluation.
unfavorable intermediate-risk, high-risk, and very-high-risk prostate
cancer: See Imaging Techniques below for a more detailed discussion.
• Bone imaging can be achieved by conventional technetium-99m-
MDP bone scan. Imaging Techniques
o Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 Imaging techniques are useful for staging and for detecting metastases
sodium fluoride, C-11 choline, F-18 fluciclovine, Ga-68 and tumor recurrence. Current clinical imaging techniques for prostate
prostate-specific membrane antigen (PSMA)-11, or F-18 cancer include conventional radiography (ie, x-rays), ultrasound, CT, MRI,
piflufolastat PSMA can be considered for equivocal results single photon emission computed tomography (SPECT, scintigraphy), and
on initial bone imaging. PET. Some of these modalities have the ability to assess both anatomy
• Soft tissue imaging of the pelvis, abdomen, and chest can include and tumor function/biology. For example, functional MR sequences can be
chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. added to conventional anatomic MR sequences in a clinical examination
mpMRI is preferred over CT for pelvic staging. such as diffusion-weighted imaging (DWI) to assess tumor cellularity or
• Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT MR spectroscopy (MRS) to assess tumor metabolism.
or PET/MRI can be considered for bone and soft tissue (full body)
Different modalities can also be merged to maximize prostate cancer
imaging.
assessment. For example, the functional information obtained with PET
o Because of the increased sensitivity and specificity of
can be combined with the spatial and anatomic information with either CT
PSMA-PET tracers for detecting micrometastatic disease
(ie, PET/CT) or MRI (ie, PET/MRI) to inform about the locations of tumor
compared to conventional imaging (CT, MRI) at both initial
foci for diagnosis or therapy response. Another example of the advantage
staging and biochemical recurrence, the Panel does not
of combining modalities is MR-ultrasound fusion guided biopsy (eg, MR-
feel that conventional imaging is a necessary prerequisite
TRUS) where MRI datasets containing information on suspicious lesions
to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI
identified by the radiologist are used by the urologist to navigate
can serve as an equally effective, if not more effective front-
ultrasound-guided biopsies of the prostate for more accurate diagnosis.169
line imaging tool for these patients.
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Prostate Cancer
More details on each technique are outlined in the algorithm under biopsy cores, while reducing detection of low-grade and insignificant
Principles of Imaging. cancers.173-175 In fact, a recently published clinical study identified that MRI-
targeted biopsy synergized with conventional systematic biopsy to identify
Multiparametric MRI (mpMRI) more clinically significant cancers.176 Second, mpMRI aids in better
The use of mpMRI in the staging and characterization of prostate cancer assessment of extracapsular extension (T staging), with high negative
has increased in the last few years. mpMRI examinations typically include predictive values (NPVs) in patients with low-risk disease.177 mpMRI
three sequences: T2-weighted imaging, DWI, and dynamic contrast results may inform decision-making regarding nerve-sparing operation.178
enhancement (DCE) imaging. There has been increased interest in Third, mpMRI is equivalent to CT scan for staging of pelvic lymph
biparametric imaging that excludes the use of gadolinium contrast in nodes.179,180 Finally, mpMRI outperforms bone scan and targeted x-rays for
prostate MRI examinations; however, more data are needed to identify the detection of bone metastases, with a sensitivity of 98% to 100% and
risk groups who would benefit most from this approach.170 In general, it is specificity of 98% to 100% (vs. sensitivity of 86% and specificity of 98%–
recommended that mpMRI be performed on a 3 Tesla (3T) magnetic 100% for bone scan plus targeted x-rays).181
strength MRI scanner. This is the highest strength scanner in routine
clinical use and provides the best possible evaluation of prostate cancer. PET Imaging
The use of PET/CT or PET/MRI imaging using tracers other than F-18
Additional instrumentation can be used, such as an endorectal coil (ERC) fluorodeoxyglucose (FDG) for staging of small-volume recurrent or
to improve image quality. If a lower strength 1.5T MRI cancer is required metastatic prostate cancer has rapidly expanded in recent years.169
for a patient because of indwelling medical device incompatibility with 3T Currently, there are five PET tracers that are FDA approved for use in
MRI, an ERC is recommended. Use of ERC in routine prostate imaging is patients with prostate cancer: Ga-68 PSMA-11 (PSMA-HBED-CC), F-18
controversial. Current data suggest that a 3T exam with ERC may not be piflufolastat (DCFPyL), C-11 choline, F-18 fluciclovine, and F-18 sodium
significantly better than a 3T exam without ERC. Moreover, there may not fluoride. Although these tracers are approved for the evaluation of patients
be a significant difference in image interpretation between a 1.5T with with biochemical recurrence, the PSMA tracers Ga-68 PSMA-11 and F-18
ERC and 3T without ERC.171 The use of ERC in prostate MRI also piflufolastat are also approved for patients at initial staging with suspected
introduces new problems into the clinical workflow including patient metastatic disease. Tracer distribution in patients with prostate cancer can
discomfort, prostate distortion, increased scanner time and expense, and be imaged with either PET/CT or PET/MRI modalities. Although CT and
requirement of someone experienced to place the ERC. MRI are equivalent in the assessment of lymphadenopathy, PET/MRI has
the added advantage over PET/CT with enhanced tissue contrast that is
Evidence supports the implementation of mpMRI in several aspects of
especially important in evaluation of pelvic anatomy and prostate cancer
prostate cancer management.169 First, mpMRI helps detect larger and/or
assessment. Table 2 summarizes the FDA-cleared PET imaging tracers
more poorly differentiated cancers (ie, Grade Group ≥2).172 mpMRI has
studied in prostate cancer. F-18 FDG PET should not be used routinely,
been incorporated into MRI-TRUS fusion-targeted biopsy protocols, which
because data are limited in patients with prostate cancer and suggest that
has led to an increase in the diagnosis of high-grade cancers with fewer
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Prostate Cancer
its sensitivity is significantly lower than that seen with the above described level PPV validated by anatomic lesion co-localization) for piflufolastat
tracers.182-184 PET/CT is 85% to 87%.198 Thus, PSMA-11 and piflufolastat are considered
equivalent. Because of the increased sensitivity and specificity of PSMA
PSMA-PET refers to a growing body of radiopharmaceuticals that target PET tracers for detecting micrometastatic disease compared to
prostate specific membrane antigen (PSMA) on the surface of prostate conventional imaging (CT, MRI) at both initial staging and biochemical
cells. Because of the high density of PSMA receptors on the surface of recurrence, the Panel does not feel that conventional imaging is a
cancer cells relative to adjacent prostate, PSMA-PET has the advantage necessary prerequisite to PSMA-PET and that PSMA PET/CT or PSMA-
of high signal-to-noise relative to adjacent tissues. The mechanistic role of PET/MRI can serve as an equally effective, if not more effective front-line
androgen receptor signaling in PSMA regulation is still being investigated, imaging tool for these patients.
as multiple reports in animals and humans suggest that androgen
modulation can affect PSMA expression and may even be dichotomous in PET/CT or PET/MRI detect small-volume disease in bone and soft
patients with castration-naïve versus castrate-resistant disease.185-187 tissues.199,200 The reported sensitivity and specificity of C-11 choline
There are multiple PSMA radiopharmaceuticals at various stages of PET/CT in restaging patients with biochemical recurrence ranges from
investigation. At this time, the NCCN Guidelines only recommend two 32% to 93% and from 40% to 93%, respectively.201-210 The reported
PSMA tracers: the currently FDA-approved PSMA agents, F-18 sensitivity and specificity of F-18 fluciclovine PET/CT ranges from 37% to
piflufolastat and Ga-68 PSMA-11. F-18 piflufolastat PSMA or Ga-68 90% and from 40% to 100%, respectively.207,211,212 A prospective study
PSMA-11 PET/CT or PET/MRI can be considered as an alternative to compared F-18 fluciclovine and C-11 choline PET/CT scans in 89 patients,
standard imaging of bone and soft tissue for initial staging, the detection of and agreement was 85%.207 Thus, choline and fluciclovine are considered
biochemically recurrent disease, and as workup for progression with bone equivalent in the evaluation of patients with biochemical recurrence. The
scan plus CT or MRI for the evaluation of bone, pelvis, and abdomen. panel believes that F-18 fluciclovine PET/CT or PET/MRI or C-11 choline
PET/CT or PET/MRI may be used in patients with biochemical recurrence
Studies suggest that PSMA PET imaging has a higher sensitivity than C- after primary treatment for further soft tissue and/or bone evaluation after
11 choline or F-18 fluciclovine PET imaging, especially at very low PSA bone scan, chest CT, and abdominal/pelvic CT or abdominal/pelvic MRI.
levels.188-193 The reported sensitivity and specificity for PSMA-11 PET/CT in
the detection of nodal involvement in primary staging of patients with The use of these PET tracers can lead to changes in clinical management.
intermediate-, high-, and very-high-risk disease is 40% and 95%, The FALCON trial showed that results of F-18 fluciclovine PET/CT in 104
respectively.194 The patient-level positive predictive value (PPV) in patients with biochemical recurrence after definitive therapy resulted in a
detection of lesions in patients with BCR is 92%.195 Similarly, the reported change in management for 64%.213 In addition, the LOCATE trial
sensitivity and specificity for piflufolastat PET/CT in the detection of nodal demonstrated that fluciclovine frequently changed management plans in
involvement in primary staging of patients with unfavorable intermediate-, patients with biochemical recurrence.214 In a similar fashion, data also
high-, and very-high-risk disease is 31% to 42% and 96% to 99%, show that PSMA PET has the ability to change radiation treatment
respectively.196,197 The patient-level correct localization rate (CLR; patient- planning in 53% (N = 45) of patients with high- and very-high-risk prostate
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Prostate Cancer
cancer using PSMA-11 as well as change management in over half of a result in earlier use of newer and more expensive therapies, which may
prospective cohort of 635 patients with BCR.215,216 However, whether not improve oncologic outcomes or OS.
changes to treatment planning because of PET tracers have an impact on
long-term survival remains to be studied. Risks of Imaging
As with any medical procedure, imaging is not without risk. Some of these
F-18 sodium fluoride targets osteoblast activity where the fluoride is risks are concrete and tangible, while others are less clear. Risks
deposited into new bone formation, thus limiting use of this agent to the associated with imaging include exposure to ionizing radiation, adverse
detection of osseous metastases. Fluoride PET/CT has greater sensitivity reaction to contrast media, false-positive scans, and overdetection.
than standard bone scintigraphy in the detection of bone metastases, with
77% to 94% sensitivity, 92% to 99% specificity, and 82% to 97% PPV.217 Exposure to Ionizing Radiation
However, emerging evidence indicates that other tracers such as PSMA Deterministic and stochastic are two types of effects from exposure to
are at least equivalent to fluoride in the detection of osseous metastases ionizing radiation by x-ray, CT, or PET/CT. Deterministic effects are those
with the added advantage of soft tissue metastasis detection.218 that occur at a certain dose level, and include events such as cataracts
and radiation burns. No effect is seen below the dose threshold. Medical
The Panel believes that bone imaging can be achieved by conventional imaging is always performed almost below the threshold for deterministic
technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or effects. Stochastic effects tend to occur late, increase in likelihood as dose
PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine, Ga-68 increases, and have no known lower “safe” limit. The major stochastic
PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal effect of concern in medical imaging is radiation-induced malignancy.
results on initial bone imaging. Alternatively, Ga-68 PSMA-11 or F-18 Unfortunately, no direct measurements are available to determine risk of
piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and cancer arising from one or more medical imaging events, so risks are
soft tissue (full body) imaging. 219-222 calculated using other models (such as from survivors of radiation
exposure). The literature is conflicting with regard to the precise risk of
Histologic or radiographic confirmation of involvement detected by PET
secondary malignancies in patients undergoing medical imaging
imaging is recommended whenever feasible due to the presence of false
procedures. There is a small but finite risk of developing secondary
positives. Although false positives exist, literature suggests that these are
malignancies as a result of medical imaging procedures, and the risk is
outweighed by the increase in true positives detected by PET relative to
greatest in young patients. However, the absolute risk of fatal malignancy
bone scintigraphy. To reduce the false-positive rate, physicians should
arising from a medical imaging procedure is very low, and is difficult to
consider the intensity of PSMA-PET uptake and correlative CT findings in
detect given the prevalence of cancer in the population and the multiple
the interpretation of scans. Several reporting systems have been proposed
factors that contribute to oncogenesis.225 Efforts should be made to
but will not have been validated or widely used.223,224 Moreover, although
minimize dose from these procedures, which begin with judicious use of
PET imaging may change treatment,214 it may not change oncologic
imaging only when justified by the clinical situation. Harm may arise from
outcome. Earlier detection of bone metastatic disease, for instance, may
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Prostate Cancer
not imaging a patient, through disease non-detection, or from erroneous Accurate and medically relevant interpretation of imaging studies requires
staging. familiarity and expertise in the imaging modality, attention to detail in
image review, knowledge of tumor biology, and familiarity with treatment
Adverse Reaction to Contrast Media
options and algorithms. Challenging cases are best addressed through
Many imaging studies make use of contrast material delivered by oral, direct communication, either physician-to-physician or in a multidisciplinary
intravenous, or rectal routes. The use of contrast material may improve tumor board setting.
study performance, but reactions to contrast material may occur and they
should be used only when warranted. Some patients develop adverse Medical imaging is a critical tool in the evaluation and management of
reactions to iodinated intravenous contrast material. Most reactions are patients with malignancy. However, as with any medical procedure,
mild cutaneous reactions (eg, urticaria, pruritus) but occasionally severe imaging is not without risks to patients. Inappropriate use of imaging also
reactions can be life-threatening (bronchospasm or anaphylaxis). The risk has been identified as a significant contributor to health care costs in the
of severe reaction is low with non-ionic contrast materials.226 Both United States and worldwide. Therefore, imaging should be performed
iodinated CT contrast material and gadolinium-based MR contrast only when medically appropriate, and in a manner that reduces risk (eg,
materials can be problematic in patients with reduced renal function. minimizing radiation dose). An algorithmic approach to the use of imaging,
Gadolinium MR contrast media, in particular, is contraindicated in patients such as by NCCN and the Appropriateness Criteria developed by the
with acute renal failure or stage V chronic kidney disease (glomerular American College of Radiology,228 can assist in medical decision-making.
filtration rate [GFR] <15).227 Patients in this category are significantly more
likely to develop nephrogenic systemic fibrosis (NSF). Centers performing Observation
imaging studies with contrast materials should have policies in place to Observation involves monitoring the course of prostate cancer with a
address the use of contrast in these patients. history and physical exam no more often than every 12 months (without
surveillance biopsies) until symptoms develop or are thought to be
False-Positive Scans and Overdetection
imminent. If patients under observation become symptomatic, an
Every imaging test has limitations for sensitivity, specificity, and accuracy
assessment of disease burden can be performed, and treatment or
that involve both the nature of the imaging modality as well as the
palliation can be considered. Observation thus differs from active
interpreting physician. Harm can arise when a tumor or tumor recurrence
surveillance. The goal of observation is to maintain QOL by avoiding
is not detected (ie, false negative), but harm to the patient and added
noncurative treatment when prostate cancer is unlikely to cause mortality
expense to the medical system also can result from false-positive scans.
or significant morbidity. The main advantage of observation is avoidance
Extensive workup of imaging findings that may otherwise be benign or
of possible side effects of unnecessary definitive therapy or ADT.
indolent (ie, overdetection) can lead to significant patient anxiety,
However, patients may develop urinary retention or pathologic fracture
additional and unnecessary imaging, and invasive procedures that carry
without prior symptoms or increasing PSA level.
their own risks for adverse outcomes.
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Prostate Cancer
Observation is applicable to patients who are older or frail with comorbidity patients identified only 8 prostate cancer deaths and 5 cases of
that will likely out-compete prostate cancer for cause of death. Johansson metastasis.241
and colleagues229 observed that only 13% of patients developed
metastases 15 years after diagnosis of T0–T2 disease and only 11% had Further, the ProtecT study, which randomized 1643 patients with localized
died from prostate cancer. Because prostate cancer will not be treated for prostate cancer to active surveillance, radical prostatectomy, or RT, found
cure for patients with shorter life expectancies, observation for as long as no significant difference in the primary outcome of prostate cancer
possible is a reasonable option based on physician discretion. Monitoring mortality at a median of 10 years follow-up.242 Of 17 prostate cancer
should include PSA and physical exam no more often than every 6 deaths (1% of study participants), 8 were in the active surveillance group,
months, but will not involve surveillance biopsies or radiographic imaging. 5 were in the operation group, and 4 were in the radiation group (P = .48
When symptoms develop or are imminent, patients can begin palliative for the overall comparison). However, a 12.2% absolute increase in the
ADT. rate of disease progression and a 3.4% absolute increase in the rate of
metastases or prostate cancer death were seen in the active surveillance
Active Surveillance group.242,243 Approximately 23% of participants had Gleason scores 7–10,
Active surveillance (formerly referred to as watchful waiting, expectant and 5 of 8 deaths in the active surveillance group were in this subset.
management, or deferred treatment) involves actively monitoring the Patient-reported outcomes were compared among the 3 groups.244 The
course of the disease with the expectation to deliver curative therapy if the operation group experienced the greatest negative effect on sexual
cancer progresses. Unlike observation, active surveillance is mainly function and urinary continence, whereas bowel function was worst in the
applicable to younger patients with seemingly indolent cancer with the radiation group.
goal to defer or avoid treatment and its potential side effects. Because
In addition, studies have shown that active surveillance does not adversely
these patients have a longer life expectancy, they should be followed
impact psychological well-being or QOL.244-249
closely and treatment should start promptly should the cancer progress so
as not to miss the chance for cure. The proportion of patients with low-risk prostate cancer choosing active
surveillance in the Veterans Affairs Integrated Health Care System
Several large active surveillance cohort studies have shown that between
increased from 2005 to 2015: from 4% to 39% of those younger than 65
50% and 68% of those eligible for active surveillance may safely avoid
years and from 3% to 41% of those ≥65 years.250 An analysis of the SEER
treatment, and thus the possible associated side effects of treatment, for
database found a similar trend, with the use of active surveillance in
at least 10 years.230-232 For example, in one study, 55% of the population
patients with low-risk prostate cancer increasing from 14.5% in 2010 to
remained untreated at 15 years.231 Although a proportion of patients on
42.1% in 2015.251 An international, hospital-based, retrospective analysis
active surveillance will eventually undergo treatment, the delay does not
of greater than 115,000 patients with low-risk prostate cancer reported that
appear to impact cure rates, and numerous studies have shown that active
active surveillance utilization increased, but the proportions were lower at
surveillance can be a safe option for many patients.230-240 In fact, a 2015
7% in 2010 and 20% in 2014.252
meta-analysis of 26 active surveillance cohort studies that included 7627
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Ultimately, a recommendation for active surveillance must be based on cancer255,256 or 100 patients with low-risk prostate cancer257 to prevent one
careful individualized weighing of a number of factors: life expectancy, death from the disease. The controversy regarding overtreatment of
general health condition, disease characteristics, potential side effects of prostate cancer and the value of prostate cancer early detection 255-261 has
treatment, and patient preference. Shared decision-making, after been further informed by publication of the Goteborg study, a subset of the
appropriate counseling on the risks and benefits of the various options, is European Randomized Study of Screening for Prostate Cancer
critical. (ERSPC).262,263 Many believe that this study best approximates proper use
of PSA for early detection because it was population-based and involved a
The panel believes there is an urgent need for further clinical research 1:1 randomization of 20,000 participants who received PSA every 2 years
regarding the criteria for recommending active surveillance, the criteria for and used thresholds for prostate biopsy of PSA >3 and >2.5 since 2005.
reclassification on active surveillance, and the schedule for active The 14-year follow-up reported in 2010 was longer than the European
surveillance especially as it pertains to prostate biopsies, which pose an study as a whole (9 years) and the Prostate, Lung, Colorectal, and
increasing burden. One important ongoing study that can help answer Ovarian (PLCO) trial (11.5 years). Prostate cancer was diagnosed in
these questions is the prospective multi-institutional Canary PASS cohort 12.7% of the screened group compared to 8.2% of the control group.
study, which has been funded by the NCI.237 Nine hundred five patients, Prostate cancer mortality was 0.5% in the screened group and 0.9% in the
median age 63 years and median follow-up 28 months, demonstrated 19% control group, which gave a 40% absolute cumulative risk reduction of
conversion to therapy. Much should be learned about the criteria for prostate cancer death (compared to ERSPC 20% and PLCO 0%).262 Most
selection of and progression on active surveillance as this cohort and impressively, 40% of the patients were initially managed using active
research effort mature. surveillance and 28% were still on active surveillance at the time these
results were analyzed. To prevent a prostate cancer death, 12 individuals
Rationale
would need to be diagnosed and treated as opposed to the ERSPC as a
The NCCN Guidelines Panel remains concerned about the problems of whole where 37 individuals needed to be treated. Analysis of 18-year
overtreatment related to the increased frequency of diagnosis of prostate follow-up data from the Goteborg study reduced the number needed to be
cancer from widespread use of PSA for early detection or screening (see diagnosed to prevent 1 prostate cancer death to 10.264 Thus, early
the NCCN Guidelines for Prostate Cancer Early Detection, available at detection, when applied properly, should reduce prostate cancer mortality.
www.NCCN.org). However, that reduction comes at the expense of overtreatment that may
occur in as many as 50% of patients treated for PSA-detected prostate
The debate about the need to diagnose and treat every individual who has
cancer.265
prostate cancer is fueled by the high prevalence of prostate cancer upon
autopsy of the prostate253; the high frequency of positive prostate biopsies The best models of prostate cancer detection and progression estimate
in individuals with normal DREs and serum PSA values254; the contrast that 23% to 42% of all U.S. screen-detected cancers were overtreated266
between the incidence and mortality rates of prostate cancer; and the and that PSA detection was responsible for up to 12.3 years of lead-time
need to treat an estimated 37 patients with screen-detected prostate bias.267 The NCCN Guidelines Panel responded to these evolving data
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with careful consideration of which patients should be recommended Active Surveillance in Low-Risk Disease
active surveillance. However, the NCCN Guidelines Panel recognizes the Panel consensus is that active surveillance is preferred for most patients
uncertainty associated with the estimation of chance of competing causes with low-risk prostate cancer and a life expectancy greater than or equal to
of death; the definition of very-low-, low-, and favorable intermediate-risk 10 years. However, the panel recognizes that there is heterogeneity
prostate cancer; the ability to detect disease progression without across the low-risk group, and that some factors may be associated with
compromising chance of cure; and the chance and consequences of an increased probability of near-term grade reclassification including high
treatment side effects. PSA density, a high number of positive cores (eg, ≥3), high genomic risk
(from tissue-based molecular tumor analysis), and/or a known BRCA2
Patient Selection germline mutation.273-275 Of note, core involvement in the major active
Epstein and colleagues268 introduced clinical criteria to predict surveillance cohort studies was generally low (see Table 1 in the
pathologically “insignificant” prostate cancer. Insignificant, or very-low-risk, Principles of Active Surveillance and Observation, in the algorithm above).
prostate cancer is identified by: clinical stage T1c, biopsy Grade Group 1, Therefore, in some of patients with low-risk prostate cancer, upfront
the presence of disease in fewer than 3 biopsy cores, ≤50% prostate treatment with radical prostatectomy or prostate RT may be preferred
cancer involvement in any core, and PSA density <0.15 ng/mL/g. Despite based on shared decision-making with the patient.
the usefulness of these criteria, physicians are cautioned against using
Active Surveillance in Favorable Intermediate-Risk Disease
these as the sole decision maker. Studies have shown that as many as
8% of cancers that qualified as insignificant using the Epstein criteria were The literature on outcomes of active surveillance in patients with
not organ-confined based on postoperative findings.269,270 A new intermediate-risk prostate cancer is limited.276 In the PIVOT trial, patients
nomogram may be better.271 Although many variations upon this definition with clinically localized prostate cancer and a life expectancy greater than
have been proposed (reviewed by Bastian and colleagues272), a or equal to 10 years were randomized to radical prostatectomy or
consensus of the NCCN Guidelines Panel was reached that insignificant observation.277 Of the 120 participants with intermediate-risk disease who
prostate cancer, especially when detected early using serum PSA, poses were randomized to observation, 13 died from prostate cancer, a non-
little threat to individuals with a life expectancy of less than 20 years. The significant difference compared with 6 prostate cancer deaths in 129
confidence that Americans with very-low-risk prostate cancer have a very participants with intermediate-risk disease in the radical prostatectomy
small risk of prostate cancer death is enhanced by lead time bias arm (HR, 0.50; 95% CI, 0.21–1.21; P = .12). After longer follow-up
introduced by PSA early detection that ranges from an estimated 12.3 (median 12.7 years), a small difference was seen in all-cause mortality in
years in a 55-year-old individual to 6 years in a 75-year-old individual.267 those with intermediate-risk disease (absolute difference, 14.5 percentage
points; 95% CI, 2.8–25.6), but not in those with low-risk disease (absolute
At this time, the NCCN Panel consensus is that active surveillance is difference, 0.7 percentage points; 95% CI, -10.5–11.8).278 Urinary
preferred for all patients with very-low-risk prostate cancer and life incontinence and erectile and sexual dysfunction, however, were worse
expectancy greater than 10 years. through 10 years in the radical prostatectomy group. These results and the
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Prostate Cancer
less-than-average health of participants in the PIVOT study279 suggest that was higher for white patients than for black or Hispanic patients, but
patients with competing risks may safely be offered active surveillance. survival for distant stage disease was higher for black patients than white
patients. In an analysis that spanned 2010 to 2012, African Americans had
Other prospective studies of active surveillance that included patients with a higher lifetime risk of developing (18.2% vs. 13.3%) and dying from
intermediate-risk prostate cancer resulted in favorable prostate cancer- (4.4% vs. 2.4%) prostate cancer compared to Caucasian Americans.286 In
specific survival rates of 94% to 100% for the full cohorts.231,234,235 one study, the increase in prostate-cancer-specific mortality in African
However, with extended follow-up, the Toronto group has demonstrated American patients was limited to those with grade group 1.287 Multiple
inferior metastasis-free survival for patients with intermediate-risk prostate studies have shown that African Americans with very-low-risk prostate
cancer (15-year metastasis-free survival for cases of Gleason 6 or less cancer may harbor high-grade (Grade Group ≥2) cancer that is not
with PSA <10 ng/mL, 94%; Gleason 6 or less with PSA 10–20 ng/mL, detected by pre-treatment biopsies. Compared to Caucasian Americans
94%; Gleason 3+4 with PSA 20 ng/mL or less, 84%; and Gleason 4+3 matched on clinical parameters, African Americans have been reported to
with PSA 20 ng/mL or less, 63%).280 have a 1.7- to 2.3-fold higher change of pathologic upgrading.288,289
However, other studies have not seen different rates of upstaging or
Overall, the Panel interpreted these data to show that a subset of patients
upgrading.290,291 For example, in a retrospective study of 895 patients in the
with favorable intermediate-risk prostate cancer and life expectancy
SEARCH database, no significant differences were seen in the rates of
greater than 10 years may be considered for active surveillance. However,
pathologic upgrading, upstaging, or biochemical recurrence between
the precise inclusion criteria and follow-up protocols need continued
African American and Caucasian Americans.290
refinement. Patients must understand that a significant proportion of those
clinically staged as having favorable intermediate-risk prostate cancer may Several studies have reported that, among patients with low-risk prostate
have higher risk disease.281-284 Particular consideration to active cancer who are enrolled in active surveillance programs, African
surveillance may be appropriate for those patients with a low percentage Americans have higher risk of disease progression to higher Gleason
of Gleason pattern 4 cancer, low tumor volume, low PSA density, and/or grade or volume cancer than Caucasian Americans.292-295 African
low genomic risk (from tissue-based molecular tumor analysis), but should Americans in the low- to intermediate-risk categories also appear to suffer
be approached with caution, include informed decision-making, and use from an increased risk of biochemical recurrence after treatment.296 In
close monitoring for progression. addition, African American patients with low-risk or favorable intermediate-
risk prostate cancer have an increase in all-cause mortality after
Role of Race in Decisions Regarding Active Surveillance
treatment, mainly due to cardiovascular complications after ADT.297
Race is emerging as an important factor to consider when contemplating
active surveillance, particularly for African-American patients. A CDC Reasons for these clinical disparities are under investigation, but treatment
analysis of population-based cancer registries found that from 2003 to disparities and access to health care may play a significant role.298,299 In
2017, the incidence of prostate cancer was higher in black individuals than fact, results of some studies suggest that racial disparities in prostate
in white individuals, Hispanic individuals, American Indian/Alaska natives, cancer outcomes are minimized when health care access is equal.300-303
and Asian/Pacific islanders.285 Five-year survival for all stages combined
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Prostate Cancer
Strategies to improve risk-stratification for African Americans considering PSA-based bloodwork, and/or molecular tumor analysis. However, all
active surveillance may include mpMRI in concert with targeted image- patients should undergo a confirmatory prostate biopsy within 1 to 2 years
guided biopsies, which have been reported to improve detection of of their diagnostic biopsy.
clinically significant tumors in some individuals.304
Active Surveillance Program
Confirmatory Testing The current NCCN recommendations for the active surveillance program
Confirmatory testing can help facilitate early identification of those patients include PSA no more often than every 6 months unless clinically indicated;
who may be at a higher risk of future grade reclassification or cancer DRE no more often than every 12 months unless clinically indicated;
progression. Since an initial prostate biopsy may underestimate tumor repeat prostate biopsy no more often than every 12 months unless
grade or volume, confirmatory testing is strongly recommended within the clinically indicated; and repeat mpMRI no more often than every 12
first 6 to 12 months of diagnosis for patients who are considering active months unless clinically indicated. Repeat molecular tumor analysis is
surveillance. discouraged during active surveillance. Results of a study of 211 patients
with Grade Group 1 prostate cancer who had initial and repeat mpMRIs
Before starting on an active surveillance program, mpMRI with calculation and PSA monitoring suggest that a negative initial mpMRI predicts a low
of PSA density should be considered to confirm candidacy for active risk of Gleason upgrading by systematic biopsy.307 In addition, PSA
surveillance if not performed during initial workup.305 Patients with PI- velocity was significantly associated with subsequent progression in those
RADS 4 or 5 on mpMRI have an increased risk of biopsy progression with an initial negative mpMRI. In contrast, those with high-risk visible
during active surveillance.306 lesions on mpMRI before initiation of active surveillance had an increased
risk of progression. A meta-analysis of 43 studies found the sensitivity and
In patients with low and favorable intermediate risk, molecular tumor
NPV for mpMRI to be 0.81 and 0.78, respectively.308 An analysis of
analysis can also be considered before deciding whether to pursue active
patients in Canary PASS found that mpMRI had an NPV and PPV for
surveillance (see Tumor Multigene Molecular Testing, above). One study
detecting Grade Group ≥2 cancer of 83% and 31%, respectively.309
examined the role of molecular tumor analysis for predicting upgrading on
Another study found the NPV of mpMRI to be 80%.310
surveillance biopsy or the presence of adverse pathology on eventual
radical prostatectomy in patients in an active surveillance cohort.163 In this Whereas the intensity of surveillance may be tailored on an individual
study, results of the molecular testing did not significantly improve risk basis (eg, based on life expectancy and risk of reclassification), most
stratification over the use of clinical variables alone. patients should have prostate biopsies incorporated as part of their
monitoring, but no more often than every 12 months, because PSA
If results of mpMRI and/or molecular testing are concerning, a repeat
kinetics may not be reliable for predicting progression. Repeat biopsy is
biopsy may be appropriate.
useful to determine whether higher Gleason grade exists, which may
Early confirmatory testing may not be necessary in patients who have had influence prognosis and hence the decision to continue active surveillance
a complete workup including mpMRI prior to diagnostic biopsy, advanced or proceed to definitive local therapy.311 A repeat prostate biopsy should
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Prostate Cancer
also be considered if the prostate exam changes, if mpMRI (if done) include: increase in tumor volume, a rise in PSA density, as well as patient
suggests more aggressive disease, or if PSA increases. However, anxiety. Considerations for a change in management strategy should be
literature suggests that as many as 7% of patients undergoing prostate made in the context of the patient’s life expectancy.
biopsy will suffer an adverse event,259 and those who develop urinary tract
infection are often fluoroquinolone-resistant.312 Radical prostatectomy may Each of the major active surveillance series has used different criteria for
become technically challenging after multiple sets of biopsies, especially reclassification.230,231,236-239,322-325 Reclassification criteria were met by 23%
as it pertains to potency preservation.313 Therefore, many clinicians choose of patients with a median follow-up of 7 years in the Toronto experience,323
to wait 2 years for a biopsy if there are no signs of progression. 36% of patients with a median follow-up of 5 years in the Johns Hopkins
experience,230 and 16% of patients with a median follow-up of 3.5 years in
If the PSA level increases and systematic prostate biopsy remains the University of California, San Francisco (UCSF) experience239 (Table 3).
negative, mpMRI may be considered to exclude the presence of anterior Uncertainty regarding reclassification criteria and the desire to avoid
cancer.314 missing an opportunity for cure drove several reports that dealt with the
validity of commonly used reclassification criteria. The Toronto group
In patients with a suspicious lesion on mpMRI, MRI-US fusion biopsy demonstrated that a PSA trigger point of PSADT less than 3 years could
improves the detection of higher grade (Grade Group ≥2) cancers. Early not be improved upon by using a PSA threshold of 10 or 20, PSADT
experience supports the utilization of mpMRI in biopsy protocols to better calculated in various ways, or PSA velocity greater than 2 ng/mL/y.326 The
risk stratify patients under active surveillance.315-317 However, more recent Johns Hopkins group used biopsy-demonstrated reclassification to
studies have shown that a significant proportion of high-grade cancers are Gleason pattern 4 or 5 or increased tumor volume on biopsy as their
detected with systematic biopsy and not targeted biopsy in patients on criteria for reclassification. Of 290 patients on an annual prostate biopsy
active surveillance.318-320 program, 35% demonstrated reclassification at a median follow-up of 2.9
years.327 Neither PSADT (area under the curve [AUC], 0.59) nor PSA
Patients should be transitioned to observation (see Observation, above)
velocity (AUC, 0.61) was associated with prostate biopsy reclassification.
when life expectancy is less than 10 years.
Both groups have concluded that PSA kinetics cannot replace regular
Considerations for Treatment of Patients on Active Surveillance prostate biopsy, although treatment of most patients who demonstrate
reclassification on prostate biopsy prevents evaluation of biopsy
Reliable parameters of prostate cancer progression await the results of
reclassification as a criterion for treatment or reduction of survival.
ongoing clinical trials. PSADT is not considered reliable enough to be used
Treatment of all patients who developed Gleason pattern 4 on annual
alone to detect disease progression.321 If repeat biopsy shows Grade
prostate biopsies has thus far resulted in only 2 prostate cancer deaths
Group ≥3 disease, or if tumor is found in a greater number of biopsy cores
among 1298 patients (0.15%) in the Johns Hopkins study.230 However, it
or in a higher percentage of a given biopsy core, cancer progression may
remains uncertain whether treatment of all who progressed to Gleason
have occurred. Grade reclassification on repeat biopsy is the most
pattern 4 was necessary. Studies remain in progress to identify the best
common factor influencing a change in management from active
surveillance to treatment. Other factors affecting decisions to actively treat
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Prostate Cancer
trigger points when interventions with curative intent may still be In comparison, among 192 patients on active surveillance who underwent
successful. delayed treatment at a median of 2 years after diagnosis in the Johns
Hopkins experience, 5-year biochemical PFS was 96% for those who
The Toronto group published findings on three patients who died of underwent radical prostatectomy and 75% for those who underwent
prostate cancer in their experience with 450 patients on active radiation.325 The two groups were similar by pathologic Gleason grade,
surveillance.323 These three deaths led them to revise their criteria for pathologic stage, and margin positivity. All patients treated by radical
offering active surveillance, because each of these three patients probably prostatectomy after progression on active surveillance had freedom from
had metastatic disease at the time of entry on active surveillance. The 450 biochemical progression at a median follow-up of 37.5 months, compared
patients were followed for a median of 6.8 years; OS was 78.6% and to 97% of those in the primary radical prostatectomy group at a median
prostate cancer-specific survival was 97.2%.323 Of the 30% (n = 145) of follow-up of 35.5 months. A later publication from this group showed that
patients who progressed, 8% had an increase in Gleason grade, 14% had 23 of 287 patients who were treated after active surveillance (8%)
a PSADT less than 3 years, 1% developed a prostate nodule, and 3% experienced biochemical recurrence, and the rate was independent of the
were treated because of anxiety. One hundred thirty-five of these 145 type of treatment.230 Several studies have shown that delayed radical
patients were treated: 35 by radical prostatectomy, 90 by EBRT with or prostatectomy does not increase the rates of adverse pathology.237,330-332
without ADT, and 10 with ADT alone. Follow-up is available for 110 of
these patients, and 5-year biochemical PFS is 62% for those undergoing Radical Prostatectomy
radical prostatectomy and 43% for those undergoing radiation. Longer- Radical prostatectomy is appropriate for any patient whose cancer
term follow-up of this cohort was reported in 2015.231 The 10- and 15-year appears clinically localized to the prostate. However, because of potential
actuarial cause-specific survival rates for the entire cohort were 98.1% and perioperative morbidity, radical prostatectomy should generally be
94.3%, respectively. Only 15 of 993 (1.5%) patients had died of prostate reserved for patients whose life expectancy is 10 years or more.
cancer, an additional 13 patients (1.3%) had developed metastatic Stephenson and colleagues128 reported a low 15-year prostate cancer-
disease, and only 36.5% of the cohort had received treatment by 10 years. specific mortality of 12% in patients who underwent radical prostatectomy
In an analysis of 592 patients enrolled in this cohort who had 1 or more (5% for patients with low-risk disease), although it is unclear whether the
repeat prostate biopsies, 31.3% of cases were upgraded. Fifteen percent favorable prognosis is due to the effectiveness of the procedure or the low
of upgraded cases were upgraded to Gleason ≥8, and 62% of total lethality of cancers detected in the PSA era.
upgraded cases proceeded to active treatment.328 Another analysis of this
cohort revealed that metastatic disease developed in 13 of 133 patients Radical prostatectomy was compared to watchful waiting in a randomized
with Gleason 7 disease (9.8%) and 17 of 847 patients with Gleason ≤6 trial of 695 patients with early-stage prostate cancer (mostly T2).333,334 With
disease (2.0%).329 PSADT and the number of positive scores were also a median follow-up of 12.8 years, those assigned to the radical
predictors of increased risk for the development of metastatic disease. prostatectomy group had significant improvements in disease-specific
survival, OS, and risk of metastasis and local progression.333 The reduction
in mortality was confirmed at 18 years of follow-up, with an absolute
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Prostate Cancer
difference of 11%.334 Overall, 8 patients needed to be treated to avert one Overall and cancer-specific 10-year survival ranged from 54% to 89% and
death; that number fell to 4 for patients younger than 65 years of age. 70% to 83%, respectively.341 Patient selection is important, and post-RT
Longer follow-up results were also reported, in which the cumulative recurrence radical prostatectomy should only be performed by highly
incidence of death from prostate cancer was 19.6% and 31.3% in the experienced surgeons.
radical prostatectomy and watchful waiting groups, respectively, at 23
years, with a mean increase of 2.9 years of life in the radical Operative Techniques and Adverse Effects
prostatectomy group.335 The results of this trial offer high-quality evidence Long-term cancer control has been achieved in most patients with both the
to support radical prostatectomy as a treatment option for clinically retropubic and the perineal approaches to radical prostatectomy; high-
localized prostate cancer. volume surgeons in high-volume centers generally achieve superior
outcomes.343,344 Laparoscopic and robot-assisted radical prostatectomy are
Some patients at high or very high risk may benefit from radical commonly used and are considered comparable to conventional
prostatectomy. In an analysis of 842 patients with Gleason scores 8 to 10 approaches in experienced hands.345-347 In a cohort study using SEER
at biopsy who underwent radical prostatectomy, predictors of unfavorable Medicare-linked data on 8837 patients, minimally invasive compared to
outcome included PSA level over 10 ng/mL, clinical stage T2b or higher, open radical prostatectomy was associated with shorter length of hospital
Gleason score 9 or 10, higher number of biopsy cores with high-grade stay, less need for blood transfusions, and fewer surgical complications,
cancer, and over 50% core involvement.336 Patients without these but rates of incontinence and erectile dysfunction were higher.348 A second
characteristics showed higher 10-year biochemical-free and disease- large study reported no difference in overall complications, readmission,
specific survival after radical prostatectomy compared to those with and additional cancer therapies between open and robot-assisted radical
unfavorable findings (31% vs. 4% and 75% vs. 52%, respectively). Radical prostatectomy, although the robotic approach was associated with higher
prostatectomy is an option for patients with high-risk disease and in select rates of genitourinary complications and lower rates of blood
patients with very-high-risk disease. transfusion.349 Oncologic outcome of a robotic versus open approach was
similar when assessed by use of additional therapies348 or rate of positive
Retrospective data and population-based studies suggest that radical
surgical margins,350 although longer follow-up is necessary. A meta-
prostatectomy with PLND can be an effective option for patients with cN1
analysis on 19 observational studies (n = 3893) reported less blood loss
disease.337-339 Extrapolation of results of STAMPEDE arm H, in which
and lower transfusion rates with minimally invasive techniques than with
EBRT to the primary tumor improved OS and other endpoints in patients
open operation.350 Risk of positive surgical margins was the same. Two
with low-volume metastatic disease, also suggests that local treatment to
more recent meta-analyses showed a statistically significant advantage in
the prostate may be beneficial in patients with advanced disease.340
favor of a robotic approach compared to an open approach in 12-month
Radical prostatectomy is a treatment option for patients experiencing urinary continence351 and potency recovery.352 Early results from a
biochemical recurrence after primary EBRT, but morbidity (incontinence, randomized controlled phase 3 study comparing robot-assisted
erectile dysfunction, and bladder neck contracture) remains significantly laparoscopic radical prostatectomy and open radical retropubic
higher than when radical prostatectomy is used as initial therapy.341,342 prostatectomy in 326 patients were published in 2016.353,354 Urinary
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Prostate Cancer
function and sexual function scores and rates of postoperative bundles.360 The ability of mpMRI to detect extracapsular extension can aid
complications did not differ significantly between the groups at 6, 12, and in decision-making in nerve-sparing surgery.178
24 months after surgery. Rates of positive surgical margins were similar,
based on a superiority test (10% in the open group vs. 15% in the robotic Pelvic Lymph Node Dissection
group). Assessment of oncologic outcomes from this trial will be limited The decision to perform PLND should be guided by the probability of nodal
because postoperative management and additional cancer therapies were metastases. The NCCN Guidelines Panel chose 2% as the cutoff for
not standardized between the groups.353 PLND because this avoids 47.7% of PLNDs at a cost of missing 12.1% of
positive pelvic lymph nodes.133 A more recent analysis of 26,713 patients
An analysis of the Prostate Cancer Outcomes Study on 1655 patients with in the SEER database treated with radical prostatectomy and PLND
localized prostate cancer compared long-term functional outcomes after between 2010 and 2013 found that the 2% nomogram threshold would
radical prostatectomy or EBRT.355 At 2 and 5 years, patients who avoid 22.3% of PLNDs at a cost of missing 3.0% of positive pelvic lymph
underwent radical prostatectomy reported higher rates of urinary nodes.361 The Panel recommends use of a nomogram developed at
incontinence and erectile dysfunction but lower rates of bowel urgency. Memorial Sloan Kettering Cancer Center that uses pretreatment PSA,
However, no significant difference was observed at 15 years. In a large clinical stage, and Gleason sum to predict the risk of pelvic lymph node
retrospective cohort study involving 32,465 patients, those who received metastases.133
EBRT had a lower 5-year incidence of urologic procedures than those who
underwent radical prostatectomy, but higher incidence for hospital PLND should be performed using an extended technique.362,363 An
admissions, rectal or anal procedures, open surgical procedures, and extended PLND includes removal of all node-bearing tissue from an area
secondary malignancies.356 bounded by the external iliac vein anteriorly, the pelvic side wall laterally,
the bladder wall medially, the floor of the pelvis posteriorly, Cooper’s
Return of urinary continence after radical prostatectomy may be improved ligament distally, and the internal iliac artery proximally. Removal of more
by preserving the urethra beyond the prostatic apex and by avoiding lymph nodes using the extended technique has been associated with
damage to the distal sphincter mechanism. Bladder neck preservation increased likelihood of finding lymph node metastases, thereby providing
may allow more rapid recovery of urinary control.357 Anastomotic strictures more complete staging.364-366 A survival advantage with more extensive
that increase the risk of long-term incontinence are less frequent with lymphadenectomy has been suggested by several studies, possibly due to
modern surgical techniques. Recovery of erectile function is related elimination of microscopic metastases,365,367-369 although definitive proof of
directly to the degree of preservation of the cavernous nerves, age at oncologic benefit is lacking.370 PLND can be performed safely
surgery, and preoperative erectile function. Improvement in urinary and laparoscopically, robotically, or as an open procedure, and complication
sexual function has been reported with nerve-sparing techniques.358,359 rates should be similar among the three approaches.
Replacement of resected nerves with nerve grafts does not appear to be
effective for patients undergoing wide resection of the neurovascular
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Prostate Cancer
Radiation Therapy fractionated IMRT, with one trial showing fewer treatment failures with a
RT techniques used in prostate cancer include EBRT, proton radiation, moderately fractionated regimen.380-389 Toxicity was similar between
and brachytherapy. EBRT techniques include IMRT and hypofractionated, moderately hypofractionated and conventional regimens in some380,384,387,388
image-guided SBRT. An analysis that included propensity-score matching but not all of the trials.382,385,386 In addition, efficacy results varied among the
of patients showed that, among younger patients with prostate cancer, trials, with some showing noninferiority or similar efficacy and others
stereotactic body RT (SBRT) and intensity-modulated RT (IMRT) had showing that hypofractionation may be less effective than conventional
similar toxicity profiles whereas proton radiation was associated with fractionation schemes. These safety and efficacy differences are likely a
reduced urinary toxicity and increased bowel toxicity. The cost of proton result of differences in fractionation schedules.390 In addition, results of a
therapy was almost double that of IMRT, and SBRT was slightly less large cohort study showed no differences in QOL or urinary or bowel
expensive.371 function between those that received hypofractionated versus
conventional regimens.391 Overall, the panel believes that hypofractionated
The panel believes that highly conformal RT (CRT) techniques should be IMRT techniques, which are more convenient for patients, can be
used to treat localized prostate cancer. Photon and proton beam radiation considered as an alternative to conventionally fractionated regimens when
are both effective at achieving highly CRT with acceptable and similar clinically indicated. The panel lists fractionation schemes that have shown
biochemical control and long-term side effect profiles. Radiation acceptable efficacy and toxicity on PROS-F page 3 of 5 in the algorithm
techniques are discussed in more detail below. above. An ASTRO/ASCO/AUA evidence-based guideline regarding the
use of hypofractionated radiation in patients with localized prostate cancer
External Beam Radiation Therapy concluded that moderately fractionated regimens are justified for routine
Over the past several decades, EBRT techniques have evolved to allow use in this setting and provides more detail on the topic.392
higher doses of radiation to be administered safely. Three-dimensional
(3D) CRT (3D-CRT) uses computer software to integrate CT images of the Daily prostate localization using image-guided RT (IGRT) is essential with
patients’ internal anatomy in the treatment position, which allows higher either 3D-CRT or IMRT for target margin reduction and treatment
cumulative doses to be delivered with lower risk of late effects.144,372-374 The accuracy. Imaging techniques, such as ultrasound, implanted fiducials,
second-generation 3D technique, IMRT, has been used increasingly in electromagnetic targeting and tracking, or endorectal balloon, can improve
practice.375 IMRT reduced the risk of gastrointestinal toxicities and rates of cure rates and decrease complications.
post-recurrence therapy compared to 3D-CRT in some but not all older
These techniques have permitted safer dose escalation, and results of
retrospective and population-based studies, although treatment cost is
randomized trials have suggested that dose escalation is associated with
increased.376-379
improved biochemical outcomes.393-398 Kuban and colleagues396 published
More recently, moderately hypofractionated image-guided IMRT regimens an analysis of their dose-escalation trial of 301 patients with stage T1b to
(2.4–4 Gy per fraction over 4–6 weeks) have been tested in randomized T3 prostate cancer. Freedom from biochemical or clinical recurrence was
trials, and their efficacy has been similar or non-inferior to conventionally higher in the group randomized to 78 Gy compared to 70 Gy (78% vs.
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Prostate Cancer
59%, P = .004) at a median follow-up of 8.7 years. The difference was Biomaterials have been developed, tested, and FDA approved to serve as
even greater among patients with diagnostic PSA >10 ng/mL (78% vs. spacer materials when inserted between the rectum and prostate.406,407 In a
39%, P = .001). A longer follow-up (mean 14.3 years) found that randomized phase 3 multicenter clinical trial of patients undergoing image-
improvements in biochemical and clinical recurrences were sustained, with guided IMRT (IG-IMRT), where the risk of late (3-year) common
lower rates of additional cancer treatment and better prostate cancer- terminology criteria for adverse events (CTCAE) was grade 2 or higher,
specific mortality.399 OS was not improved. physician-recorded rectal complications declined from 5.7% to 0% in the
control versus hydrogel spacer group.408 The hydrogel spacer group had a
An analysis of the National Cancer Database found that dose escalation significant reduction in bowel QOL decline. No significant differences in
(75.6–90 Gy) resulted in a dose-dependent improvement in OS for adverse events were noted in those receiving hydrogel placement versus
patients with intermediate- or high-risk prostate cancer.400 In light of these controls. Results of a secondary analysis of this trial suggest that use of a
findings, the conventional 70 Gy dose is no longer considered adequate. A perirectal spacer may decrease the sexual side effects of radiation. 409
dose of 75.6 to 79.2 Gy in conventional fractions to the prostate (with or Spacer implantation, however, is quite expensive and may be associated
without seminal vesicles) is appropriate for patients with low-risk cancers. with rare complications such as rectum perforation and urethral
Patients Intermediate-risk and high-risk disease should receive doses of damage.410,411 Retrospective data also support its use in similar patients
up to 81.0 Gy.376,401,402 undergoing brachytherapy. Overall, the panel believes that biocompatible
and biodegradable perirectal spacer materials may be implanted between
Data suggested that EBRT and radical prostatectomy were effective for
the prostate and rectum in patients undergoing external radiotherapy with
the treatment of localized prostate cancer.403 EBRT of the primary prostate
organ-confined prostate cancer in order to displace the rectum from high
cancer shows several distinct advantages over radical prostatectomy.
radiation dose regions. Patients with obvious rectal invasion or visible T3
EBRT avoids complications associated with operation, such as bleeding
and posterior extension should not undergo perirectal spacer implantation.
and transfusion-related effects, and risks associated with anesthesia, such
as myocardial infarction and pulmonary embolus. 3D-CRT and IMRT If the cancer recurs, radical prostatectomy after RT is associated with a
techniques are widely available and are possible for patients over a wide higher risk of complications than primary radical prostatectomy.412
range of ages. EBRT has a low risk of urinary incontinence and stricture Contraindications to EBRT include prior pelvic irradiation, active
and a good chance of short-term preservation of erectile function.404 inflammatory disease of the rectum, or a permanent indwelling Foley
catheter. Relative contraindications include very low bladder capacity,
The disadvantages of EBRT include a treatment course of 8 to 9 weeks.
chronic moderate or severe diarrhea, bladder outlet obstruction requiring a
Up to 50% of patients have some temporary bladder or bowel symptoms
suprapubic catheter, and inactive ulcerative colitis.
during treatment. There is a low but definite risk of protracted rectal
symptoms from radiation proctitis, and the risk of erectile dysfunction EBRT for Early Disease
increases over time.404,405 The risk of late rectal complications following RT EBRT is one of the principal treatment options for clinically localized
is related to the volume of the rectum receiving doses of radiation close to prostate cancer. The NCCN Guidelines Panel consensus was that modern
or exceeding the radiation dose required to control the primary tumor.
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Prostate Cancer
EBRT and surgical series show similar PFS in patients with low-risk Some earlier data suggested that the use of docetaxel in combination with
disease treated with radical prostatectomy or EBRT. In a study of 3546 ADT and EBRT may benefit fit patients with high- and very-high-risk
patients treated with brachytherapy plus EBRT, disease-free survival localized disease. The GETUG 12 trial randomized 413 patients with high-
(DFS) remained steady at 73% between 15 and 25 years of follow-up.413 or very-high-risk prostate cancer to IMRT and ADT or ADT, docetaxel, and
The panel lists several acceptable dosing schemas in the guidelines. The estramustine.427 After a median follow-up of 8.8 years, 8-year relapse-free
NRG Oncology/RTOG 0126 randomized clinical trial compared 79.2 Gy survival was 62% in the combination therapy arm and 50% in the ADT-
(44 fractions) and 70.2 Gy (39 fractions), both in 1.8 Gy fractions, in 1499 only arm (adjusted HR, 0.71; 95% CI, 0.54–0.94; P = .017). The
patients with intermediate-risk prostate cancer.414 After a median follow-up multicenter, phase 3 NRG Oncology RTOG 0521 trial randomized 563
of 8.4 years, the escalated dose reduced biochemical recurrences, but patients with high- or very-high-risk prostate cancer ADT plus EBRT with
increased late toxicity and had no effect on OS. or without docetaxel.428 After a median follow-up of 5.7 years, 4-year OS
was 89% (95% CI, 84%–92%) for ADT/EBRT and 93% (95% CI, 90%–
EBRT for Patients with High-Risk or Very-High-Risk Disease
96%) for ADT/EBRT/docetaxel (HR, 0.69; 90% CI, 0.49–0.97; one-sided P
EBRT has demonstrated efficacy in patients with high-risk and very-high- = .03). Improvements were also seen in DFS and the rate of distant
risk prostate cancer. One study randomized 415 patients to EBRT alone or metastasis. In the STAMPEDE trial, the addition of docetaxel to EBRT and
EBRT plus 3-year ADT.415 In another study (RTOG 8531), 977 patients ADT improved FFS in the non-metastatic group (HR, 0.60; 95% CI, 0.45–
with T3 disease treated with EBRT were randomized to adjuvant ADT or 0.80; P < .01).429 OS analysis did not show a significant difference, but was
ADT at relapse.416 Two other randomized phase 3 trials evaluated long- limited in power. Based on these data, the panel recommends the addition
term ADT with or without radiation in a population of patients who mostly of docetaxel added to EBRT and 2 years of ADT as an option for patients
had T3 disease.417-420 In all four studies, the combination group showed with very-high-risk prostate cancer. The Panel recommends the addition of
improved disease-specific survival and OS compared to single-modality docetaxel to ADT plus EBRT as an option for patients with very-high-risk
treatment. Patients with a PSA nadir >0.5 ng/mL after radiation and 6 prostate cancer, but does not recommend it for patients with high-risk
months of ADT have an adjusted HR for all-cause mortality of 1.72 (95% prostate cancer at this time.
CI, 1.17–2.52; P = .01) compared with patients who received radiation
only.421 The Panel recommends the addition of abiraterone to ADT plus EBRT as
an option for patients with very-high-risk prostate cancer (fine-particle
Prophylactic nodal radiation should be considered in this population. 422-424 abiraterone can also be used, category 2B). This recommendation is
The randomized controlled phase 3 POP-RT trial showed that pelvic based on data from the STAMPEDE trial. In STAMPEDE, the HRs for FFS
radiation can improve biochemical failure-free survival (FFS) and DFS in patients with non-metastatic disease treated with EBRT/ADT plus
compared with prostate-only radiation in patients with high- and very-high- abiraterone compared with EBRT/ADT was 0.21 (95% CI, 0.15–0.31).430
risk prostate cancer.425 The randomized phase 3 FLAME trial showed that
a focal radiation boost to the mpMRI-visible lesion can improve
biochemical DFS in this population.426
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Prostate Cancer
A head-to-head comparison of ADT with either abiraterone or docetaxel in the primary tumor in patients with low metastatic burden who are
this setting and in patients with metastatic disease showed no difference in beginning ADT.432-436
safety or in efficacy endpoints including OS.431
The Panel recommends against EBRT to the primary tumor in the case of
EBRT for Node-Positive Disease high-volume M1 disease based on the HORRAD and STAMPEDE
EBRT with neoadjuvant, concurrent, and/or adjuvant ADT is the preferred trials.340,437 No improvement in OS was seen from the addition of EBRT to
option for patients with clinical N1 disease. Abiraterone can be added. In the primary when combined with standard systemic therapy in patients
addition, ADT alone or with abiraterone are options. In each case, the use with high-volume M1 disease in either trial.
of the fine-particle formulation of abiraterone is a category 2B
recommendation. Stereotactic Body Radiation Therapy
The relatively slow proliferation rate of prostate cancer is reflected in a low
For adjuvant therapy for node-positive disease after radical prostatectomy, α/β ratio,438 most commonly reported between 1 and 4. These values are
see Adjuvant Therapy for pN1, below. similar to that for the rectal mucosa. Because the α/β ratio for prostate
EBRT to the Primary Tumor in Low-Volume M1 Disease
cancer is similar to or lower than the surrounding tissues responsible for
most of the toxicity reported with radiation, appropriately designed
Patients with newly diagnosed, low-volume metastatic prostate cancer can
radiation treatment fields and schedules using extremely hypofractionated
be considered for ADT with EBRT to the primary tumor based on results
regimens should result in similar cancer control rates without increased
from the randomized controlled phase 3 STAMPEDE trial.340 In this
risk of late toxicity.
multicenter, international study, 2061 patients were randomized to lifelong
ADT with or without EBRT to the primary tumor (either 55 Gy in 20 daily SBRT is a technique that delivers highly conformal, high-dose radiation in
fractions over 4 weeks or 36 Gy in 6 weekly fractions over 6 weeks). The five or fewer treatment fractions, which are safe to administer only with
primary outcome of OS by intention-to-treat analysis was not met (HR, precise, image-guided delivery.439 Single-institution series with median
0.92; 95% CI, 0.80–1.06; P = .266), but EBRT improved the secondary follow-up as long as 6 years report excellent biochemical PFS and similar
outcome of FFS (HR, 0.76; 95% CI, 0.68–0.84; P < .0001). In a pre- early toxicity (bladder, rectal, and QOL) compared to standard radiation
planned subset analysis, outcomes of patients with high metastatic burden techniques.438-444 According to a pooled analysis of phase 2 trials, the 5-
(defined as visceral metastases; ≥4 bone metastases with ≥1 outside the year biochemical relapse-free survival is 95%, 84%, and 81% for patients
vertebral bodies or pelvis; or both) and those with low metastatic burden with low-, intermediate-, and high-risk disease, respectively.445 A study of
(all others) were determined. EBRT improved OS (adjusted HR, 0.68; 95% individual patient data from a cohort of 2142 patients with low- or
CI, 0.52–0.90), prostate cancer-specific survival (adjusted HR, 0.65; 95% intermediate-risk prostate cancer from 10 single-institution phase 2 trials
CI, 0.47–0.90), FFS (adjusted HR, 0.59; 95% CI, 0.49–0.72), and PFS and 2 multi-institutional phase 2 trials found that the 7-year cumulative
(adjusted HR, 0.78; 95% CI, 0.63–0.98) in patients with low metastatic rates of biochemical recurrence were 4.5%, 8.6%, and 14.9% for low-risk
burden, but not in patients with high metastatic burden. Randomized disease, favorable intermediate-risk disease, and unfavorable
clinical trials are ongoing to better test the value of removal or radiation of
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Prostate Cancer
intermediate-risk disease, respectively.446 Severe acute toxicity was rare, because earlier studies found it less effective than EBRT for high-risk
at 0.6% for grade 3 or higher genitourinary toxic events and 0.09% for disease.101,454 However, increasing evidence suggests that technical
grade 3 or higher gastrointestinal toxic events. Late (7-year cumulative advancements in brachytherapy may provide a role for contemporary
incidence) toxicity rates were 2.4% and 0.4% for grade 3 or higher brachytherapy in high-risk localized and locally advanced prostate
genitourinary toxic events and gastrointestinal toxic events, respectively. cancer.455,456
SBRT may be associated with more toxicity than moderately fractionated The advantage of brachytherapy is that the treatment is completed in 1
IMRT. One retrospective study of 4005 patients reported higher day with little time lost from normal activities. In appropriate patients, the
genitourinary toxicity at 24 months after SBRT than IMRT (44% vs. 36%; P cancer-control rates appear comparable to radical prostatectomy (over
= .001).447 Another phase 2 trial found increased toxicity with doses >47.5 90%) for low-risk prostate cancer with medium-term follow-up.457 In
Gy delivered in 5 fractions.448 An analysis using the SEER database also addition, the risk of incontinence is minimal in patients without a previous
reported that SBRT was more toxic than IMRT.449 Overall, prospective transurethral resection of the prostate (TURP), and erectile function is
evidence supports the use of SBRT in the setting of localized prostate preserved in the short term.405 Disadvantages of brachytherapy include the
cancer.450 requirement for general anesthesia and the risk of acute urinary retention.
Irritative voiding symptoms may persist for as long as 1 year after
Several phase 3 trials have been initiated comparing conventional implantation. The risk of incontinence is greater after TURP because of
regimens to SBRT.451-453 Preliminary results show that the genitourinary acute retention and bladder neck contractures, and many patients develop
and bowel toxicity is similar with the two techniques. In addition, the progressive erectile dysfunction over several years. IMRT causes less
HYPO-RT-PC trial demonstrated non-inferiority of 42.7 Gy in seven acute and late genitourinary toxicity and similar freedom from biochemical
fractions to 78.0 Gy in 39 fractions with respect to FFS in patients with recurrence compared with iodine-125 or palladium-103 permanent seed
intermediate-to-high-risk prostate cancer.453 implants.458,459 Current brachytherapy techniques attempt to improve the
radioactive seed placement and radiation dose distribution.
SBRT/extremely hypofractionated IG-IMRT regimens (6.5 Gy per fraction
or greater) can be considered as an alternative to conventionally There are currently two methods for prostate brachytherapy: low dose-rate
fractionated regimens at clinics with appropriate technology, physics, and (LDR) and high dose-rate (HDR). LDR brachytherapy consists of
clinical expertise. Longer follow-up and prospective multi-institutional data placement of permanent seed implants in the prostate. The short range of
are required to evaluate longer-term results, especially because late the radiation emitted from these low-energy sources allows delivery of
toxicity theoretically could be worse in hypofractionated regimens adequate dose levels to the cancer within the prostate, with excessive
compared to conventional fractionation (1.8–2.0 Gy per fraction). irradiation of the bladder and rectum avoided. Post-implant dosimetry
should be performed to document the quality of an LDR implant.460 HDR
Brachytherapy
brachytherapy, which involves temporary insertion of a radiation source, is
Brachytherapy involves placing radioactive sources into the prostate a newer approach.
tissue. Brachytherapy has been used traditionally for low-risk cases
MS-29
Prostate Cancer
Two groups have observed a lower risk of urinary frequency, urgency, and for brachytherapy alone. Either LDR or HDR brachytherapy can be used in
rectal pain with HDR brachytherapy compared with LDR brachytherapy this setting.
(permanent seed implant).461,462 Vargas and colleagues463 reported that
HDR brachytherapy results in a lower risk of erectile dysfunction than LDR Retrospective analyses show that LDR or HDR brachytherapy alone can
brachytherapy. Commonly prescribed doses for LDR and HDR be effective and well tolerated in this population.464-468 A phase 2 trial in
brachytherapy are listed in the guidelines. 300 patients with intermediate-risk prostate cancer also found LDR
brachytherapy alone to be safe and effective.469 However, randomized
For patients with very large or very small prostates, symptoms of bladder controlled trials comparing brachytherapy to radical prostatectomy or
outlet obstruction (high International Prostate Symptom Score), or a EBRT in this population are limited. In a single-center trial, 165 patients
previous TURP, seed implantation may be more difficult. These patients with low-risk prostate cancer were randomized to LDR brachytherapy with
also have an increased risk of side effects. Neoadjuvant ADT may be used iodine-125 seeds or radical prostatectomy. The 2-year biochemical FFS
to shrink the prostate to an acceptable size; however, increased toxicity is rates were similar between the groups at 96.1% after brachytherapy and
expected from ADT, and prostate size may not decline in some patients. 97.4% after radical prostatectomy (P = .35).470 At 6-month follow-up,
The potential toxicity of ADT must be weighed against the possible benefit continence was better in the brachytherapy group whereas potency was
of target reduction. better in the radical prostatectomy group.
Ideally, the accuracy of brachytherapy treatment should be verified by Brachytherapy Boost

daily prostate localization with techniques of IGRT: CT, ultrasound, LDR or HDR brachytherapy can be added as a boost to EBRT plus ADT in
implanted fiducials, or electromagnetic targeting/tracking. Endorectal patients with unfavorable intermediate-, high-, or very-high-risk prostate
balloons may be used to improve prostate immobilization. Perirectal cancer being treated with curative intent. Combining EBRT and
spacer materials (discussed under External Beam Radiation Therapy, brachytherapy allows dose escalation while minimizing acute or late
above) may be employed when the previously mentioned techniques are toxicity in patients with high-risk localized or locally advanced cancer.471-474
insufficient to improve oncologic cure rates and/or reduce side effects due This combination has demonstrated improved biochemical control over
to anatomic geometry or other patient-related factors (eg, medication EBRT plus ADT alone in randomized trials, but with higher toxicity.475-477 An
usage, comorbid conditions). Patients with obvious rectal invasion or analysis of a cohort of 12,745 patients with high-risk disease found that
visible T3 and posterior extension should not undergo perirectal spacer treatment with brachytherapy (HR, 0.66; 95% CI, 0.49–0.86) or
implantation. brachytherapy plus EBRT (HR, 0.77; 95% CI, 0.66–0.90) lowered disease-
specific mortality compared to EBRT alone.478
Brachytherapy Alone for Localized Disease
Brachytherapy alone is an option for patients with very low, low, or The randomized ASCENDE-RT trial compared two methods of dose
favorable intermediate-risk prostate cancer, depending on life expectancy. escalation in 398 patients with intermediate- or high-risk prostate cancer:
Patients with high-risk cancers are generally considered poor candidates dose-escalated EBRT boost to 78 Gy or LDR brachytherapy boost.479 All
patients were initially treated with 12 months of ADT and pelvic EBRT to
MS-30
Prostate Cancer
46 Gy. An intention-to-treat analysis found that the primary endpoint of metastasis than either radical prostatectomy or EBRT with ADT.488 In
biochemical PFS was 89% versus 84% at 5 years; 86% versus 75% at 7 addition, an analysis of outcomes of almost 43,000 patients with high-risk
years; and 83% versus 62% at 9 years for the LDR versus EBRT boost prostate cancer in the National Cancer Database found that mortality was
arms (log-rank P < .001). Toxicity was higher in the brachytherapy arm, similar in patients treated with EBRT, brachytherapy, and ADT versus
with the cumulative incidence of grade 3 genitourinary events at 5 years of those treated with radical prostatectomy, but was worse in those treated
18.4% for brachytherapy boost and 5.2% for EBRT boost (P < .001).480 A with EBRT and ADT.489
trend for increased gastrointestinal toxicity with brachytherapy boost was
also seen (cumulative incidence of grade 3 events at 5 years, 8.1% vs. To address historical trial data concerns for increased toxicity incidence
3.2%; P = .12). However, at 6-year follow-up, health-related QOL was associated with brachytherapy boost, careful patient selection and
similar between the groups in most domains, except that physical and contemporary planning associated with lesser toxicity, such as use of
urinary function scales were significantly lower in the LDR arm.481 Whereas recognized organ at risk dose constraints, use of high-quality ultrasound
the toxicity is increased with the use of brachytherapy boost, this and other and other imaging, and prescription of dose as close as possible to the
randomized controlled trials have failed to show an improvement in OS or target without excessive margins should be implemented.
cancer-specific survival.482
Post-Recurrence Brachytherapy
Addition of ADT (2 or 3 years) to brachytherapy and EBRT is common for Brachytherapy can be considered in patients with biochemical recurrence
patients at high risk of recurrence. The outcome of trimodality treatment is after EBRT. In a retrospective study of 24 patients who had EBRT as
excellent, with 9-year PFS and disease-specific survival reaching 87% and primary therapy and permanent brachytherapy after biochemical
91%, respectively.483,484 However, it remains unclear whether the ADT recurrence, the cancer-free and biochemical relapse-free survival rates
component contributes to outcome improvement. D’Amico and colleagues were 96% and 88%, respectively, after a median follow-up of 30 months.490
studied a cohort of 1342 patients with PSA over 20 ng/mL and clinical Results of a phase 2 study of post-recurrence HDR brachytherapy after
T3/T4 and/or Gleason score 8 to 10 disease.485 Addition of either EBRT or EBRT included relapse-free survival, distant metastases-free survival, and
ADT to brachytherapy did not confer an advantage over brachytherapy cause-specific survival rates of 68.5%, 81.5%, and 90.3%, respectively, at
alone. The use of all three modalities reduced prostate cancer-specific 5 years.491 Toxicities were mostly grade 1 and 2 and included
mortality compared to brachytherapy alone (adjusted HR, 0.32; 95% CI, gastrointestinal toxicity and urethral strictures, and one case of Grade 3
0.14–0.73). Other analyses did not find an improvement in recurrence rate urinary incontinence. In another prospective phase 2 trial, the primary
when ADT was added to brachytherapy and EBRT.486,487 endpoint of grade ≥3 late treatment-related gastrointestinal and
genitourinary adverse events at 9 to 24 months after post-recurrence
A large, multicenter, retrospective cohort analysis that included 1809 brachytherapy was below the unacceptable threshold, at 14%.492
patients with Gleason score 9–10 prostate cancer found that multimodality
therapy with EBRT, brachytherapy, and ADT was associated with Data on the use of brachytherapy after permanent brachytherapy are
improved prostate cancer-specific mortality and longer time to distant limited, but the panel agrees that it can be considered for carefully
selected patients. Decisions regarding the use of brachytherapy in the
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Prostate Cancer
recurrent-disease setting should consider comorbidities, extent of disease, proton therapy plan and vice versa, they do not accurately predict clinically
and potential complications. Brachytherapy in this setting is best meaningful endpoints.
performed at high-volume centers.
Comparative effectiveness studies have been published in an attempt to
Proton Therapy compare toxicity and oncologic outcomes between proton and photon
Proton beam RT has been used to treat patients with cancer since the therapies. Two comparisons between patients treated with proton therapy
1950s. Proponents of proton therapy argue that this form of RT could have or EBRT report similar early toxicity rates.494,495 A prospective QOL
advantages over x-ray (photon)-based radiation in certain clinical comparison of patient-reported outcomes using the EPIC instrument
circumstances. Proton therapy and x-ray–based therapies like IMRT can between IMRT (204 patients) and proton therapy (1234 patients)
deliver highly conformal doses to the prostate. Proton-based therapies will concluded that “No differences were observed in summary score changes
deliver less radiation dose to some of the surrounding normal tissues like for bowel, urinary incontinence, urinary irritative/obstructive, and sexual
muscle, bone, vessels, and fat not immediately adjacent to the prostate. domains between the 2 cohorts” after up to 2 years of follow-up.496 A
These tissues do not routinely contribute to the morbidity of prostate Medicare analysis of 421 patients treated with proton therapy and a
radiation and are relatively resilient to radiation injury; therefore, the matched cohort of 842 patients treated with IMRT showed less
benefit of decreased dose to these types of normal, non-critical tissues genitourinary toxicity at 6 months for protons, although the difference
has not been apparent. The critical normal structures adjacent to the disappeared after 1 year.495 No other significant differences were seen
prostate that can create prostate cancer treatment morbidity include the between the groups. In contrast, a single-center report of prospectively
bladder, rectum, neurovascular bundles, and occasionally small bowel. collected QOL data revealed significant problems with incontinence, bowel
dysfunction, and impotence at 3 months, 12 months, and greater than 2
The weight of the current evidence about prostate cancer treatment years after treatment with proton therapy.494 In that report, only 28% of
morbidity supports the notion that the volume of the rectum and bladder patients with normal erectile function maintained it after therapy. The
that receives radiobiologically high doses of radiation near the prescription largest retrospective comparative effectiveness analysis to date comparing
radiation dose accounts for the likelihood of long-term treatment morbidity, IMRT to proton therapy was performed using SEER-Medicare claims data
as opposed to higher volume, lower dose exposures. Numerous for the following long-term endpoints: gastrointestinal morbidity, urinary
dosimetric studies have been performed trying to compare x-ray–based incontinence, non-incontinence urinary morbidity, sexual dysfunction, and
IMRT plans to proton therapy plans to illustrate how one or the other type hip fractures.497 With follow-up as mature as 80 months and using both
of treatment can be used to spare the bladder or rectum from higher dose propensity scoring and instrumental variable analysis, the authors
parts of the exposure. These studies suffer from the biases and talents of concluded that patients receiving IMRT therapy had statistically
the investigators who plan and create computer models of dose deposition significantly lower gastrointestinal morbidity than patients receiving proton
for one therapy or the other.493 Although dosimetric studies in-silico can therapy, whereas rates of urinary incontinence, non-incontinence urinary
suggest that the right treatment planning can make an IMRT plan beat a morbidity, sexual dysfunction, hip fractures, and additional cancer
therapies were statistically indistinguishable between the cohorts.
MS-32
Prostate Cancer
However, firm conclusions regarding differences in toxicity or effectiveness The NCCN Panel believes no clear evidence supports a benefit or
of proton and photon therapy cannot be drawn because of the limitations decrement to proton therapy over IMRT for either treatment efficacy or
inherent in retrospective/observational studies. long-term toxicity. Conventionally fractionated prostate proton therapy can
be considered a reasonable alternative to x-ray–based regimens at clinics
The costs associated with proton beam facility construction and proton with appropriate technology, physics, and clinical expertise.
beam treatment are high compared to the expense of building and using
the more common photon linear accelerator-based practice.495 The Radiation for Distant Metastases
American Society for Radiation Oncology (ASTRO) evaluated proton EBRT is an effective means of palliating isolated bone metastases from
therapy and created a model policy to support the society’s position on prostate cancer. Studies have confirmed the common practice in Canada
payment coverage for proton beam therapy in 2014.498 This model policy and Europe of managing prostate cancer with bone metastases with a
was updated in 2017 and recommends coverage of proton therapy for the short course of radiation to the bone. A short course of 8 Gy x 1 is as
treatment of non-metastatic prostate cancer if the patient is enrolled in effective as, and less costly than, 30 Gy in 10 fractions.500 In a randomized
either an institutional review board (IRB)-approved study or a multi- trial of 898 patients with bone metastases, grade 2–4 acute toxicity was
institutional registry that adheres to Medicare requirements for Coverage observed less often in the 8-Gy arm (10%) than in the 30-Gy arm (17%) (P
with Evidence Development (CED). The policy states: “In the treatment of = .002); however, the retreatment rate was higher in the 8-Gy group (18%)
prostate cancer, the use of [proton beam therapy] is evolving as the than in the 30-Gy group (9%) (P < .001).501 In another study of 425
comparative efficacy evidence is still being developed. In order for an patients with painful bone metastases, a single dose of 8 Gy was non-
informed consensus on the role of [proton beam therapy] for prostate inferior to 20 Gy in multiple fractions in terms of overall pain response to
cancer to be reached, it is essential to collect further data, especially to treatment.502 The SCORAD randomized trial failed to show non-inferiority
understand how the effectiveness of proton therapy compares to other RT for ambulatory status of single-fraction 8-Gy EBRT to 20 Gy in 5
modalities such as IMRT and brachytherapy. There is a need for more fractions.503
well-designed registries and studies with sizable comparator cohorts to
help accelerate data collection. Proton beam therapy for primary treatment The Panel notes that 8 Gy as a single dose is as effective for pain
of prostate cancer should only be performed within the context of a palliation at any bony site as longer courses of radiation, but re-treatment
prospective clinical trial or registry.” rates are higher. Other regimens (ie, 30 Gy in 10 fractions or 37.5 Gy in 15
fractions) may be used as alternative palliative dosing depending on
A prospective phase 2 clinical trial enrolled 184 patients with low- or clinical scenario (both category 2B).
intermediate-risk prostate cancer who received 70 Gy of hypofractionated
proton therapy in 28 fractions.499 The 4-year rate of biochemical-clinical Radiation to metastases has also been studied in the oligometastatic
FFS was 93.5% (95% CI, 89%–98%). Grade ≥2 acute GI and urologic setting. The ORIOLE phase 2 randomized trial randomized 54 patients
toxicity rates were 3.8% and 12.5%, respectively. Late GI and urologic with recurrent castration-naïve prostate cancer and 1 to 3 metastases to
toxicity rates were 7.6% and 13.6%, respectively, at 4 years. receive SABR or observation at a 2:1 ratio.504 The primary outcome
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Prostate Cancer
measure was progression at 6 months by increasing PSA, progression approval of Lu-177-PSMA-617 was based on the international, open-label
detected by conventional imaging, symptomatic progression, initiation of phase III VISION trial of 831 patients with M1 CRPC and PSMA-positive
ADT for any reason, or death. Progression at 6 months was lower in metastatic lesions. Patients were previously treated with at least one
patients in the SABR arm than in the observation arm (19% vs. 61%; P = androgen receptor-directed therapy and one or two taxane-based
.005). The secondary endpoint of PFS was also improved in the patients chemotherapy regimens. Patients had at least one PSMA-positive
who received SABR (not reached vs. 5.8 months; HR, 0.30; 95% CI, 0.11– metastatic lesion and no PSMA-negative lesions determined by gallium-68
0.81; P = .002). The SABR-COMET phase 2, international trial (Ga-68) labeled PSMA-11 PET/CT imaging. Patients were randomized in
randomized 99 patients with controlled primary tumors and 1 to 5 a 2:1 ratio to receive standard of care (abiraterone, enzalutamide,
metastatic lesions at 10 centers to standard of care or standard of care bisphosphonates, radiation therapy, denosumab, and/or glucocorticoids)
plus SABR.505 Sixteen patients had prostate cancer. After a median follow- and Lu-177-PSMA-617 (7.4 GBq or 200 mCi every 6 weeks for 4-6 cycles)
up of 51 months, the 5-year OS rate was higher in the SABR group or standard of care alone. 507
(17.7% vs. 42.3%; stratified log-rank P = .006), as was the 5-year PFS
rate (3.2% vs. 17.3%; P = .001). No differences were seen in adverse The median OS was improved in the Lu-177-PSMA-617 group compared
events or QOL. to the control group (15.3 months vs. 11.3 months; HR, 0.62; 95% CI,
0.52–0.74; P < .001). Similarly, the median PFS was improved in the Lu-
The Panel believes that SBRT to metastases can be considered in the 177-PSMA-617 group compared to the control group (8.7 months vs. 3.4
following circumstances: months; HR, 0.40; 99.2% CI, 0.29–0.57; P < .001). The incidence of grade
• In patients with limited metastatic disease to the vertebra or ≥3 adverse events (particularly anemia, thrombocytopenia, lymphopenia,
paravertebral region when ablation is the goal (eg, concern for and fatigue) was significantly higher in the Lu-177-PSMA-617 group
impending fracture or tumor encroachment on spinal nerves or compared to the control group. 507
vertebra).
The NCCN Panel recommends Lu-177-PSMA-617 as a category 1, useful
• In patients with oligometastatic progression where PFS is the goal.
in certain circumstances treatment option for patients with ≥1 PSMA-
• In symptomatic patients where the lesion occurs in or immediately
positive lesion and/or metastatic disease that is predominately PSMA-
adjacent to a previously irradiated treatment field.
positive and with no dominant PSMA-negative metastatic lesions who
Lutetium Lu 177 vipivotide tetraxetan have been treated previously with androgen receptor-directed therapy and
Lutetium Lu 177 vipivotide tetraxetan (Lu-177-PSMA-617) is a a taxane-based chemotherapy. PSMA-negative lesions are defined as
radiopharmaceutical that is administered intravenously and is indicated for metastatic disease that lacks PSMA uptake including bone with soft tissue
PSMA-positive M1 CRPC that has been treated with androgen receptor components ≥1.0 cm, lymph nodes ≥2.5 cm in short axis, and solid organ
pathway inhibition and taxane-based chemotherapy.506 The active moiety metastases ≥1.0 cm in size. The NCCN Panel believes that both Ga-68
is a radionuclide which delivers radiation to PSMA-expressing and PSMA-11 or F-18 piflufolastat PSMA imaging can be used to determine
surrounding cells, inducing DNA damage which leads to cell death.506 The eligibility.
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Prostate Cancer
Radium-223 and Other Radiopharmaceuticals associated with an increased frequency of bone fractures compared with
In May 2013, the U.S. Food and Drug Administration (FDA) approved placebo. The Panel therefore does not recommend this combination.
radium-223 dichloride, an alpha particle-emitting radioactive agent. This
first-in-class radiopharmaceutical was approved for treatment of metastatic Radium-223 is a category 1 option to treat symptomatic bone metastases
CRPC in patients with symptomatic bone metastases and no known without visceral metastases. Hematologic evaluation should be performed
visceral metastatic disease. Approval was based on clinical data from a according to the FDA label before treatment initiation and before each
multicenter, phase 3, randomized trial (ALSYMPCA) that included 921 subsequent dose.513 Radium-223 given in combination with chemotherapy
patients with symptomatic CRPC, two or more bone metastases, and no (such as docetaxel) outside of a clinical trial has the potential for additive
known visceral disease.508 Fifty-seven percent of the patients received myelosuppression.513 It is not recommended for use in combination with
prior docetaxel and all patients received best supportive care. Patients docetaxel or any other systemic therapy except ADT. It should not be used
were randomized in a 2:1 ratio to 6 monthly radium-223 intravenous in patients with visceral metastases, and it should be given with
injections or placebo. Compared to placebo, radium-223 significantly concomitant denosumab or zoledronic acid.
improved OS (median 14.9 months vs. 11.3 months; HR, 0.70; 95% CI,
Beta-emitting radiopharmaceuticals are an effective and appropriate
0.058–0.83; P < .001) and prolonged time to first skeletal-related event
option for patients with widespread metastatic disease, particularly if they
(SRE) (median 15.6 months vs. 9.8 months). Preplanned subset analyses
are no longer candidates for effective chemotherapy.514 Because many
showed that the survival benefit of radium-223 was maintained regardless
patients have multifocal bone pain, systemic targeted treatment of skeletal
of prior docetaxel use.509 Intention-to-treat analyses from ALSYMPCA
metastases offers the potential of pain relief with minimal side effects.
showed that radium-223 also may reduce the risk of symptomatic SREs.510
Unlike the alpha-emitting agent radium-223, beta emitters confer no
Grade 3/4 hematologic toxicity was low (3% neutropenia, 6%
survival advantage and are palliative. Beta-emitting radiopharmaceuticals
thrombocytopenia, and 13% anemia), likely due to the short range of
developed for the treatment of painful bone metastases most commonly
radioactivity.508 Fecal elimination of the agent led to generally mild non-
used for prostate cancer include strontium-89 (89Sr) or samarium-153
hematologic side effects, which included nausea, diarrhea, and vomiting.
(153Sm).515,516 The risk of bone marrow suppression, which might influence
Radium-223 was associated with improved or slower decline of QOL in
the ability to provide additional systemic chemotherapy, should be
ALSYMPCA.511
considered before this therapy is initiated.
The multicenter, international, double-blind, placebo-controlled, phase 3
Comparison of Treatment Options for Localized Disease
ERA 223 trial randomized bone-metastatic patients with chemotherapy-
naïve CRPC to abiraterone with or without radium-223.512 The patients Several large prospective, population/cohort-based studies have
were asymptomatic or mildly symptomatic. The primary endpoint of compared the outcomes of patients with localized prostate cancer treated
symptomatic skeletal event-free survival in the intention-to-treat population with EBRT, brachytherapy, radical prostatectomy, observation, and/or
was not met. In fact, the addition of radium-223 to abiraterone was active surveillance. Barocas et al compared radical prostatectomy, EBRT,
and active surveillance in 2550 patients and found that, after 3 years,
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Prostate Cancer
radical prostatectomy was associated with a greater decrease in urinary prostatectomy. At this time, the panel recommends only cryosurgery and
and sexual function than either EBRT or active surveillance.517 Active high-intensity focused ultrasound (HIFU; category 2B) as local therapy
surveillance, however, was associated with an increase in urinary irritative options for RT recurrence in the absence of metastatic disease.
symptoms. Health-related QOL measures including bowel and hormonal
function were similar among the groups, as was disease-specific survival. Cryosurgery, also known as cryotherapy or cryoablation, is an evolving
minimally invasive therapy that damages tumor tissue through local
Chen et al compared radical prostatectomy, EBRT, and brachytherapy freezing. In the initial disease setting, the reported 5-year biochemical
against active surveillance in 1141 patients.518 As in the Barocas study, disease-free rate after cryotherapy ranged from 65% to 92% in patients
radical prostatectomy was associated with greater declines in sexual and with low-risk disease using different definitions of biochemical
urinary function than other treatments at 3 months. In this study, EBRT recurrence.521 A report suggests that cryotherapy and radical
was associated with worse short-term bowel function, and both EBRT and prostatectomy give similar oncologic results for unilateral prostate
brachytherapy were associated with worsened urinary obstructive and cancer.522 A study by Donnelly and colleagues523 randomly assigned 244
irritative symptoms. By 2 years, however, differences among the groups patients with T2 or T3 disease to either cryotherapy or EBRT. All patients
compared with active surveillance were insignificant. Results of a received neoadjuvant ADT. There was no difference in 3-year OS or DFS.
systematic review showed similar findings to these studies.519 Patients who received cryotherapy reported poorer sexual function.524 For
patients with locally advanced cancer, cryoablation was associated with
Another study examined patient-reported outcomes in greater than 2000 lower 8-year biochemical progression-free rate compared to EBRT in a
patients with localized prostate cancer managed by radical prostatectomy, small trial of 62 patients, although disease-specific survival and OS were
brachytherapy, EBRT with or without ADT, or active surveillance.520 By 5 similar.525
years, most functional differences were minimal between management
approaches. However, radical prostatectomy was associated with worse Cryosurgery has been assessed in patients with recurrent disease after
incontinence in the full cohort and with worse sexual function in those with RT.526-528 In one registry-based study of 91 patients, the biochemical DFS
unfavorable intermediate-, high-, or very-high-risk disease than those rates at 1, 3, and 5 years were 95.3%, 72.4%, and 46.5%, respectively.
managed with EBRT and ADT. Adverse events included urinary retention (6.6%), incontinence (5.5%),
and rectourethral fistula (3.3%).528
Other Local Therapies
Many therapies have been investigated for the treatment of localized HIFU has been studied for treatment of initial disease.529,530 A prospective
prostate cancer in the initial disease and recurrent settings, with the goals multi-institutional study used HIFU in 111 patients with localized prostate
of reducing side effects and matching the cancer control of other cancer.529 The radical treatment-free survival rate was 89% at 2 years, and
therapies. Cryotherapy or other local therapies are not recommended as continence and erectile functions were preserved in 97% and 78% of
routine primary therapy for localized prostate cancer due to lack of long- patients, respectively, at 12 months. Morbidity was acceptable, with a
term data comparing these treatments to radiation or radical grade III complication rate of 13%. In another prospective multi-
institutional study, 625 patients with localized prostate cancer were treated
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Prostate Cancer
with HIFU.531 Eighty-four percent of the cohort had intermediate- or high- assessment; anxiety, depression, trauma, and distress; hormone-related
risk disease. The primary endpoint of FFS was 88% at 5 years (95% CI, symptoms; sexual dysfunction) and on the promotion of physical activity,
85%–91%). Pad-free urinary continence was reported by 98% of weight management, and proper immunizations in survivors.
participants. Other case series studies have seen similar results.532,533
Patients After Initial Definitive Therapy
534-540
HIFU also has been studied for treatment of radiation recurrence. For patients initially treated with intent to cure, serum PSA levels should
Analysis of a prospective registry of patients treated with HIFU for be measured every 6 to 12 months for the first 5 years and then annually.
radiation recurrence revealed median biochemical recurrence-free survival PSA testing every 3 months may be better for patients at high risk of
at 63 months, 5-year OS of 88%, and cancer-specific survival of 94%.541 recurrence. When prostate cancer recurred after radical prostatectomy,
Morbidity was acceptable, with a grade III/IV complication rate of 3.6%. Pound and colleagues found that 45% of patients experienced recurrence
Analysis of a separate prospective registry showed that 48% of those who within the first 2 years, 77% within the first 5 years, and 96% by 10
received HIFU following radiotherapy recurrence were able to avoid ADT years.546 Local recurrence may result in substantial morbidity and can, in
at a median follow-up of 64 months.542 rare cases, occur in the absence of a PSA elevation. Therefore, annual
DRE is appropriate to monitor for prostate cancer recurrence and to detect
Other emerging local therapies, such as focal laser ablation and vascular-
colorectal cancer. Similarly, after RT, the monitoring of serum PSA levels
targeted photodynamic (VTP) therapy have also been studied.543,544 The
is recommended every 6 months for the first 5 years and then annually
multicenter, open-label, phase 3, randomized controlled CLIN1001
and a DRE is recommended annually. The clinician may opt to omit the
PCM301 trial compared VTP therapy (IV padeliporfin, optical fibers
DRE if PSA levels remain undetectable.
inserted into the prostate, and subsequent laser activation) to active
surveillance in 413 patients with low-risk prostate cancer.545 After a median Patients with Castration-Naïve Disease on ADT
follow-up of 24 months, 28% of participants in the VTP arm had disease
The intensity of clinical monitoring for patients on ADT for castration-naïve
progression compared with 58% in the active surveillance arm (adjusted
disease is determined by the response to initial ADT, EBRT, or both.
HR, 0.34; 95% CI, 0.24–0.46; P < .0001). Negative prostate biopsy results
Follow-up evaluation of these patients should include history and physical
were more prevalent in the VTP group (49% vs. 14%; adjusted RR, 3.67;
examination and PSA measurement every 3 to 6 months based on clinical
95% CI, 2.53–5.33; P < .0001). The most common serious adverse event
judgment. Imaging can be considered periodically to monitor treatment
in the VTP group was urinary retention (3 of 206 patients), which resolved
response. The relative risk for bone metastasis or death increases as
within 2 months in all cases.
PSADT falls; a major inflection point appears at PSADT of 8 months. Bone
Disease Monitoring imaging should be performed more frequently in these patients.547
Please refer to the NCCN Guidelines for Survivorship (available at Patients with Localized Disease Under Observation
www.NCCN.org) for recommendations regarding common consequences
Patients with localized disease on observation follow the same monitoring
of cancer and cancer treatment (eg, cardiovascular disease risk
recommendations as patients with castration-naïve disease who are on
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Prostate Cancer
ADT, except that the physical exam and PSA measurement should only Post-Radical Prostatectomy Treatment
be done every 6 months. Most patients who have undergone radical prostatectomy are cured of
prostate cancer. However, some patients will have adverse pathologic
Workup for Progression
features, positive lymph nodes, or biochemical persistence or recurrence.
Castrate levels of testosterone should be documented if clinically indicated Some patients have detectable PSA after radical prostatectomy due to
in patients with signs of progression, with adjustment of ADT as benign prostate tissue in the prostate fossa. They have low stable PSAs
necessary. If serum testosterone levels are <50 ng/dL, the patient should and a very low risk of prostate cancer progression.549,550 Serial PSA
undergo disease workup with bone and soft tissue imaging (see Imaging measurements can be helpful for stratifying patients at highest risk of
Techniques above for more details): progression and metastases.
• Bone imaging can be achieved by conventional technetium-99m-
MDP bone scan. Selecting patients appropriately for adjuvant radiation is difficult.
o Plain films, CT, MRI, or PET/CT or PET/MRI with F-18
sodium fluoride, C-11 choline, F-18 fluciclovine, Ga-68 Adjuvant/Early Treatment for Adverse Features
PSMA-11, or F-18 PyL PSMA can be considered for Adjuvant radiation with or without ADT can be given to patients with PSA
equivocal results on initial bone imaging. persistence (PSA does not fall to undetectable levels) or adverse
• Soft tissue imaging of pelvis, abdomen, and chest can include pathologic features (ie, positive margins, seminal vesicle invasion,
chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. extracapsular extension) who do not have lymph node metastases.
• Alternatively, Ga-68 PSMA-11 or F-18 PyL PSMA PET/CT or Positive surgical margins are unfavorable, especially if diffuse (>10-mm
PET/MRI can be considered for bone and soft tissue (full body) margin involvement or ≥3 sites of positivity) or associated with persistent
imaging. serum levels of PSA. The defined target volumes include the prostate
o Because of the increased sensitivity and specificity of bed.551 Monitoring after radical prostatectomy is also appropriate, with
PSMA-PET tracers for detecting micrometastatic disease consideration of early EBRT for a detectable and rising PSA or PSA >0.1
compared to conventional imaging (CT, MRI) at both initial ng/mL.
staging and biochemical recurrence, the Panel does not
Decisions about when to initiate post-radical prostatectomy radiation and
feel that conventional imaging is a necessary prerequisite
whether to include ADT are complex. The Panel recommends use of
to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI
nomograms and consideration of age and comorbidities, clinical and
can serve as an equally effective, if not more effective front-
pathologic information, PSA levels, PSADT, and Decipher molecular
line imaging tool for these patients.
assay to individualize treatment discussion. Older trials conducted by
ASCO has published guidelines on the optimal imaging strategies for SWOG and EORTC showed that post-prostatectomy adjuvant radiation
patients with advanced prostate cancer.548 ASCO recommendations are improved biochemical PFS in patients with extraprostatic disease at
generally consistent with those provided here. radical prostatectomy.552-554 More recent randomized trials that used
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Prostate Cancer
modern surgical and radiation techniques provide high-level evidence that retrospective analysis of radical prostatectomy specimens from patients in
can be used to counsel patients and are discussed herein. RTOG 9601 suggest that those with low PSA and a low Decipher score
derived less benefit (development of distant metastases, OS) from
In the RADICALS-RT trial, 1396 patients with adverse features after bicalutamide than those with a high Decipher score.562 Patients with high
radical prostatectomy were followed for a median 4.9 years and no Decipher genomic classifier scores (GC >0.6) should be strongly
differences were seen in 5-year biochemical PFS and freedom from non- considered for EBRT and addition of ADT when the opportunity for early
protocol hormone therapy.555 However, urinary incontinence and grade 3– EBRT has been missed.
4 urethral strictures were more frequent in the adjuvant therapy group. The
GETUG-AFU 17 trial and the TROG 08.03/ANZUP RAVES trial were both Overall, the Panel believes that adjuvant or early EBRT after recuperation
terminated early for unexpectedly low event rates, but similarly found no from operation may be beneficial in patients with one or more adverse
evidence of oncologic benefit with increased risk of genitourinary toxicity laboratory or pathologic features, which include positive surgical margin,
and erectile dysfunction when adjuvant therapy was used.556,557 Another seminal vesicle invasion, and/or extracapsular extension as noted in the
randomized trial, however, saw an improvement in 10-year survival for guideline by the American Urological Association (AUA) and ASTRO.563
biochemical recurrence with the use of adjuvant therapy (HR, 0.26; 95%
CI, 0.14–0.48; P < .001).558 The value of whole pelvic irradiation in this setting is unclear due to a lack
of benefit in PFS in two trials (RTOG 9413 and GETUG 01)423,424,564,565;
Systematic reviews come to conflicting conclusions on the utility of whole pelvic radiation may be appropriate for selected patients.
immediate post-prostatectomy radiation in patients with adverse
features.559,560 A retrospective cohort analysis of more than 26,000 patients Adjuvant Therapy for pN1
concluded that patients with adverse features after radical prostatectomy Adjuvant therapy can also be given to patients with positive lymph nodes
(ie, Gleason 8–10; pT3/4; pN1) should be candidates for adjuvant found during or after radical prostatectomy. Several management options
radiation because a reduction in all-cause mortality was observed in such should be considered. ADT is a category 1 option, as discussed below
patients.561 (see Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for
Regional Disease).566 Retrospective data show that initial observation may
A limited amount of data inform the decision regarding the addition of ADT be safe in some patients with N1 disease at radical prostatectomy,
to EBRT in this setting. The ongoing SPPORT trial (NCT00567580) of because 28% of a cohort of 369 patients remained free from biochemical
patients with PSA levels between 0.1 and 2.0 ng/mL at least 6 weeks after recurrence at 10 years.567 Therefore, another option is monitoring with
radical prostatectomy has reported preliminary results on clinicaltrials.gov. consideration of early treatment for a detectable and rising PSA or PSA
The primary outcome measure of percentage of participants free from >0.1 ng/mL, based further on extrapolation of data from RADICALS-RT,
progression (FFP) at 5 years was 70.3 (95% CI, 66.2–74.3) for those who GETUG-AFU 17, and TROG 08.03/ANZUP RAVES.555-557 A third option is
received EBRT to the prostate bed and 81.3 (95% CI, 77.9–84.6) for those the addition of pelvic EBRT to ADT (category 2B). This last
who received EBRT with 4 to 6 months of ADT (luteinizing hormone- recommendation is based on retrospective studies and a National Cancer
releasing hormone [LHRH] agonist plus antiandrogen). Results of a
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Prostate Cancer
Database analysis that demonstrated improved biochemical recurrence- restaging, and a nomogram125,578 may prove useful to predict response, but
free survival, cancer-specific survival, and all-cause survival with post- it has not been validated.
prostatectomy EBRT and ADT compared to adjuvant ADT alone in
patients with lymph node metastases.568-571 The utility of imaging for patients with an early biochemical recurrence
after radical prostatectomy depends on disease risk before operation and
Biochemical Recurrence After Radical Prostatectomy pathologic stage, Gleason grade, PSA, and PSADT after recurrence.
Patients who experience biochemical recurrence after radical Patients with low- and intermediate-risk disease and low postoperative
prostatectomy fall into three groups: 1) those whose PSA level does not serum PSA levels have a very low risk of positive bone scans or CT
fall to undetectable levels after radical prostatectomy (persistent disease); scans.579,580 In a series of 414 bone scans performed in 230 patients with
2) those who achieve an undetectable PSA after radical prostatectomy biochemical recurrence after radical prostatectomy, the rate of a positive
with a subsequent detectable PSA level that increases on two or more bone scan for patients with PSA >10 ng/mL was only 4%.581
subsequent laboratory determinations (PSA recurrence); or 3) the
The specific staging tests depend on the clinical history, but should include
occasional case with persistent but low PSA levels attributed to slow PSA
a calculation of PSADT to inform nomogram use and counseling. In
metabolism or residual benign tissue. Consensus has not defined a
addition, bone imaging; chest CT; abdominal/pelvic CT or
threshold level of PSA below which PSA is truly “undetectable.”549 Group 3
abdominal/pelvic MRI; C-11 choline PET/CT or PET/MRI or F-18
does not require further evaluation until PSA increases, but the workup for
fluciclovine PET/CT or PET/MRI; and prostate bed biopsy may be useful.
1 and 2 must include an evaluation for distant metastases.
The Decipher molecular assay can be considered for prognostication after
Several retrospective studies have assessed the prognostic value of radical prostatectomy (category 2B). A meta-analysis of five studies with
various combinations of pretreatment PSA levels, Gleason scores, 855 patients and median follow-up of 8 years found that the 10-year
PSADT, and the presence or absence of positive surgical margins.572-576 A cumulative incidence metastases rates for patients classified as low,
large retrospective review of 501 patients who received radiation for intermediate, and high risk by Decipher after radical prostatectomy were
detectable and increasing PSA after radical prostatectomy575 showed that 5.5%, 15.0%, and 26.7%, respectively (P < .001).582
the predictors of progression were Gleason score 8 to 10, pre-EBRT PSA
Bone imaging is appropriate when patients develop symptoms or when
level >2 ng/mL, seminal vesicle invasion, negative surgical margins, and
PSA levels are increasing rapidly. In one study, the probability of a positive
PSADT ≤10 months. However, prediction of systemic disease versus local
bone scan for a patient not on ADT after radical prostatectomy was less
recurrence and hence responsiveness to postoperative radiation has
than 5% unless the PSA increased to 40 to 45 ng/mL.583 A prostate bed
proven unfeasible for individual patients using clinical and pathologic
biopsy may be helpful when imaging suggests local recurrence.
criteria.577 Delivery of adjuvant or post-recurrence EBRT becomes both
therapeutic and diagnostic—PSA response indicates local Patients with PSA recurrence (undetectable PSA that increases on two or
persistence/recurrence. Delayed biochemical recurrence requires more measurements) after radical prostatectomy may be observed or
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Prostate Cancer
undergo primary EBRT with or without ADT if distant metastases are not acceptable for selected patients, with ADT delayed until symptoms
detected. develop or PSA levels suggest that symptoms are imminent. In all cases,
the form of primary or secondary systemic therapy should be based on the
Large retrospective cohort studies support the use of EBRT in the setting hormonal status of the patient.
of biochemical recurrence, because it is associated with decreased all-
cause mortality and increased prostate cancer-specific survival.577,584 The Post-Radiation Recurrence
recommended post-radical prostatectomy EBRT dose is 64 to 72 Gy and The 2006 Phoenix definition was revised by ASTRO and the RTOG in
may be increased for gross recurrence that has been proven by biopsy. Phoenix: 1) PSA rise by 2 ng/mL or more above the nadir PSA is the
The target volume includes the prostate bed and may include the whole standard definition for biochemical recurrence after EBRT with or without
pelvis in selected patients.551 Treatment is most effective when pre- hormonal therapy; and 2) A recurrence evaluation should be considered
treatment PSA level is below 0.5 ng/mL.578 Paradoxically, post-recurrence when PSA has been confirmed to be increasing after radiation even if the
EBRT was shown to be most beneficial when the PSADT time was less rise above nadir is not yet 2 ng/mL, especially in candidates for additional
than 6 months in a cohort analysis of 635 patients,577 although another local therapy who are young and healthy.590 Retaining a strict version of
study of 519 patients reported mortality reduction for both those with the ASTRO definition allows comparison with a large existing body of
PSADT less than 6 months and those with PSADT greater than or equal to literature. Rapid increase of PSA may warrant evaluation (prostate biopsy)
6 months.584 Most patients with prolonged PSADT may be observed prior to meeting the Phoenix definition, especially in younger or healthier
safely.585 patients.
Six months of concurrent/adjuvant ADT can be coadministered with Workup for RT recurrence typically includes PSADT calculation, bone
radiation in patients with rising PSA levels based on the results of imaging, TRUS biopsy, and prostate MRI; in addition, a chest CT, an
GETUG-16.586,587 However, a secondary analysis of RTOG 9601 found that abdominal/pelvic CT or abdominal/pelvic MRI, C-11 choline PET/CT or
patients with PSA ≤0.6 ng/mL had no OS improvement with the addition of PET/MRI, or F-18 fluciclovine PET/CT or PET/MRI can be considered.
bicalutamide to EBRT.588 Two years instead of 6 months of ADT can be
considered in addition to radiation for patients with persistent PSA after Local radiation recurrences are most responsive to additional therapy
radical prostatectomy or for PSA levels that exceed 1.0 ng/mL at the time when PSA levels at the time of treatment are low (<5 ng/mL). Biopsy
of initiation of therapy, based on results of RTOG 9601.589 For 2 years of should be encouraged at the time of radiation biochemical recurrence if
ADT, level 1 evidence supports 150 mg bicalutamide daily but an LHRH staging workup does not reveal metastatic disease. Prostate biopsy in the
agonist could be considered as an alternative.589 setting of suspected local recurrence after radiation should be considered,
including biopsy at the junction of the seminal vesicle and prostate,
ADT alone becomes the treatment when there is proven or high suspicion because this is a common site of recurrence.
for distant metastases after PSA recurrence. Pelvic radiation is not
recommended but may be given to the site of bone metastasis if in weight- Options for therapy for those with positive biopsy but low suspicion of
bearing bones or if the patient is symptomatic. Observation remains metastases to distant organs and a life expectancy greater than 10 years
Version 2.2023 © 2023 National Comprehensive Cancer Network© ©
(NCCN ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Prostate Cancer
include observation or radical prostatectomy with PLND in selected cases prostate cancer who were not treated with curative intent therapy reported
by highly experienced surgeons. Radical prostatectomy after RT no survival benefit from primary ADT after adjusting for demographic and
recurrence can result in long-term disease control, but is often associated clinical variables.595 Placing patients with early prostate cancer on ADT
with impotence and urinary incontinence.591 Other options for localized should not be routine practice.
interventions include cryotherapy,592 HIFU (category 2B),534-537,541,542 and
brachytherapy (reviewed by Allen and colleagues593 and discussed in Antiandrogen monotherapy (bicalutamide) after completion of primary
Post-Recurrence Brachytherapy, above). Treatment, however, needs to treatment was investigated as an adjuvant therapy in patients with
be individualized based on the patient's risk of progression, the likelihood localized or locally advanced prostate cancer, but results did not support
of success, and the risks involved with therapy. For those with a life its use in this setting.596,597
expectancy less than or equal to 10 years, positive biopsy, and no distant
Castrate levels of serum testosterone (<50 ng/dL; <1.7 nmol/L) should be
metastases, observation or ADT are appropriate options.
achieved with ADT, because low nadir serum testosterone levels were
Negative TRUS biopsy after post-radiation biochemical recurrence poses shown to be associated with improved cause-specific survival in the PR-7
clinical uncertainties. Therefore, mpMRI or full-body PET imaging can be study.598 Patients who do not achieve adequate suppression of serum
considered (see Imaging Techniques, above). In the absence of testosterone (<50 ng/dL) with medical or surgical castration can be
detectable metastases with a negative biopsy, observation or ADT are considered for additional hormonal manipulations (with estrogen,
options for patients with PSA recurrence after radiation. antiandrogens, LHRH antagonists, or steroids), although the clinical
benefit remains uncertain. Monitoring testosterone levels 12 weeks after
Patients with radiographic evidence of distant metastases should proceed first dose of LHRH therapy and upon increase in PSA should be
to ADT for castration-naïve disease. considered.
Androgen Deprivation Therapy ADT for Clinically Localized (N0,M0) Disease

ADT is administered as primary systemic therapy for regional or advanced ADT should not be used as monotherapy in clinically localized prostate
disease and as neoadjuvant/concomitant/adjuvant therapy in combination cancer unless there is a contraindication to definitive local therapy, such
with radiation in localized or locally advanced prostate cancers. as life expectancy less than 5 years and comorbidities. Under those
circumstances, ADT may be an acceptable alternative if the disease is
In the community, ADT has been commonly used as primary therapy for high or very high risk (see Palliative ADT, below).
early-stage, low-risk disease, especially in the patients who are older. This
practice has been challenged by a large cohort study of 66,717 patients In the clinically localized setting, ADT using an LHRH agonist—alone or
≥66 years of age with T1–T2 tumors.594 No 15-year survival benefit was with a first-generation antiandrogen—or an LHRH antagonist can be used
found in patients receiving ADT compared to observation alone. Similarly, as a neoadjuvant, concurrent, and/or adjuvant to EBRT in patients with
another cohort study of 15,170 patients diagnosed with clinically localized unfavorable intermediate-, high-, or very-high-risk prostate cancer, as
described in more detail below.
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Prostate Cancer
ADT used as neoadjuvant treatment before radical prostatectomy is cohort of 397 patients with a median follow-up of 9.2 years, results
strongly discouraged outside of a clinical trial. demonstrated no significant difference in ADT+EBRT versus
ADT+EBRT+TEE in OS (65% vs. 63%; P = .81), biochemical recurrence
Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for
(58% vs. 54%; P = .82), distant metastases (16% vs. 14%; P = .42), or
Intermediate-Risk Disease
DFS (22% vs. 26%; P = .61), but a substantial increase in toxicity (3.9%
The addition of short-term ADT to radiation improved OS and cancer-
vs. 0% treatment-related deaths), which resulted in early closure of the
specific survival in three randomized trials containing 20% to 60% of
trial.607 Thus, the fact that 6 months of ADT improved survival compared to
patients with intermediate-risk prostate cancer (Trans Tasman Radiation
EBRT alone does not mean it is better than 4 months of ADT, and the fact
Oncology Group [TROG] 9601, Dana Farber Cancer Institute [DFCI]
that systemic chemotherapy is effective in one setting (high-volume
95096, and Radiation Therapy Oncology Group [RTOG] 9408).589,599-601
metastatic disease or CRPC) should not lead to the assumption that it will
Only a cancer-specific survival benefit was noted in a fourth trial that
be beneficial in other settings (eg, high-risk localized disease).608,609
recruited mostly patients with high-risk disease (RTOG 8610).602 Results of
the EORTC 22991 trial showed that the addition of 6 months of ADT At this time, the Panel recommends 4 to 6 months of ADT when EBRT is
significantly improved biochemical DFS compared with radiation alone in given to patients as initial treatment of unfavorable intermediate-risk
those with intermediate-risk (75% of study population) and high-risk prostate cancer. If brachytherapy is added to EBRT in this setting, then 4
disease.603 A secondary analysis of the RTOG 9408 trial showed that the to 6 months of ADT is optional.
benefit of ADT given with EBRT in patients intermediate-risk prostate
cancer was limited to those in the unfavorable subset.604 Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for High-Risk or
Very-High-Risk Disease
RTOG 9910 and RTOG 9902 reinforced two important principles ADT combined with EBRT is an effective primary treatment for patients at
concerning the optimal duration of ADT and use of systemic high risk or very high risk, as discussed in the Radiation Therapy section
chemotherapy in conjunction with EBRT.605,606 RTOG 9910 is a phase 3 above. Combination therapy was consistently associated with improved
randomized trial targeting patients with intermediate-risk prostate cancer disease-specific survival and OS compared to single-modality treatment in
that compared 4 months to 9 months of ADT. RTOG 9408 had previously randomized phase 3 studies.415,416,418,419,610
shown that 4 months of ADT combined with EBRT improved survival in
those with intermediate-risk disease compared to EBRT alone.601 Increasing evidence favors long-term over short-term
Consistent with earlier studies, RTOG 9910 demonstrated that there is no neoadjuvant/concurrent/adjuvant ADT for patients with high- and very-
reason to extend ADT beyond 4 months when given in conjunction with high-risk disease. The RTOG 9202 trial included 1521 patients with T2c-
EBRT in patients with intermediate-risk disease. T4 prostate cancer who received 4 months of ADT before and during
EBRT.611 They were randomized to no further treatment or an additional 2
RTOG 9902 compared long-term ADT and EBRT with and without years of ADT. At 10 years, the long-term group was superior for all
paclitaxel, estramustine, and etoposide (TEE) chemotherapy in patients endpoints except OS. A subgroup analysis of patients with a Gleason
with locally advanced, high-risk prostate cancer.607 In the randomized score of 8 to 10 found an advantage in OS for long-term ADT at 10 years
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Prostate Cancer
(32% vs. 45%, P = .0061). At a median follow-up of 19.6 years, long-term neoadjuvant/concurrent/adjuvant ADT (category 1, see Neoadjuvant,
ADT was superior for all endpoints including OS in the entire cohort (12% Concurrent, and/or Adjuvant ADT with EBRT for Regional Disease,
relative reduction; P = .03).612 below). For those patients with N1 disease who are treated with radiation
to the prostate and pelvic nodes, abiraterone acetate (abiraterone) with
The EORTC 22961 trial also showed superior survival when 2.5 years of ADT should be considered for a total of 2 years. Abiraterone should not be
ADT were added to EBRT given with 6 months of ADT in 970 patients, coadministered with an antiandrogen (see Abiraterone Acetate in
most of whom had T2c–T3, N0 disease.613 The DART01/05 GICOR trial Castration-Naïve Prostate Cancer, below).
also reported similar results in patients with high-risk disease.614 In a
secondary analysis of RTOG 8531, which mandated lifelong ADT for The EORTC 30846 trial randomized 234 treatment-naïve patients with
patients with locally advanced prostate cancer treated with EBRT, those node-positive prostate cancer to immediate versus delayed ADT.619 At 13
who adhered to the protocol had better survival than those who years median follow-up, the authors reported similar survival between the
discontinued ADT within 5 years.615 Two randomized phase 3 trials two arms, although the study was not powered to show non-inferiority.
showed 1.5 years of ADT was not inferior to 3 years of ADT.616,617
Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for Regional
A meta-analysis of data from 992 patients enrolled in 6 randomized Disease
controlled trials showed that a longer duration of ADT with EBRT benefited Patients initially diagnosed with pelvic lymph node-positive disease who
patients with Grade Group 4 or 5 prostate cancer.618 have a life expectancy greater than 5 years can be treated with EBRT with
2 to 3 years of neoadjuvant/concurrent/adjuvant ADT (category 1) with or
Neoadjuvant, Concurrent, and/or Adjuvant ADT with EBRT for Recurrent without abiraterone. Alternatively, they can receive primary ADT without
Disease EBRT with or without abiraterone (see Primary ADT for Lymph Node
Patients who develop PSA recurrence after radical prostatectomy without Metastases, above and Abiraterone Acetate in Castration-Naïve Prostate
evidence of metastases can receive pelvic EBRT with Cancer, below). Neoadjuvant/concurrent/adjuvant ADT options are an
neoadjuvant/concurrent/adjuvant ADT (see ADT for M0 Biochemical LHRH agonist, an LHRH agonist with a first-generation antiandrogen, or
Recurrence, below). an LHRH antagonist. Abiraterone should not be coadministered with an
antiandrogen.
ADT for Regional Disease
Primary ADT for Lymph Node Metastases The role of adjuvant ADT after radical prostatectomy is restricted to cases
Patients initially diagnosed with node-positive disease who have a life where positive pelvic lymph nodes are found, although reports in this area
expectancy greater than 5 years can be treated with primary ADT. Primary reveal mixed findings. Messing and colleagues randomly assigned 98
ADT options are orchiectomy, an LHRH agonist, an LHRH agonist with a patients who were found to have positive lymph nodes at the time of
first-generation antiandrogen, or an LHRH antagonist (category 2B); or radical prostatectomy to immediate continuous ADT or observation.566 In
orchiectomy, LHRH agonist, or LHRH antagonist with abiraterone. Another the immediate ADT arm of 47 patients, 30 remained alive, 29 of whom
option for these patients is EBRT with 2 to 3 years of were prostate cancer recurrence-free and 26 of whom were PSA
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Prostate Cancer
recurrence-free after a median follow-up of 11.9 years (range, 9.7–14.5 ADT for Castration-Naive Disease
years for survivors).566,620 Those receiving immediate ADT also had a The term “castration-naive" is used to define patients who have not been
significant improvement in OS (HR, 1.84; 95% CI, 1.01–3.35). treated with ADT and those who are not on ADT at the time of
progression. The NCCN Prostate Cancer Panel uses the term "castration-
However, these results differ from a SEER Medicare, population-based
naive" even when patients have had neoadjuvant, concurrent, and/or
test of ADT published subsequently.621 The SEER Medicare-based study
adjuvant ADT as part of RT provided they have recovered testicular
of patients who underwent radical prostatectomy and had positive lymph
function. Options for patients with castration-naïve disease who require
nodes used propensity matching to compare patients who received ADT
ADT depend on the presence of distant metastases, and can be found in
within 120 days to those who were observed. The groups had similar
full in the Guidelines algorithm above.
median and range of follow-up for survivors, but OS and prostate cancer-
specific survival were similar. The Messing study occurred prior to the ADT for castration-naïve prostate cancer can be accomplished using
PSA era, but the studies are similar in almost all other respects. The bilateral orchiectomy, an LHRH agonist or antagonist, or an LHRH agonist
Messing study showed almost unbelievable benefit, and the population- plus a first-generation antiandrogen. As discussed below, abiraterone or
based study of 731 patients showed no benefit. Furthermore, a meta- docetaxel can be added to orchiectomy, LHRH agonist, or LHRH
analysis resulted in a recommendation against ADT for pathologic lymph antagonist for M1 disease. For patients with M0 disease, observation is
node metastatic prostate cancer in the ASCO guidelines.622 In addition, a preferred over ADT.
cohort analysis of 731 patients with positive nodes did not demonstrate a
survival benefit of ADT initiated within 4 months of radical prostatectomy LHRH agonists and LHRH antagonists appear equally effective in patients
compared to observation.621 At this time, the Panel recommends that with advanced prostate cancer.623
patients with lymph node metastases found at radical prostatectomy
should be considered for immediate ADT (category 1) with or without Medical or surgical castration combined with an antiandrogen is known as
EBRT (category 2B), but that observation is also an option for these combined androgen blockade. No prospective randomized studies have
patients. demonstrated a survival advantage with combined androgen blockade
over the serial use of an LHRH agonist and an antiandrogen.622 Meta-
Palliative ADT analysis data suggest that bicalutamide may provide an incremental
Palliative ADT can be given to patients with a life expectancy of less than relative improvement in OS by 5% to 20% over LHRH agonist
or equal to 5 years who have high-risk, very-high-risk, regional, or monotherapy.624,625 However, others have concluded that more complete
metastatic prostate cancer. Palliative ADT also can be given to patients disruption of the androgen axis (with finasteride, dutasteride, or
with disease progression during observation, usually when symptoms antiandrogen added to medical or surgical castration) provides little if any
develop or when changes in PSA levels suggest that symptoms are benefit over castration alone.626,627 Combined androgen blockade therapy
imminent. The options in this setting are orchiectomy, LHRH agonist, or adds to cost and side effects, and prospective randomized evidence that
LHRH antagonist (category 2B for LHRH antagonist). combined androgen blockade is more efficacious than ADT is lacking.
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Prostate Cancer
Antiandrogen monotherapy appears to be less effective than medical or 75%; P = .84). The incidence of major adverse cardiovascular events was
surgical castration and is not recommended for primary ADT. Furthermore, 2.9% in the relugolix arm and 6.2% in the leuprolide arm (HR, 0.46; 95%
dutasteride plus bicalutamide showed no benefit over bicalutamide alone CI, 0.24–0.88). The Panel includes relugolix alone as an option for ADT in
in patients with locally advanced or metastatic prostate cancer.628 patients with castration-naïve disease. However, the Panel notes that data
are limited on long-term adherence of oral relugolix and the potential
Recent evidence suggests that orchiectomy may be safer than an LHRH effects non-adherence may have on optimal ADT. Ongoing monitoring for
agonist. Four hundred twenty-nine patients with metastatic prostate cancer sustained suppression of testosterone (<50 ng/dL) can be considered, and
who underwent orchiectomy were compared to 2866 patients who relugolix may not be a preferred agent if adherence is uncertain.
received LHRH agonist between 1995 and 2009. Orchiectomy was
associated with lower risk of fracture, peripheral arterial disease, and It is important to note that the HERO trial did not include patients receiving
cardiac-related complications, although risk was similar for diabetes, deep curative intent therapy (ie, individuals getting definitive EBRT plus ADT).
vein thrombosis, pulmonary embolism, and cognitive disorders.629 Post- Furthermore, relugolix shows a shorter time to testosterone recovery,
hoc analysis of a randomized trial of LHRH antagonist versus LHRH which might be associated with a higher risk of death from prostate
agonist found lower risk of cardiac events in patients with existing cardiac cancer.633 Therefore, although the Panel considers relugolix to be an
disease treated with LHRH antagonist.630 The heart and T lymphocytes acceptable option in the curative-intent setting, additional studies in this
have receptors for LHRH. Therefore, LHRH agonists may affect cardiac setting are needed.
contractility, vascular plaque stability, and inflammation.631
Patients should be queried about adverse effects related to ADT.
A new LHRH antagonist, relugolix, has been studied as ADT in patients Intermittent ADT should be used for those who experience significant side
with advanced prostate cancer in the randomized phase 3 HERO trial.632 In effects of ADT (see Intermittent Versus Continuous ADT, below).
this study, 622 patients received relugolix (120 mg orally once daily) and
ADT for M0 Biochemical Recurrence
308 received leuprolide (injections every 3 months) for 48 weeks. The
patients had recurrence after primary definitive therapy, newly diagnosed Controversy remains about the timing and duration of ADT when disease
metastatic castration-naïve disease, or advanced localized disease persists or recurs after local therapy. Many believe that early ADT is best,
deemed unlikely to be cured with definite therapy. The primary endpoint, but cancer control must be balanced against side effects. Early ADT is
sustained castrate levels of testosterone (<50 ng per deciliter) through 48 associated with increased side effects and the potential development of
weeks, showed noninferiority and superiority of relugolix over leuprolide the metabolic syndrome.
(96.7%; 95% CI, 94.9–97.9 vs. 88.8% [95% CI, 84.6–91.8]; P < .001 for
Patients with an increasing PSA level and with no symptomatic or clinical
superiority). The secondary endpoint of castrate levels of testosterone on
evidence of cancer after definitive treatment present a therapeutic
day 4 was also improved in the relugolix arm (56% vs. 0%). However,
dilemma regarding the role of ADT. Some of these patients will ultimately
relugolix did not achieve superiority in the key clinical secondary endpoint
die of their cancer. Timing of ADT for patients whose only evidence of
of castration resistance-free survival compared to leuprolide (74% vs.
cancer is increasing PSA is influenced by PSA velocity (PSADT), patient
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Prostate Cancer
and physician anxiety, the short-term and long-term side effects of ADT, Primary ADT for M1 Castration-Naïve Prostate Cancer
and underlying comorbidities of the patient. Early ADT is acceptable, but ADT with treatment intensification is preferred for most patients with
an alternative is close observation until progression of cancer, at which metastatic prostate cancer. ADT alone is appropriate for some patients.622
time appropriate therapeutic options may be considered. Earlier ADT may A PSA value ≤4 ng/mL after 7 months of ADT is associated with improved
be better than delayed therapy, although the definitions of early and late survival of patients newly diagnosed with metastatic prostate cancer.636
(ie, what level of PSA) remain controversial. The multicenter phase 3
TROG 03.06/VCOG PR 01-03 [TOAD] trial randomized 293 patients with ADT options for M1 castration-naïve disease are:
PSA relapse after operation or radiation (n = 261) or who were not • Orchiectomy ± docetaxel
considered for curative treatment (n = 32) to immediate ADT or ADT • LHRH agonist alone ± docetaxel
delayed by a recommended interval of greater than or equal to 2 years.634 • LHRH agonist plus first-generation antiandrogen ± docetaxel
Five-year OS was improved in the immediate therapy arm compared with • LHRH antagonist ± docetaxel
the delayed therapy arm (91.2% vs. 86.4%; log-rank P = .047). No • Orchiectomy plus abiraterone, apalutamide, or enzalutamide
significant differences were seen in the secondary endpoint of global • LHRH agonist plus abiraterone, apalutamide, or enzalutamide
health-related QOL at 2 years.635 In addition, there were no differences • LHRH antagonist plus abiraterone, apalutamide, or enzalutamide
over 5 years in global QOL, physical functioning, role or emotional
functioning, insomnia, fatigue, dyspnea, or feeling less masculine. In patients with overt metastases in weight-bearing bone who are at risk of
However, sexual activity was lower and the hormone treatment-related developing symptoms associated with the flare in testosterone with initial
symptoms score was higher in the immediate ADT group compared with LHRH agonist alone, antiandrogen therapy should precede or be
the delayed ADT group. Most clinical trials in this patient population coadministered with LHRH agonist for at least 7 days to diminish ligand
require PSA level ≥0.5 mg/dL (after radical prostatectomy) or “nadir + 2” binding to the androgen receptor.637,638 LHRH antagonists rapidly and
(after radiation) for enrollment. directly inhibit the release of androgens, unlike LHRH agonists that initially
stimulate LHRH receptors prior to hypogonadism. Therefore, no initial flare
The Panel believes that the benefit of early ADT is uncertain and must be is associated with these agents and coadministration of antiandrogen is
balanced against the risk of ADT side effects. Patients with an elevated unnecessary.
PSA and/or a shorter PSADT (rapid PSA velocity) and an otherwise long
life expectancy should be encouraged to consider ADT earlier. Patients The data supporting the addition of abiraterone, apalutamide,
who opt for ADT should consider the intermittent approach. The timing of enzalutamide, or docetaxel to ADT in this setting are discussed below.
ADT initiation should be individualized according to PSA velocity, patient These are all category 1, preferred options; the fine-particle formulation of
anxiety, and potential side effects. Patients with shorter PSADT or rapid abiraterone (discussed in Abiraterone Acetate in M1 CRPC, below) can be
PSA velocity and long life expectancy may be encouraged to consider added to ADT as a category 2B option. ADT (LHRH agonist, LHRH
early ADT. Patients with prolonged PSADTs who are older are excellent antagonist, or orchiectomy) with EBRT to the primary tumor for low-
candidates for observation.
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Prostate Cancer
volume metastatic disease is discussed in EBRT to the Primary Tumor in rare but slightly increased with abiraterone. The overall discontinuation
Low-Volume M1 Disease, above. rate due to side effects was 12%. Patient-reported outcomes were
improved with the addition of abiraterone, with improvements in pain
Abiraterone Acetate in Castration-Naïve Prostate Cancer
intensity progression, fatigue, functional decline, prostate cancer-related
In February 2018, the FDA approved abiraterone in combination with symptoms, and overall health-related QOL.643 A limitation of this trial is that
prednisone for metastatic castration-naïve prostate cancer.639,640 This only 27% of placebo-treated patients received abiraterone or enzalutamide
approval was based on two randomized phase 3 clinical trials of at progression, and only 52% of these patients received any life-
abiraterone and low-dose prednisone plus ADT that were reported in prolonging therapy.641
patients with newly diagnosed metastatic prostate cancer or high-risk or
node-positive disease (STAMPEDE and LATITUDE) that demonstrated A second randomized trial (STAMPEDE) of 1917 patients with castration-
improved OS over ADT alone.641 In LATITUDE, 1199 patients with high- naïve prostate cancer demonstrated similar OS benefits.430 However,
risk, metastatic, castration-naïve prostate cancer were randomized to unlike LATITUDE, STAMPEDE eligibility permitted patients with high-risk
abiraterone with prednisone 5 mg once daily or matching placebos. High- N0,M0 disease (2 of 3 high-risk factors: stage T3/4, PSA >40, or Gleason
risk disease was defined as at least two of the following: Gleason score 8– score 8–10; n = 509), or N1,M0 disease (pelvic nodal metastases; n =
10, ≥3 bone metastases, and visceral metastases.641 Efficacy was 369) in addition to M1 patients, who made up the majority of patients (n =
demonstrated at the first interim analysis, and the trial was unblinded. The 941). The majority of patients were newly diagnosed, while a minority had
primary endpoint of OS was met and favored abiraterone (HR, 0.62; 95% recurrent, high-risk, or metastatic disease after local therapy (n = 98).
CI, 0.51–0.76; P < .0001). Estimated 3-year OS rates improved from 49% Thus, STAMPEDE was a heterogeneous mix of patients with high-risk,
to 66% at 30 months follow-up. Secondary endpoints were improved and non-metastatic, node-positive, or M1 disease. In M1 patients, treatment
included delayed castration-resistant radiographic progression (from with abiraterone plus prednisone was continued until progression. In
median 14.8–33.2 months), PSA progression (7.4–33.2 months), time to patients with N1 or M0 disease, 2 years of abiraterone plus prednisolone
pain progression, and initiation of chemotherapy. After the first interim was used if curative-intent EBRT was utilized. OS was improved in the
analysis, 72 patients crossed over from placebo to abiraterone. Final OS overall population (HR, 0.63; 95% CI, 0.5–0.76; P < .0001) and in the M1
analysis of LATITUDE after a median follow-up of 51.8 months showed and N1 subsets, without any heterogeneity of treatment effect by
median OS was significantly longer in the abiraterone group than in the metastatic status. The survival benefit of abiraterone was larger in patients
placebo group (53.3 months vs. 36.5 months; HR, 0.66; 95% CI, 0.56– <70 years of age than those ≥70 years (HR, 0.94 vs. HR, 0.51). Patients
0.78; P < .0001).642 who were older also suffered increased toxicities, which suggests
heterogeneity in clinical benefits by age and comorbidity. The secondary
Adverse events were higher with abiraterone and prednisone but were endpoint of FFS, which included PSA recurrence, was improved overall
generally mild in nature and largely related to mineralocorticoid excess (ie, (HR, 0.29; P < .0001) and in all subgroups regardless of M1 (HR, 0.31),
hypertension, hypokalemia, edema), hormonal effects (ie, fatigue, hot N1 (HR, 0.29), or M0 (HR, 0.21) status. No heterogeneity for FFS was
flushes), and liver toxicity.641 Cardiac events, such as atrial fibrillation, were observed based on subgroups or by age. In this trial, subsequent life-
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Prostate Cancer
prolonging therapy was received by 58% of those in the control group, Apalutamide in Castration-Naïve Prostate Cancer
which included 22% who received abiraterone and 26% who received The double-blind phase 3 TITAN clinical trial randomized 1052 patients
enzalutamide. Thus, these data reflect a survival advantage of initial with metastatic, castration-naïve prostate cancer to ADT with apalutamide
abiraterone in newly diagnosed patients compared with deferring therapy (240 mg/day) or placebo.645 Participants were stratified by Gleason score
to the CRPC setting. at diagnosis, geographic region, and previous docetaxel treatment. The
median follow-up was 22.7 months. Both primary endpoints were met:
Adverse events in STAMPEDE were similar to that reported in LATITUDE, radiographic PFS (68.2% vs. 47.5% at 24 months; HR for radiographic
but were increased in patients who were older, with higher incidences of progression or death, 0.48; 95% CI, 0.39–0.60; P < .001) and OS (82.4%
grade 3–5 adverse events with abiraterone (47% vs. 33%) and 9 versus 3 vs. 73.5% at 24 months; HR for death, 0.67; 95% CI, 0.51–0.89; P = .005).
treatment-related deaths. Severe hypertension or cardiac disorders were Adverse events that were more common with apalutamide than with
noted in 10% of patients and grade 3–5 liver toxicity in 7%, which placebo included rash, hypothyroidism, and ischemic heart disease.
illustrates the need for blood pressure and renal and hepatic function Health-related QOL was maintained during treatment.646 At final analysis of
monitoring. TITAN, median OS was improved with apalutamide plus ADT compared
with ADT alone after a median follow-up of 44 months (NR vs. 52.2
Taken together, these data led the NCCN Panel to recommend
months; HR, 0.65; 95% CI, 0.53–0.79; P < .001)647
abiraterone with 5-mg once-daily prednisone as a treatment option with
ADT for patients with newly diagnosed, M1, castration-naïve prostate Apalutamide is a category 1 option for patients with M1 castration-naïve
cancer (category 1). Alternatively, the fine-particle formulation of prostate cancer. The FDA approved this indication in September of
abiraterone can be used (category 2B; see Abiraterone Acetate in M1 2019.648,649
CRPC, below). For patients undergoing curative-intent treatment for N1
disease, abiraterone can be added to EBRT with 2 to 3 years of Enzalutamide in Castration-Naïve Prostate Cancer
neoadjuvant/concurrent/adjuvant ADT or can be given with ADT for The open-label randomized phase 3 ENZAMET clinical trial compared
castration-naïve disease (without EBRT). The fine-particle formulation of enzalutamide (160 mg/day) plus ADT (LHRH analog or surgical castration)
abiraterone is an option (category 2B; see Abiraterone Acetate in M1 with a first-generation antiandrogen (bicalutamide, nilutamide, or
CRPC, below). However, there was insufficient survival, FFS data, and flutamide) plus ADT in 1125 patients with metastatic castration-naïve
follow-up available to recommend abiraterone for patients with high-risk or prostate cancer.650 Stratification was by volume of disease, planned use of
very-high-risk N0 M0 prostate cancer. Further follow-up and dedicated early docetaxel, planned use of bone anti-resorptive therapy, comorbidity
ongoing clinical trials are needed in this curative-intent RT population. score, and trial site. The primary endpoint of OS was met at the first
interim analysis with median follow-up of 34 months (HR for death, 0.67;
Abiraterone can be given at 250 mg/day and administered following a low- 95% CI, 0.52–0.86; P = .002). Enzalutamide also improved secondary
fat breakfast, as an alternative to the dose of 1000 mg/day after an endpoints, such as PFS using PSA levels and clinical PFS.
overnight fast (see Abiraterone Acetate in M1 CRPC, below).644 The cost
savings may reduce financial toxicity and improve adherence.
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Prostate Cancer
In the double-blind randomized phase 3 ARCHES clinical, 1150 patients a median follow-up of 6.9 years, the intermittent approach was non-inferior
with metastatic castration-naïve prostate cancer were randomized to to continuous ADT with respect to OS (8.8 vs. 9.1 years, respectively; HR,
receive ADT with either enzalutamide (160 mg/day) or placebo. 1.02; 95% CI, 0.86–1.21). More patients died from prostate cancer in the
Participants were stratified by disease volume and prior docetaxel use. intermittent ADT arm (120 of 690 patients) than in the continuous ADT arm
The primary endpoint was radiographic PFS, which was improved in the (94 of 696 patients), but this was balanced by more non-prostate cancer
enzalutamide group after a median follow-up of 14.4 months (19.0 months deaths in the continuous ADT arm. Physical function, fatigue, urinary
vs. not reached; HR, 0.39; 95% CI, 0.30–0.50; P < .001).651 problems, hot flashes, libido, and erectile dysfunction showed modest
improvement in the intermittent ADT group. The test population was
The safety of enzalutamide in these trials was similar to that seen in heterogenous, so it remains unclear which of these asymptomatic patients
previous trials in the castration-resistant setting. Adverse events benefitted from treatment. It is possible that many of these patients could
associated with enzalutamide in these trials included fatigue, seizures, and have delayed ADT without harm. The test population had a low disease
hypertension.650,651 burden and 59% of deaths in the trial were not related to prostate cancer.
Follow-up longer than 6.9 years may be required for disease-specific
Enzalutamide is a category 1 option for patients with M1 castration-naïve
deaths to out-balance deaths by other causes.
prostate cancer.
An unplanned Cox regression analysis of the trial showed that patients
Intermittent Versus Continuous ADT
with Gleason sum greater than 7 in the continuous ADT arm had a median
ADT is associated with substantial side effects, which generally increase survival (8 years) that was 14 months longer than those with the same
with the duration of treatment. Intermittent ADT is an approach based on Gleason sum in the intermittent ADT arm (6.8 years).654 In this situation,
the premise that cycles of androgen deprivation followed by re-exposure patients should be given the option to weigh the effects of ADT on QOL
may delay “androgen independence,” reduce treatment morbidity, and against a possible impact on survival, although pathology was not centrally
improve QOL.652,653 Some patients who have no ADT-related morbidity reviewed and the study was not powered to detect small differences in
may find the uncertainty of intermittent ADT not worthwhile. Intermittent survival based on Gleason sum.655
ADT requires close monitoring of PSA and testosterone levels, especially
during off-treatment periods, and patients may need to switch to The multinational European ICELAND trial randomized 702 participants
continuous therapy upon signs of disease progression. with locally advanced or biochemically recurrent prostate cancer to
continuous or intermittent ADT.656 Clinical outcomes, which included time
Intermittent ADT in Non-Metastatic Disease
to PSA progression, PSA PFS, OS, mean PSA levels over time, QOL, and
The Canadian-led PR.7 trial was a phase 3 trial of intermittent versus adverse events, were similar between the arms.
continuous ADT in patients with non-metastatic prostate cancer who
experienced biochemical recurrence after primary or post-recurrence A 2015 meta-analysis identified 6 randomized controlled trials comparing
EBRT.654 One thousand three hundred eighty-six patients with PSA >3 continuous with intermittent ADT in patients with locally advanced prostate
ng/mL were randomly assigned to intermittent ADT or continuous ADT. At cancer and found no difference in mortality and progression and an
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Prostate Cancer
advantage of the intermittent approach in terms of QOL and adverse A population-based analysis that included 9772 patients with advanced
effects.657 prostate cancer aged greater than or equal to 66 years showed that
intermittent ADT reduced the risks of total serious cardiovascular events
Intermittent ADT in Metastatic Disease
by 36%, heart failure by 38%, and pathologic fracture by 48%, compared
Hussain and colleagues658 conducted the SWOG (Southwest Oncology with continuous ADT.660 Furthermore, several meta-analyses of
Group) 9346 trial to compare intermittent and continuous ADT in patients randomized controlled trials reported no difference in survival between
with metastatic disease. After 7 months of induction ADT, 1535 patients intermittent ADT and continuous ADT.661-663 Another recent analysis
whose PSA dropped to 4 ng/mL or below (thereby demonstrating concluded that the non-inferiority of intermittent to continuous ADT in
androgen sensitivity) were randomized to intermittent or continuous ADT. terms of survival has not been clearly demonstrated.664 Still, the
At a median follow-up of 9.8 years, median survival was 5.1 years for the intermittent approach leads to marked improvement in QOL compared to
intermittent ADT arm and 5.8 years for the continuous ADT arm. The HR the continuous approach in most studies, and the Panel believes that
for death with intermittent ADT was 1.10 with a 90% CI between 0.99 and intermittent ADT should be strongly considered.
1.23, which exceeded the prespecified upper boundary of 1.20 for non-
inferiority. The authors stated that the survival results were inconclusive, A more personalized approach could be to treat all patients with metastatic
and that a 20% greater mortality risk with the intermittent approach cannot disease with ADT. After 7 months of ADT, patients can be assigned a risk
be ruled out. The study demonstrated better erectile function and mental category based on the PSA value at that time point636: low risk is defined
health in patients receiving intermittent ADT at 3 months, but the by a PSA less than 0.2 ng/mL (median survival of 75 months);
difference became insignificant thereafter, most likely due to intermediate risk is defined by a PSA between 0.2 and 4.0 ng/mL (median
contamination of assessments of those on the intermittent arm who may survival of 44 months), and high risk is defined by a PSA higher than 4.0
have returned to ADT at the prespecified time points. A secondary ng/mL (median survival of 13 months). Those patients who have few or no
analysis of SWOG 9346 showed that intermittent ADT did not reduce symptoms related to ADT after 7 months of therapy will not benefit from
endocrine, bone, or cognitive events, whereas it increased the incidence intermittent ADT in terms of QOL, and therefore continuous ADT is
of ischemic and thrombotic events.659 reasonable because it is easier to administer.655 However, for those
patients with significant side effects impacting QOL, intermittent ADT
In a post-hoc stratification analysis of the trial, patients with minimal should be considered for those with low or intermediate risk after a
disease had a median survival of 5.4 years when receiving intermittent discussion about the impact on survival. A final consideration is based on
ADT versus 6.9 years when receiving continuous ADT (HR, 1.19; 95% CI, a subgroup analysis of S9346 that suggested that those who initially
0.98–1.43).658 The median survival was 4.9 years in the intermittent ADT present with pain have better survival on continuous therapy than
arm compared to 4.4 years in the continuous ADT arm for patients with intermittent therapy.
extensive disease (HR, 1.02; 95% CI, 0.85–1.22). These subgroup
analyses are hypothesis-generating.
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Adverse Effects of Traditional ADT Bone Health During ADT

ADT has a variety of adverse effects including hot flashes, vasomotor Medical or surgical ADT is associated with greater risk for osteoporosis
instability, loss of libido, erectile dysfunction, shrinkage of penis and and clinical fractures. In large population-based studies, for example, ADT
testicles, loss of muscle mass and strength, fatigue, anemia, breast was associated with a 21% to 54% relative increase in fracture risk.676-678
enlargement and tenderness/soreness, depression and mood swings, hair Longer treatment duration conferred greater fracture risk. Age and
loss, osteoporosis, greater incidence of clinical fractures, obesity, insulin comorbidity also were associated with higher fracture incidence. In a
resistance, alterations in lipids, and greater risk for diabetes, acute kidney population-based cohort of 3295 patients, surgical castration was
injury, and cardiovascular disease.665-667 The intensity and spectrum of associated with a significantly lower risk of fractures than medical
these side effects vary greatly. In general, the side effects of continuous castration using an LHRH agonist (HR, 0.77; 95% CI, 0.62–0.94;
ADT increase with the duration of treatment. In addition, some forms of P = .01).631 ADT increases bone turnover and decreases bone mineral
ADT may result in lower risk than others. For example, relugolix was density,679-682 a surrogate for fracture risk in patients with non-metastatic
associated with a lower risk of major adverse cardiovascular events than disease. Bone mineral density of the hip and spine decreases by
leuprolide in the phase 3 HERO study (also see ADT for Castration-Naïve approximately 2% to 3% per year during initial therapy. Most studies have
Disease, above), although the FDA considered these results in HERO to reported that bone mineral density continues to decline steadily during
be exploratory and therefore did not allow for these data to be included in long-term therapy. ADT significantly decreases muscle mass,683 and
the prescribing information for relugolix.632 Overall, very limited prospective treatment-related sarcopenia appears to contribute to frailty and increased
head-to-head studies to date have evaluated the cardiovascular toxicity of risk of falls in patients who are older.
LHRH agonists versus LHRH antagonists as the primary endpoint.
The NCCN Guidelines Panel recommends screening and treatment for
Recent evidence suggests that a link between ADT and cognitive decline, osteoporosis according to guidelines for the general population from the
dementia, or future Alzheimer’s disease may exist, although data are National Osteoporosis Foundation.684 A baseline bone mineral density
inconsistent, the risk is low, and the link remains to be proven.668-675 study should be considered for the patients on ADT. The National
Osteoporosis Foundation guidelines include: 1) calcium (1000–1200 mg
Patients and their medical providers should be advised about these risks daily from food and supplements) and vitamin D3 (400–1000 IU daily); and
prior to treatment. Many side effects of ADT are reversible or can be 2) additional treatment for males aged greater than or equal to 50 years
avoided or mitigated. For example, physical activity can counter many of with low bone mass (T-score between -1.0 and -2.5, osteopenia) at the
these symptoms and should be recommended (see NCCN Guidelines for femoral neck, total hip, or lumbar spine by dual-energy x-ray
Survivorship, available at www.NCCN.org). Use of statins also should be absorptiometry (DEXA) scan and a 10-year probability of hip fracture
considered. greater than or equal to 3% or a 10-year probability of a major
osteoporosis-related fracture greater than or equal to 20%. Fracture risk
can be assessed using the algorithm FRAX®, recently released by
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WHO.685 ADT should be considered “secondary osteoporosis” using the infarction (HR, 1.11; P = .03). Studies that evaluated the potential
FRAX® algorithm. relationship between ADT and cardiovascular mortality have produced
mixed results.602,690-697 In a Danish cohort of 31,571 patients with prostate
Earlier randomized controlled trials demonstrated that bisphosphonates cancer, medical castration was associated with an increased risk for
increase bone mineral density, a surrogate for fracture risk, during ADT.686- myocardial infarction (HR, 1.31; 95% CI, 1.16–1.49) and stroke (HR, 1.19;
688
In 2011, the FDA approved denosumab as a treatment to prevent bone 95% CI, 1.06–1.35) whereas surgical castration was not.698 Other
loss and fractures during ADT. Denosumab binds to and inhibits the population-based studies resulted in similar findings.631,699 However, a
receptor activator of NF-B ligand (RANKL) to blunt osteoclast function Taiwan National Health Insurance Research Database analysis found no
and delay generalized bone resorption and local bone destruction. difference in ischemic events with LHRH agonist therapy or
Approval was based on a phase 3 study that randomized 1468 patients orchiectomy.700 A French database study showed the cardiovascular risk
with non-metastatic prostate cancer undergoing ADT to either biannual to be similar in patients taking LHRH agonists and antagonists.701
denosumab or placebo. At 24 months, denosumab increased bone However, some data suggest that LHRH antagonists might be associated
mineral density by 6.7% and reduced fractures (1.5% vs. 3.9%) compared with a lower risk of cardiac events within 1 year in patients with preexisting
to placebo.689 Denosumab also was approved for prevention of SREs in cardiovascular disease (history of myocardial ischemia, coronary artery
patients with bone metastasis (see Chemotherapy, Immunotherapy, and disease, myocardial infarction, cerebrovascular accident, angina pectoris,
Targeted Therapy). or coronary artery bypass) compared with agonists.630 Patients with a
recent history of cardiovascular disease appear to have higher risk,702 and
Currently, treatment with denosumab (60 mg every 6 months), zoledronic
increased physical activity may decrease the symptoms and
acid (5 mg IV annually), or alendronate (70 mg PO weekly) is
cardiovascular side effects of patients treated with ADT.703
recommended when the absolute fracture risk warrants drug therapy. A
baseline DEXA scan before start of therapy and a follow-up DEXA scan Several mechanisms may contribute to greater risk for diabetes and
after one year of therapy is recommended by the International Society for cardiovascular disease during ADT. ADT increases fat mass and
Clinical Densitometry to monitor response. Use of biochemical markers of decreases lean body mass.683,704,705 ADT with an LHRH agonist increases
bone turnover is not recommended. There are no existing guidelines on fasting plasma insulin levels706,707 and decreases insulin sensitivity.708 ADT
the optimal frequency of vitamin D testing, but vitamin D levels can be also increases serum levels of cholesterol and triglycerides.706,709
measured when DEXA scans are obtained.
ADT may also prolong the QT/QTc interval. Providers should consider
Diabetes and Cardiovascular Disease whether the benefits of ADT outweigh the potential risks in patients with
In a landmark population-based study, ADT was associated with higher congenital long QT syndrome, congestive heart failure, and frequent
incidence of diabetes and cardiovascular disease.690 After controlling for electrolyte abnormalities, and in patients taking drugs known to prolong
other variables, which included age and comorbidity, ADT with an LHRH the QT interval. Electrolyte abnormalities should be corrected, and
agonist was associated with increased risk for new diabetes (HR, 1.44; P
< .001), coronary artery disease (HR, 1.16; P < .001), and myocardial
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periodic monitoring of electrocardiograms and electrolytes should be with continued ADT is an option mainly for patients with shorter PSADT
considered. (≤10 months) as described below, because the androgen receptor may
remain active.
Cardiovascular disease and diabetes are leading causes of morbidity and
mortality in the general population. Based on the observed adverse For patients who develop metastatic CRPC, metastatic lesion biopsy is
metabolic effects of ADT and the association between ADT and higher recommended, as is MSI/MMR testing, if not previously performed. If MSI-
incidence of diabetes and cardiovascular disease, screening for and H or dMMR is found, referral to genetic counseling should be made to
intervention to prevent/treat diabetes and cardiovascular disease are assess for the possibility of Lynch syndrome. These patients should also
recommended for patients receiving ADT. Whether strategies for have germline and tumor testing to check for mutations in homologous
screening, prevention, and treatment of diabetes and cardiovascular recombination genes (ie, BRCA1, BRCA2, ATM, PALB2, FANCA) if not
disease in patients receiving ADT should differ from those of the general done previously.712 This information may be used for genetic counseling,
population remains uncertain. early use of platinum chemotherapy, use of PARP inhibitors, or eligibility
for clinical trials.
Progression to and Management of CRPC
Most patients with advanced disease eventually stop responding to TMB testing should also be considered for patients with metastatic CRPC
traditional ADT and are categorized as castration-resistant (also known as to inform possible use of pembrolizumab in later lines of therapy (see
castration-recurrent). CRPC is prostate cancer that progresses clinically, Pembrolizumab, below).
radiographically, or biochemically despite castrate levels of serum
ADT is continued in patients with metastatic CRPC while additional
testosterone (<50 ng/dL).710 Patients whose disease progresses to CRPC
therapies, including secondary hormone therapies, chemotherapies,
during primary ADT should receive a laboratory assessment to assure a
immunotherapies, radiopharmaceuticals, and/or targeted therapies, are
castrate level of testosterone (<50 ng/dL; <1.7 nmol/L). Imaging tests may
sequentially applied, as discussed in the sections that follow; all patients
be indicated to monitor for signs of distant metastases. Factors affecting
should receive best supportive care. The Panel defined treatment options
the frequency of imaging include individual risk, age, overall patient health,
for patients with metastatic CRPC based on previous exposure to
PSA velocity, and Gleason grade.
docetaxel and to a novel hormone therapy. Novel hormone therapies
For patients who develop CRPC, ADT with an LHRH agonist or antagonist include abiraterone, enzalutamide, darolutamide, or apalutamide received
should be continued to maintain castrate serum levels of testosterone for metastatic castration-naïve disease, M0 CRPC, or previous lines of
(<50 ng/dL). therapy for M1 CRPC.
Patients with CRPC and no signs of distant metastasis on conventional The Panel notes that relugolix has not been adequately studied in
imaging studies (M0) can consider observation with continued ADT if combination with potent androgen receptor inhibitors such as
PSADT is greater than 10 months (preferred), because these patients will enzalutamide, apalutamide, darolutamide, or abiraterone acetate, nor has
have a relatively indolent disease history.711 Secondary hormone therapy it been studied in combination with docetaxel or cabazitaxel
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chemotherapy. Potential drug interactions include induction of cytochrome androgen in CRPC refutes earlier beliefs that CRPC was resistant to
P450 enzymes and reduced concentration and efficacy of relugolix with further hormone therapies. The development of novel hormonal agents
enzalutamide or apalutamide and cardiac QTc interactions with demonstrating efficacy in the non-metastatic and metastatic CRPC setting
abiraterone. Further studies of relugolix dosing and drug interactions with dramatically changed the paradigm of CRPC treatment.
commonly used agents in advanced prostate cancer are needed to ensure
patient safety and proper dosing. Therefore, relugolix is not recommended Abiraterone Acetate in M1 CRPC
in combination with other therapies at this time. In April 2011, the FDA approved the androgen synthesis inhibitor,
abiraterone, in combination with low-dose prednisone, for the treatment of
The decision to initiate therapy in the CRPC setting after disease patients with metastatic CRPC who have received prior chemotherapy
progression on one or more treatments should be based on the available containing docetaxel.
high-level evidence of safety, efficacy, and tolerability of these agents and
the application of this evidence to an individual patient. Prior exposures to FDA approval in the post-docetaxel, metastatic CRPC setting was based
therapeutic agents should be considered. There are not much data to on the results of a phase 3, randomized, placebo-controlled trial (COU-AA-
inform the optimal sequence for delivery of these agents in patients with 301) in patients with metastatic CRPC previously treated with docetaxel-
metastatic CRPC (see Sequencing of Therapy in CRPC, below). Choice of containing regimens.717,718 Patients were randomized to receive either
therapy is based largely on clinical considerations, which include patient abiraterone 1000 mg orally once daily (n = 797) or placebo once daily (n =
preferences, prior treatment, presence or absence of visceral disease, 398), and both arms received daily prednisone. In the final analysis,
symptoms, and potential side effects. median survival was 15.8 versus 11.2 months in the abiraterone and
placebo arm, respectively (HR, 0.74; 95% CI, 0.64–0.86; P < .0001).718
NCCN recommends that patients being treated for CRPC be closely Time to radiographic progression, PSA decline, and pain palliation also
monitored with radiologic imaging (ie, CT, bone imaging), PSA tests, and were improved by abiraterone.718,719
clinical exams for evidence of progression. Therapy should be continued
until clinical progression or intolerability in cases where PSA or bone FDA approval in the pre-docetaxel setting occurred on December 10,
imaging changes may indicate flare rather than true clinical 2012, and was based on the randomized phase 3 COU-AA-302 trial of
progression.713,714 The sequential use of these agents is reasonable in a abiraterone and prednisone (n = 546) versus prednisone alone (n = 542)
patient who remains a candidate for further systemic therapy. Clinical trial in patients with asymptomatic or minimally symptomatic, metastatic
and best supportive care are additional options. CRPC.720 Most participants in this trial were not taking narcotics for cancer
pain and none had visceral metastatic disease or prior ketoconazole
Secondary Hormone Therapy for CRPC exposure. The coprimary endpoint of radiographic PFS was improved by
Research has shown enhancement of autocrine and/or paracrine treatment from 8.3 to 16.5 months (HR, 0.53; P < .001). OS was improved
androgen synthesis in the tumor microenvironment of patients receiving at final analysis with a median follow-up of 49.2 months (34.7 months vs.
ADT.715,716 Androgen signaling consequent to non-gonadal sources of 30.3 months; HR, 0.81; 95% CI, 0.70–0.93; P = .003).721 Key secondary
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endpoints of time to symptomatic deterioration, time to chemotherapy originator-treated patients (37.9% vs. 12.5%). The Panel believes that the
initiation, time to pain progression, and PSA PFS improved significantly fine-particle formulation of abiraterone can be used instead of the original
with abiraterone treatment, and PSA declines (62% vs. 24% with >50% formulation of abiraterone in the treatment of patients with metastatic
decline) and radiographic responses (36% vs. 16% RECIST responses) CRPC (category 2A).
were more common.
Based on the studies described here, abiraterone is a category 1,
The most common adverse reactions with abiraterone/prednisone (>5%) preferred option for metastatic CRPC without prior novel hormone therapy.
were fatigue (39%); back or joint discomfort (28%–32%); peripheral For patients with metastatic CRPC and prior novel hormone therapy,
edema (28%); diarrhea, nausea, or constipation (22%); hypokalemia abiraterone is included in the other recommended regimens category. The
(17%); hypophosphatemia (24%); atrial fibrillation (4%); muscle discomfort fine-particle formulation of abiraterone is included under other
(14%); hot flushes (22%); urinary tract infection; cough; hypertension recommended options in all metastatic CRPC settings.
(22%, severe hypertension in 4%); urinary frequency and nocturia;
dyspepsia; or upper respiratory tract infection. The most common adverse Abiraterone should be given with concurrent steroid (either oral
drug reactions that resulted in drug discontinuation were increased prednisone 5 mg twice daily or oral methylprednisolone 4 mg twice daily,
aspartate aminotransferase and/or alanine aminotransferase (11%–12%), depending on which formulation is given) to abrogate signs of
or cardiac disorders (19%, serious in 6%). mineralocorticoid excess that can result from treatment. These signs
include hypertension, hypokalemia, and peripheral edema. Thus,
In May 2018, the FDA approved a novel, fine-particle formulation of monitoring of liver function, potassium and phosphate levels, and blood
abiraterone, in combination with methylprednisolone, for the treatment of pressure readings on a monthly basis is warranted during abiraterone
patients with metastatic CRPC.722,723 In studies of healthy males, this therapy. Symptom-directed assessment for cardiac disease also is
formulation at 500 mg was shown to be bioequivalent to 1000 mg of the warranted, particularly in patients with pre-existing cardiovascular disease.
originator formulation.724,725 In a phase 2 therapeutic equivalence study, 53
patients with metastatic CRPC who were not treated previously with A randomized phase 2 non-inferiority study of 75 patients with M1 CRPC
abiraterone, enzalutamide, radium-223, or chemotherapy (docetaxel for compared 1000 mg/day abiraterone after an overnight fast with 250
metastatic CRPC completed ≥1 year prior to enrollment was allowed) were mg/day after a low-fat breakfast.644 The primary endpoint was log change
randomized to 500 mg daily of the new, fine-particle formulation plus 4 mg in PSA, with secondary endpoints of PSA response (≥50%) and PFS. The
methylprednisolone orally twice daily or to 1000 mg of the originator primary endpoint favored the low-dose arm (log change in PSA, -1.59 vs. -
formulation daily plus 5 mg prednisone orally twice daily.726 Bioequivalence 1.19), as did the PSA response rate (58% vs. 50%), with an equal PFS of
of these doses was confirmed based on serum testosterone levels, PSA 9 months in both arms. Noninferiority of the low dose was established
response, and abiraterone pharmacokinetics. The rates of total and grade according to the predefined criteria. Therefore, abiraterone can be given at
3/4 adverse events were similar between the arms, with musculoskeletal 250 mg/day administered following a low-fat breakfast, as an alternative to
and connective tissue disorders occurring more frequently in the the dose of 1000 mg/day after an overnight fast in patients who will not
take or cannot afford the standard dose. The cost savings may reduce
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financial toxicity and improve adherence. Food impacts absorption radiographic PFS (8.3 vs. 2.9 months), and time to first SRE (16.7 vs. 13.3
unpredictably; side effects should be monitored and standard dosing months). QOL measured using validated surveys was improved with
(1000 mg on empty stomach) utilized if excess toxicity is observed on enzalutamide compared to placebo. Adverse events were mild, and
modified dosing (250 mg with food). included fatigue (34% vs. 29%), diarrhea (21% vs. 18%), hot flushes (20%
vs. 10%), headache (12% vs. 6%), and seizures (0.6% vs. 0%). The
Abiraterone with Dexamethasone in M1 CRPC
incidence of cardiac disorders did not differ between the arms.
Switching from prednisone to dexamethasone 1 mg/day can be Enzalutamide is dosed at 160 mg daily. Patients in the AFFIRM study
considered for patients with M1 CRPC with disease progression on either were maintained on LHRH agonist/antagonist therapy and could receive
formulation of abiraterone. Trials show improved PSA responses and PFS bone supportive care medications. The seizure risk in the enzalutamide
and acceptable safety using this strategy. FDA label was 0.9% versus 0.6% in the manuscript.729,731
The SWITCH study was a single-arm, open-label, phase 2 study of this Another phase 3 trial studied enzalutamide in the pre-chemotherapy
approach with 26 enrolled patients.727 The primary endpoint, the proportion setting. The PREVAIL study randomly assigned 1717 patients with
of patients with a PSA decline ≥30% in 6 weeks, was 46.2%. No chemotherapy-naïve metastatic prostate cancer to daily enzalutamide or
significant toxicities were observed, and two radiologic responses were placebo.733,734 The study was stopped early due to benefits shown in the
seen. In another study, 48 consecutive patients with mCRPC, with disease treatment arm. Compared to the placebo group, the enzalutamide group
progression on abiraterone with prednisone, were switched to abiraterone showed improved median PFS (20.0 months vs. 5.4 months) and median
with 0.5 mg/day dexamethasone.728 The primary endpoint of median PFS OS (35.3 months vs. 31.3 months). Improvements in all secondary
was 10.35 months, and PSA levels decreased or stabilized in 56% of endpoints were also observed (eg, the time until chemotherapy initiation or
patients after switching to dexamethasone. first SRE).
Enzalutamide in M0 and M1 CRPC Two randomized clinical trials have reported that enzalutamide may be
On August 31, 2012, the FDA approved enzalutamide, a next-generation superior to bicalutamide for cancer control in metastatic CRPC. The
antiandrogen, for treatment of patients with metastatic CRPC who had TERRAIN study randomized 375 patients with treatment-naïve, metastatic
received prior docetaxel chemotherapy.729,730 Approval was based on the CRPC to 160 mg/day enzalutamide or 50 mg/day bicalutamide in a 1:1
results of the randomized, phase 3, placebo-controlled trial (AFFIRM).731,732 manner.735 The enzalutamide group had significantly better PFS (defined
AFFIRM randomized 1199 patients to enzalutamide or placebo in a 2:1 as PSA progression, soft tissue progression, or development of additional
ratio and the primary endpoint was OS. Median survival was improved bony metastases) compared to the bicalutamide group (median time to
with enzalutamide from 13.6 to 18.4 months (HR, 0.63; P < .001). Survival progression, 15.7 vs. 5.8 months; HR, 0.44; 95% CI, 0.34–0.57).
was improved in all subgroups analyzed. Secondary endpoints also were
improved significantly, which included the proportion of patients with >50% The STRIVE trial randomized 396 patients with M0 or M1 treatment-naïve
PSA decline (54% vs. 2%), radiographic response (29% vs. 4%), CRPC to 160 mg/day enzalutamide or 50 mg/day bicalutamide in a 1:1
manner.736 The primary endpoint in this study was PFS, defined as either
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PSA progression, radiographic progression of disease, or death from any patients with M0 CRPC can be offered enzalutamide, if PSADT is less
cause. Enzalutamide reduced the risk of progression or death by 76% than or equal to 10 months (category 1, preferred).
compared to bicalutamide (HR, 0.24; 95% CI, 0.18–0.32). These studies
demonstrated that enzalutamide extended PFS better than bicalutamide in Patients receiving enzalutamide have no restrictions for food intake and
patients choosing an antiandrogen for secondary hormonal therapy concurrent prednisone is permitted but not required.731
treatment of CRPC. Bicalutamide can still be considered in some patients,
Apalutamide in M0 CRPC
given the different side-effect profiles of the agents and the increased cost
of enzalutamide. The FDA approved apalutamide for treatment of patients with non-
metastatic CRPC on February 14, 2018.648 This approval was based on
Thus, enzalutamide represents a category 1, preferred treatment option the phase 3 SPARTAN trial of 1207 patients with M0 CRPC and PSADT
for patients without prior novel hormone therapy in the metastatic CRPC less than or equal to 10 months.740 Participants were stratified according to
setting. For patients with metastatic CRPC and prior novel hormone PSADT (>6 months vs. ≤6 months), use of bone-sparing agents, and the
therapy, enzalutamide is included in the other recommended regimens presence of metastatic pelvic lymph nodes (N0 vs. N1). After a median
group of options. follow-up of 20.3 months, apalutamide at 240 mg/day with ADT improved
the primary endpoint of metastasis-free survival over placebo with ADT
The randomized, double-blind, placebo-controlled phase 3 PROSPER trial (40.5 months vs. 16.2 months; HR for metastasis or death, 0.28; 95% CI,
assessed the use of enzalutamide in 1401 patients with non-metastatic 0.23–0.35; P < .001). Adverse events included rash (24% vs. 5.5%),
CRPC.737 Patients with PSADT less than or equal to 10 months were fracture (11% vs. 6.5%), and hypothyroidism (8% vs. 2%). Patients with
stratified according to PSADT (<6 months vs. ≥6 months) and use of bone- M0 CRPC can be offered apalutamide, if PSADT is less than or equal to
sparing agents and randomized 2:1 to enzalutamide (160 mg/day) plus 10 months (category 1). In a prespecified exploratory analysis of
ADT or placebo plus ADT. Enzalutamide improved the primary endpoint of SPARTAN, health-related QOL was maintained in both the apalutamide
metastasis-free survival over placebo (36.6 months vs. 14.7 months; HR and placebo groups.741
for metastasis or death, 0.29; 95% CI, 0.24–0.35; P < .0001). Median OS
was longer in the enzalutamide group than in the placebo group (67.0 After a median follow-up of 52 months, final OS analysis showed that
months vs. 56.3 months; HR for death, 0.73; 95% CI, 0.61–0.89; P = participants in SPARTAN experienced an improved median OS with
0.001).738 Adverse events included fatigue (33% vs. 14%), hypertension apalutamide versus placebo (73.9 months vs. 59.9 months; HR, 0.78; 95%
(12% vs. 5%), major adverse cardiovascular events (5% vs. 3%), and CI, 0.64–0.96; P = .016).742 This longer OS reached prespecified statistical
mental impairment disorders (5% vs. 2%). Patient-reported outcomes from significance, even though 19% of participants crossed over from placebo
PROSPER indicate that enzalutamide delayed pain progression, symptom to apalutamide.
worsening, and decrease in functional status, compared with placebo.739
Apalutamide is a category 1, preferred option for patients with M0 CRPC if
The FDA expanded approval for enzalutamide to include patients with PSADT is less than or equal to 10 months.
non-metastatic CRPC on July 13, 2018,729,730 and the Panel believes that
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Darolutamide in M0 CRPC A randomized phase 2 trial, TRANSFORMER, compared the effect of

The FDA approved darolutamide for treatment of patients with non- bipolar androgen therapy (BAT) with that of enzalutamide on PFS in 195
metastatic CRPC on July 30, 2019.743,744 The phase 3 ARAMIS study patients with asymptomatic, metastatic CRPC with prior progression on
randomized 1509 patients with M0 CRPC and PSADT less than or equal abiraterone.750 BAT involves rapid cycling between high and low serum
to 10 months 2:1 to darolutamide (600 mg twice daily) or placebo.745 testosterone to disrupt the adaptive upregulation of the androgen receptor
Participants were stratified according to PSADT (>6 months vs. ≤6 that occurs with low testosterone levels. Patients in the BAT arm received
months) and the use of osteoclast-targeted agents. The median follow-up testosterone cypionate 400 mg intramuscularly once every 28 days. The
time was 17.9 months. Darolutamide improved the primary endpoint of PFS was 5.7 months in both arms (HR, 1.14; 95% CI, 0.83–1.55; P = .42).
metastasis-free survival compared to placebo (40.4 months vs. 18.4 Crossover was allowed after disease progression, and OS was similar
months; HR for metastasis or death, 0.41; 95% CI, 0.34–0.50; P < .001). between the groups. BAT resulted in more favorable patient-reported
QOL. The Panel awaits more data on this approach.
Patients in the placebo group of ARAMIS crossed over to darolutamide (n
= 170) or received other life-prolonging therapy (n = 137). Final analysis Chemotherapy, Immunotherapy, and Targeted Therapy in
occurred after a median follow-up time of 29.0 months. The risk of death Metastatic Prostate Cancer
was 31% lower in the darolutamide group than in the placebo group (HR Recent research has expanded the therapeutic options for patients with
for death, 0.69; 95% CI, 0.53–0.88; P = .003).746 OS at 3 years was 83% metastatic CRPC depending on the presence or absence of symptoms,
(95% CI, 80–86) in the darolutamide group compared with 77% (95% CI, the location of metastases, and the presence of certain biomarkers.
72–81) in the placebo group. Adverse events that occurred more
frequently in the treatment arm included fatigue (12.1% vs. 8.7%), pain in Docetaxel
an extremity (5.8% vs. 3.2%), and rash (2.9% vs. 0.9%). The incidence of Two randomized phase 3 studies evaluated docetaxel-based regimens in
fractures was similar between darolutamide and placebo (4.2% vs. symptomatic or rapidly progressive CRPC (TAX 327 and SWOG
3.6%).745 9916).609,751,752 TAX 327 compared docetaxel (every 3 weeks or weekly)
plus prednisone to mitoxantrone plus prednisone in 1006 patients.751
Darolutamide is a category 1, preferred option for patients with M0 CRPC Every-3-week docetaxel resulted in higher median OS than mitoxantrone
if PSADT is less than or equal to 10 months. (18.9 vs. 16.5 months; P = .009). This survival benefit was maintained at
extended follow-up.752 The SWOG 9916 study also showed improved
Other Secondary Hormone Therapies
survival with docetaxel when combined with estramustine compared to
Other options for secondary hormone therapy include a first-generation mitoxantrone plus prednisone.609
antiandrogen, antiandrogen withdrawal, corticosteroid, or ketoconazole
(adrenal enzyme inhibitor) with hydrocortisone.747-749 However, none of Docetaxel is FDA-approved for metastatic CRPC. The standard regimen is
these strategies has yet been shown to prolong survival in randomized every 3 weeks. An alternative to every-3-week docetaxel is a biweekly
clinical trials. regimen of 50 mg/m2. This regimen is based on a large randomized phase
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2 trial of 346 patients with metastatic CRPC randomized to either every-2- (57.6 months vs. 47.2 months; HR, 0.72; 95% CI, 0.59–0.89; P = .002).757
week docetaxel or every-3-week docetaxel, each with maintenance of Subgroup analysis showed that the survival benefit was more pronounced
ADT and prednisone.753 Patients treated with the every-2-week regimen in the 65% of participants with high-volume disease (HR, 0.63; 95% CI,
survived an average of 19.5 months compared to 17.0 months with the 0.50–0.79; P < .001). Patients with low-volume disease in CHAARTED did
every-3-week regimen (P = .015). Time-to-progression and PSA decline not derive a survival benefit from the inclusion of docetaxel (HR, 1.04;
rate favored every-2-week therapy. Tolerability was improved with every- 95% CI, 0.70–1.55; P = .86).
2-week docetaxel; febrile neutropenia rate was 4% versus 14% and other
toxicities and overall QOL were similar. The STAMPEDE trial, a multi-arm, multi-stage phase 3 trial, included
patients with both M0 and M1 castration-naïve prostate cancer.429 The
Docetaxel is the traditional mainstay of treatment for symptomatic results in the M1 population essentially confirmed the survival advantage
metastatic CRPC. Docetaxel is not commonly used for asymptomatic of adding docetaxel (75 mg/m2 IV q3 weeks x 6 doses) to ADT seen in the
patients in this setting, but may be considered when the patient shows CHAARTED trial. In STAMPEDE, extent of disease was not evaluated in
signs of rapid progression or visceral metastases despite lack of the 1087 patients with metastatic disease, but the median OS for all
symptoms. Treatment with greater than or equal to 8 cycles of docetaxel patients with M1 disease was 5.4 years in the ADT-plus-docetaxel arm
may be associated with better OS than fewer cycles in the metastatic versus 3.6 years in the ADT-only arm (a difference of 1.8 years between
CRPC setting, but prospective trials are necessary to test 6 versus 10 groups compared with a 1.1-year difference in CHAARTED). The results
cycles of docetaxel in the metastatic castration-naïve and CRPC of the STAMPEDE trial seem to confirm the results of the CHAARTED
settings.754 Retrospective analysis from the GETUG-AFU 15 trial suggests trial.
that docetaxel only benefits some patients with CRPC who received
docetaxel in the castration-naïve setting.755 Patients with low-volume metastatic disease can be offered early
treatment with docetaxel combined with ADT; however, they have less
Thus, docetaxel is a category 1 preferred option for treatment of certain benefit from treatment than patients with higher-volume disease,
docetaxel-naïve metastatic CRPC. The Panel believes that docetaxel can as this subgroup did not have definitively improved survival outcomes in
be given as a rechallenge after progression on a novel hormone in the the ECOG CHAARTED study or a similar European trial (GETUG-AFU
metastatic CRPC setting if given in the castration-naive setting. 15).756,758,759 Meta-analyses of randomized controlled trials also concluded
that docetaxel provides a significant OS benefit in this setting, with no
Docetaxel is also included as an upfront option for patients with castration- evidence that the benefit was dependent on the volume of disease.760-762
naïve prostate cancer and distant metastases based on results from two
phase 3 trials (ECOG 3805/CHAARTED and STAMPEDE).429,756 The direct randomized comparison of docetaxel with ADT and abiraterone
CHAARTED randomized 790 patients with metastatic, castration-naïve with ADT in STAMPEDE showed that the two treatment options resulted in
prostate cancer to docetaxel (75 mg/m2 IV q3 weeks x 6 doses) plus ADT similar efficacy and safety outcomes in patients with metastatic castration-
or ADT alone.756 After a median follow-up of 53.7 months, the patients in naïve prostate cancer.431
the combination arm experienced a longer OS than those in the ADT arm
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Cabazitaxel recommended for fit patients. Cabazitaxel at 25 mg/m2 may be considered

In June 2010, the FDA approved cabazitaxel, a semi-synthetic taxane for healthy patients who wish to be more aggressive.
derivative, for patients with metastatic CRPC previously treated with a
Recent results from the phase 3 FIRSTANA study suggested that
docetaxel-containing regimen. An international randomized phase 3 trial
cabazitaxel has clinical activity in patients with chemotherapy-naïve
(TROPIC) randomized 755 patients with progressive metastatic CRPC to
mCRPC.767 Median OS, the primary endpoint, was similar between 20
receive cabazitaxel 25 mg/m2 or mitoxantrone 12 mg/m2, each with daily
mg/m2 cabazitaxel, 25 mg/m2 cabazitaxel, and 75 mg/m2 docetaxel (24.5
prednisone.763 A 2.4-month improvement in OS was demonstrated with
months, 25.2 months, and 24.3 months, respectively). Cabazitaxel was
cabazitaxel compared to mitoxantrone (HR, 0.72; P < .0001). The
associated with lower rates of peripheral sensory neuropathy than
improvement in survival was balanced against a higher toxic death rate
docetaxel, particularly at 20 mg/m2 (12% vs. 25%). Therefore, patients
with cabazitaxel (4.9% vs. 1.9%), which was due, in large part, to
who are not candidates for docetaxel, who are intolerant of docetaxel, or
differences in rates of sepsis and renal failure. Febrile neutropenia was
who have pre-existing mild peripheral neuropathy should be considered
observed in 7.5% of cabazitaxel-treated patients versus 1.3% of
for cabazitaxel.767
mitoxantrone-treated patients. The incidences of severe diarrhea (6%),
fatigue (5%), nausea/vomiting (2%), anemia (11%), and thrombocytopenia The NCCN Guidelines Panel included cabazitaxel as an option after
(4%) also were higher in cabazitaxel-treated patients, which indicated the progression on docetaxel for patients with symptomatic metastatic CRPC.
need for vigilance and treatment or prophylaxis in this setting to prevent This recommendation is category 1 in patients who also had prior
febrile neutropenia. The survival benefit was sustained at an updated treatment with a novel hormone therapy based on randomized phase 3
analysis with a median follow-up of 25.5 months.764 Furthermore, results of study data (see Cabazitaxel, above).763,767 NCCN panelists agreed that
a post-hoc analysis of this trial suggested that the occurrence of grade ≥3 docetaxel rechallenge may be useful in some patients (category 2A
neutropenia after cabazitaxel treatment was associated with instead of category 1 in this setting), especially in those who have not
improvements in both PFS and OS.765 shown definitive evidence of progression on prior docetaxel therapy.
Docetaxel rechallenge can be considered in patients who received
The phase 3 open-label, multinational, non-inferiority PROSELICA study
docetaxel with ADT in the metastatic castration-naïve setting.
compared 20 mg/m2 cabazitaxel with 25 mg/m2 cabazitaxel in 1200
patients with metastatic CRPC who progressed on docetaxel.766 The lower The multicenter CARD study was a randomized, open-label clinical trial
dose was found to be noninferior to the higher dose for median OS (13.4 that compared cabazitaxel with either abiraterone or enzalutamide in 255
months [95% CI, 12.19–14.88] vs. 14.5 months [95% CI, 13.47–15.28]), patients with metastatic CRPC who had previously received docetaxel and
and grade 3/4 adverse events were decreased (39.7% vs. 54.5%). In either abiraterone or enzalutamide.768 Cabazitaxel at 25 mg/m2 with
particular, grade ≥3 neutropenia rates were 41.8% and 73.3% for the concurrent steroid improved the primary endpoint of radiographic PFS (8.0
lower and higher dose groups, respectively. Cabazitaxel at 20 mg/m2 vs. 3.7 months; HR, 0.54; P < .0001) and reduced the risk of death (13.6
every 3 weeks, with or without growth factor support, is now vs. 11.0 months; HR, 0.64; P = .008) compared with abiraterone or
enzalutamide in these patients. Cabazitaxel was also associated with an
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increased rate of pain response and delayed time to pain progression and most common grade 3–5 adverse events (fatigue, anemia, neutropenia,
SREs.769 Therefore, cabazitaxel is included in these Guidelines as a and thrombocytopenia) were all more common in the combination arm.
preferred option after progression occurs on docetaxel in patients with Post-hoc analyses showed that patients with aggressive variant disease
metastatic CRPC (category 1 after progression on docetaxel and a novel had a longer median PFS in the combination arm than the cabazitaxel arm
hormone therapy). (7.5 vs. 1.7 months; P = .017). Patients without aggressive variant tumors,
on the other hand, had similar median PFS regardless of treatment (6.5
Cabazitaxel should be given with concurrent steroids (daily prednisone or vs. 6.3 months; P = .38).
dexamethasone on the day of chemotherapy). Physicians should follow
current guidelines for prophylactic white blood cell growth factor use, Sipuleucel-T
particularly in this heavily pre-treated, high-risk population. In addition, In April 2010, sipuleucel-T became the first in a new class of cancer
supportive care should include antiemetics (prophylactic antihistamines, immunotherapeutic agents to be approved by the FDA. This autologous
H2 antagonists, and corticosteroids prophylaxis) and symptom-directed cancer “vaccine” involves collection of the white blood cell fraction-
antidiarrheal agents. Cabazitaxel was tested in patients with hepatic containing, antigen-presenting cells from each patient; exposure of the
dysfunction in a small, phase I, dose-escalation study.770 Cabazitaxel was cells to the prostatic acid phosphatase-granulocyte macrophage colony-
tolerated in patients with mild to moderate hepatic impairment. However, stimulating factor (PAP-GM-CSF recombinant fusion protein); and
cabazitaxel should not be used in patients with severe hepatic dysfunction. subsequent reinfusion of the cells. The pivotal study was a phase 3,
Cabazitaxel should be stopped upon clinical disease progression or multicenter, randomized, double-blind trial (D9902B).772 Five hundred
intolerance. twelve patients with minimally symptomatic or asymptomatic metastatic
CRPC were randomized 2:1 to receive sipuleucel-T or placebo. Eighteen
Cabazitaxel/Carboplatin
point two percent of patients had received prior chemotherapy, which
Cabazitaxel 20 mg/m² plus carboplatin AUC 4 mg/mL per minute with included docetaxel; eligibility requirements included no chemotherapy for 3
growth factor support can be considered for fit patients with aggressive months and no steroids for 1 month prior to enrollment. Median survival in
variant metastatic CRPC (visceral metastases, low PSA and bulky the vaccine arm was 25.8 months compared to 21.7 months in the control
disease, high lactate dehydrogenase (LDH), high carcinoembryonic arm. In a subset analysis, both those who did and those who did not
antigen (CEA), lytic bone metastases, NEPC histology) or unfavorable receive prior chemotherapy benefited from sipuleucel-T treatment.
genomics (defects in at least 2 of PTEN, TP53, and RB1). This Sipuleucel-T treatment resulted in a 22% reduction in mortality risk (HR,
recommendation is based on a phase 1–2, open label, randomized 0.78; 95% CI, 0.61–0.98; P = .03). Common complications included mild
study.771 In the phase 2 portion, 160 patients were randomized to receive to moderate chills (54.1%), pyrexia (29.3%), and headache (16.0%), which
cabazitaxel alone or with carboplatin, and the primary endpoint was usually were transient.
investigator-assessed PFS. In the intention-to-treat population, median
PFS was 4.5 months in the cabazitaxel arm versus 7.3 months in the A prospective registry of patients with metastatic CRPC, PROCEED,
cabazitaxel/carboplatin arm (HR, 0.69; 95% CI, 0.50–0.95; P = .018). The enrolled 1976 patients from 2011 to 2017, who were followed for a median
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of 46.6 months.773 The safety and tolerability of sipuleucel-T were pembrolizumab for this indication are 200 mg every 3 weeks or 400 mg
consistent with previous findings, and the median OS was 30.7 months every 6 weeks administered intravenously.
(95% CI, 28.6–32.2 months).
FDA-accelerated approval was based on the treatment of 149 patients
Sipuleucel-T is a category 1 option for certain patients with metastatic across five clinical studies involving MSI-H or dMMR colorectal (n = 90) or
CRPC who have not had previous treatment with docetaxel or with a novel non-colorectal (n = 59) cancer for an objective response rate of 40%
hormone therapy. Benefit of sipuleucel-T has not been reported in patients (59/149).774 All patients received greater than or equal to 1 prior regimen.
with visceral metastases and is not recommended if visceral metastases Among the non-colorectal cohorts, two patients had metastatic CRPC: one
are present. Sipuleucel-T is also not recommended for patients with small achieved a partial objective response, and the other achieved stable
cell/neuroendocrine prostate cancer. The Panel prefers that sipuleucel-T disease for greater than 9 months.
be used as initial therapy for asymptomatic or minimally symptomatic
patients with metastatic CRPC, so that disease burden is lower and A growing number of additional patients with metastatic CRPC treated with
immune function is potentially more intact. However, it is also an option for pembrolizumab have been reported.79,776-780 In an early study, 10 patients
patients with metastatic CRPC who have had prior treatment with with CRPC and non-visceral metastases (bone = 7; lymph nodes = 2;
docetaxel or a novel hormone therapy, but not for patients who have bone and liver = 1) who had disease progression on enzalutamide were
already received both. Patients should have good performance level treated with pembrolizumab and enzalutamide.776 Some of the patients
(ECOG 0-1), estimated life expectancy greater than 6 months, and no liver also had experienced disease progression on additional therapies
metastases. Clinicians and patients should be aware that the usual (docetaxel for castration-naïve disease, abiraterone, and/or sipuleucel-T).
markers of benefit (decline in PSA and improvement in bone or CT scans) Three of the 10 patients showed a near complete PSA response. Two of
are not seen. Therefore, benefit to the individual patient cannot be these three patients had radiographically measurable disease and
ascertained using currently available testing. achieved a partial radiographic response (including a response in liver
metastases). Of the remaining patients, three showed stable disease, and
Treatment subsequent to sipuleucel-T treatment should proceed as four displayed no evidence of clinical benefit. Genetic analysis of biopsy
clinically indicated, particularly if symptoms develop. tissue from two PSA responders and two PSA non-responders revealed
that one responder had an MSI-H tumor, whereas the other responder and
Pembrolizumab the non-responders did not. The nonrandomized phase Ib KEYNOTE-028
The FDA approved the use of pembrolizumab, an anti-PD1 antibody, for trial included 23 patients with advanced, progressive prostate cancer, of
treatment of patients with unresectable or metastatic MSI-H or dMMR solid whom 74% had received greater than or equal to two previous therapies
tumors who have progressed on prior treatment and who have no for metastatic disease.778 The objective response rate by investigator
satisfactory alternative treatment options on May 23, 2017.774 The review was 17.4% (95% CI, 5.0%–38.8%), with four confirmed partial
indication has since been expanded to include several cancer types, but responses. Eight patients (34.8%) had stable disease. Treatment-related
not prostate cancer specifically.775 The recommended adult doses of adverse events occurred in 61% of patients after a median follow-up of
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7.9 months; 17% of the cohort experienced grade 3/4 events (ie, grade 4 following prior treatment and who have no satisfactory alternative
lipase increase, grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 treatment options.775 Results from prospective biomarker analysis of the
fatigue). multicohort, non-randomized, open-label, phase 2 KEYNOTE-158 trial
support this approval.782 This trial included 233 evaluable patients with
KEYNOTE-199 was a multi-cohort, open-label phase II study in 258 unresectable or metastatic solid tumors, 6 of whom had prostate cancer.780
patients with metastatic CRPC and prior treatment with docetaxel and at The prospective TMB study included patients with anal, biliary, cervical,
least one novel hormonal therapy that assessed pembrolizumab in endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung,
patients regardless of MSI status.781 Cohorts 1 and 2 included patients with thyroid, and vulvar cancer. Objective responses to pembrolizumab were
PD-L1–positive (n = 133) and PD-L1–negative (n = 66) prostate cancer, seen in 30 of 102 patients in the TMB-high group (29%; 95% CI, 21%–
respectively. Cohort 3 included those with bone-predominant disease with 39%) and 43 of 688 patients in the non–TMB-high group (6%; 95% CI,
positive or negative PD-L1 expression (n = 59). The primary endpoint of 5%–8%). Safety was as expected based on other studies of
ORR in cohorts 1 and 2 was 5% (95% CI, 2%–11%) in cohort 1 and 3% pembrolizumab. Therefore, the Panel includes pembrolizumab as an
(95% CI, <1%–11%) in cohort 2. Responses were durable (range, 1.9 – option for patients with metastatic CRPC, prior docetaxel and/or novel
≥21.8 months). hormone therapy, and TMB >10 mut/Mb.
The most common adverse events from pembrolizumab are fatigue, Mitoxantrone
pruritus, diarrhea, anorexia, constipation, nausea, rash, fever, cough,
Two randomized trials assessed the role of mitoxantrone in patients with
dyspnea, and musculoskeletal pain. Pembrolizumab also may be
metastatic CRPC.783,784 Although there was no improvement in OS,
associated with immune-mediated side effects, which include colitis,
palliative responses and improvements in QOL were seen with
hepatitis, endocrinopathies, pneumonitis, or nephritis.
mitoxantrone.
Based on the available data, the Panel supports the use of pembrolizumab
Mitoxantrone can be used for palliation in symptomatic patients with
in patients with MSI-H or dMMR metastatic CRPC whose disease has
metastatic CRPC who cannot tolerate other therapies after disease
progressed through at least one line of systemic therapy for M1 CRPC.
progression on prior docetaxel.
The prevalence of MMR deficiency in metastatic CPRC is estimated at 2%
to 5%,43,777 and testing for MSI-H or dMMR can be performed using DNA Treatment Options for Patients with DNA Repair Gene Mutations
testing or immunohistochemistry. If tumor MSI-H or dMMR is identified, the
Early studies suggest germline and somatic mutations in homologous
Panel recommends referral to genetic counseling for consideration of
recombination repair (HRR) genes (eg, BRCA1, BRCA2, ATM, PALB2,
germline testing for Lynch syndrome.
FANCA, RAD51D, CHEK2) may be predictive of the clinical benefit of
In June 2020, the FDA granted accelerated approval for pembrolizumab’s poly-ADP ribose polymerase (PARP) inhibitors.785-787 PARP inhibitors are
use in patients with unresectable or metastatic TMB-high (TMB-H) [≥10 oral agents that exert their activity through the concept of synthetic
mutations/megabase (mut/Mb)] solid tumors that have progressed
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lethality.788 At present, two PARP inhibitors are approved by the FDA for a somatic or germline HRR gene mutation, and were allocated to one of
use in prostate cancer (see Olaparib and see Rucaparib, below).789,790 two cohorts: cohort A comprised patients with BRCA1/2 or ATM mutations,
and cohort B comprised patients with a mutation in at least one of 12 other
DNA repair defects have also been reported to be predictive for sensitivity HRR genes (BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2,
to platinum agents in CRPC and other cancers.791-795 Platinum agents have PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L). The primary
shown some activity in patients with CRPC without molecular selection.796 endpoint of improving radiographic PFS with olaparib versus
Studies of platinum agents in patients with CRPC that have DNA repair abiraterone/enzalutamide was met in cohort A (HR, 0.34; 95% CI, 0.25–
gene mutations are needed. 0.47; P < .001), and radiographic PFS was also superior in the entire
study population encompassing cohorts A+B (HR, 0.49; 95% CI, 0.38–
In addition, a recent study suggested that patients with metastatic CRPC
0.63; P < .001).
and germline mutations in DNA repair genes may have better outcomes if
treated with abiraterone or enzalutamide than with taxanes.51 However, it In addition, final OS analysis of PROfound showed that OS was improved
should be noted that the response of patients with metastatic CRPC and with olaparib versus abiraterone/enzalutamide in cohort A (HR, 0.69; 95%
HRR gene mutations to standard therapies is similar to the response of CI, 0.50–0.97; P = .02), despite the fact that 86 of 131 patients (66%)
patients without mutations.797,798 crossed over to olaparib after disease progression in the control arm.803
Patients with CDK12 mutations tend to have aggressive disease with high The Panel notes that there may be heterogeneity of response to olaparib
rates of metastases and short OS. They also do not respond well to based on which gene has a mutation. For example, patients with BRCA2
hormonal therapy, PARP inhibitors, or taxanes. Two large, multi- mutations experienced an OS benefit with olaparib (HR, 0.59; 95% CI,
institutional, retrospective studies have shown that 11% to 33% of patients 0.37–0.95), whereas the HR for OS in patients with ATM mutations was
with metastatic CRPC and CDK12 mutations responded to PD-1 inhibitors 0.93 (95% CI, 0.53–1.75).803 Furthermore, there were few patients in
(ie, nivolumab, pembrolizumab), some with durable responses.799,800 The PROfound with mutations in some of the genes. For example, only 4
Panel awaits more data on the use of PD-1 inhibition in patients with patients had BRIP1 mutations (2 in olaparib arm and 2 in control arm), 2
CDK12 mutations. patients had RAD51D mutations (both in olaparib arm), and no patients
had RAD51C mutations.802
Olaparib
Preliminary clinical data using olaparib suggested favorable activity of this As a result of the favorable efficacy data from the PROfound trial, the FDA
agent in patients with HRR gene mutations, but not in those without HRR approved olaparib (300 mg twice daily) in May 2020 for use in patients
mutations.786,787,801 The phase 3 PROfound study was a randomized trial with mCRPC and deleterious or suspected deleterious germline or somatic
evaluating olaparib 300 mg twice daily versus physician’s choice of HRR gene mutations in at least one of 14 genes (BRCA1, BRCA2, ATM,
abiraterone or enzalutamide in patients with mCRPC and progression on BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B,
at least one novel hormonal agent (abiraterone or enzalutamide) and up to RAD51C, RAD51D, or RAD54L) and who had previously received
one prior taxane agent (permitted but not required).802 Patients had to have
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treatment with enzalutamide or abiraterone.804 PPP2R2A was excluded that open-label single-arm phase 2 trial, patients with mCRPC harboring a
due to preliminary evidence of inferior activity of olaparib in this subset. deleterious or suspected deleterious germline or somatic BRCA1 or
BRCA2 mutation, who had previously received therapy with a novel
Since prior taxane therapy was not mandated in the PROfound study, hormonal agent plus one taxane chemotherapy, were treated with
olaparib use might be reasonable in mCRPC patients both before or after rucaparib 600 mg twice daily.805 The primary endpoint of TRITON2 was the
docetaxel treatment. Adverse events that may occur with olaparib objective response rate in patients with measurable disease, and was
treatment include anemia (including that requiring transfusion), fatigue, 43.5% (95% CI, 31.0%–56.7%) in this BRCA1/2-mutated population.
nausea or vomiting, anorexia, weight loss, diarrhea, thrombocytopenia, Median radiographic PFS, a key secondary endpoint, was 9.0 months
creatinine elevation, cough, and dyspnea. Rare but serious side effects (95% CI, 8.3–13.5 months).805 The FDA indication for rucaparib (600 mg
may include thromboembolic events (including pulmonary emboli), drug- twice daily) is for use in patients with mCRPC and deleterious or
induced pneumonitis, and a theoretical risk of myelodysplasia or acute suspected deleterious germline or somatic BRCA1 or BRCA2 mutations,
myeloid leukemia.802 and who had previously received treatment with both a novel hormonal
agent (enzalutamide or abiraterone) as well as one taxane-containing
The Panel recommends olaparib as an option for patients with metastatic
chemotherapy. Based on this information, the Panel does not generally
CRPC, previous androgen receptor-directed therapy, and an HRRm
recommend the use of rucaparib in BRCA1/2-mutated mCRPC patients
regardless of prior docetaxel therapy (category 1). The HRR genes to be
who have not previously received a taxane agent unless the patient is not
considered for use of olaparib are BRCA1, BRCA2, ATM, BARD1, BRIP1,
fit for chemotherapy. Furthermore, rucaparib should not be used in
CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D
patients with HRR gene mutations other than BRCA1/2.806 Adverse events
and RAD54L. Patients with PPP2R2A mutations in the PROfound trial
that may occur with rucaparib include anemia (including that requiring
experienced an unfavorable risk-benefit profile; therefore, olaparib is not
transfusion), fatigue, asthenia, nausea or vomiting, anorexia, weight loss,
recommended in patients with PPP2R2A mutations.
diarrhea or constipation, thrombocytopenia, increased creatinine,
Any commercially available analytically and clinically validated somatic increased liver transaminases, and rash. Rare but serious side effects of
tumor and ctDNA assays and germline assays can be used to identify rucaparib include a theoretical risk of myelodysplasia or acute myeloid
patients for treatment. Careful monitoring of complete blood counts and leukemia, as well as fetal teratogenicity.805,806 Full FDA approval of
hepatic and renal function, along with type and screens and potential rucaparib is contingent upon a favorable efficacy and safety profile of this
transfusion support and/or dose reductions as needed for severe anemia drug in the phase 3 TRITON3 study (NCT02975934), a randomized trial of
or intolerance are recommended during olaparib therapy. rucaparib versus physician’s choice of therapy (abiraterone, enzalutamide,
or docetaxel) in patients with mCRPC and a germline or somatic BRCA1/2
Rucaparib or ATM mutation who have previously received a novel hormonal agent
Rucaparib is a second PARP inhibitor approved for use in patients with but no chemotherapy for mCRPC. The results of this trial are awaited.
mCRPC.790 This agent received accelerated FDA approval in May 2020
based on the preliminary favorable data from the TRITON2 clinical trial. In
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The Panel recommends rucaparib as an option for patients with metastatic These cases may be managed by cytotoxic chemotherapy (ie,
CRPC, prior treatment with a novel hormone therapy, and a BRCA1 or cisplatin/etoposide, carboplatin/etoposide, docetaxel/carboplatin,
BRCA2 mutation. If the patient is not fit for chemotherapy, rucaparib can cabazitaxel/carboplatin).771,811,812 Physicians should consult the NCCN
be considered even if taxane-based therapy has not been given. Guidelines for Small Cell Lung Cancer (available at www.NCCN.org),
because the behavior of small cell/neuroendocrine carcinoma of the
The preferred method of selecting patients for rucaparib treatment is prostate is similar to that of small cell carcinoma of the lung.
somatic analysis of BRCA1 and BRCA2 using a circulating tumor DNA
sample. As with olaparib, careful monitoring of complete blood counts and Bone Metastases
hepatic and renal function, along with type and screens and potential In a multicenter study, 643 patients with CRPC and asymptomatic or
transfusion support and/or dose reductions as needed for severe anemia minimally symptomatic bone metastases were randomized to intravenous
or intolerance are recommended during treatment with rucaparib. zoledronic acid every 3 weeks or placebo.813 At 15 months, fewer patients
in the zoledronic acid 4-mg group than patients in the placebo group had
Small Cell/Neuroendocrine Prostate Cancer
SREs (33% vs. 44%; P = .02). An update at 24 months also revealed an
De novo small cell carcinoma in untreated prostate cancers occurs rarely increase in the median time to first SRE (488 days vs. 321 days; P =
and is very aggressive.807 Treatment-associated small cell/neuroendocrine .01).814 No significant differences were found in OS. Other
prostate cancer that occurs in patients with metastatic CRPC is more bisphosphonates have not been shown to be effective for prevention of
common.808 In a multi-institution prospective series of 202 consecutive disease-related skeletal complications. Earlier use of zoledronic acid in
patients with metastatic CRPC, all of whom underwent metastatic patients with castration-naïve prostate cancer and bone metastases is not
biopsies, small cell/neuroendocrine histology was present in 17%.808 associated with lower risk for SREs, and in general should not be used for
Patients with small cell/neuroendocrine tumors and prior abiraterone SRE prevention until the development of metastatic CRPC.815
and/or enzalutamide had a shorter OS when compared with those with
adenocarcinoma and prior abiraterone and/or enzalutamide (HR, 2.02; The randomized TRAPEZE trial used a 2 X 2 factorial design to compare
95% CI, 1.07–3.82). Genomic analysis showed that DNA repair mutations clinical PFS (pain progression, SREs, or death) as the primary outcome in
and small cell/neuroendocrine histology were almost mutually exclusive. 757 patients with bone metastatic CRPC treated with docetaxel alone or
with zoledronic acid, 89Sr, or both.816 The bone-directed therapies had no
Small cell/neuroendocrine carcinoma of the prostate should be considered statistically significant effect on the primary outcome or on OS in
in patients who no longer respond to ADT and test positive for metastases. unadjusted analysis. However, adjusted analysis revealed a small effect
These relatively rare tumors are associated with low PSA levels despite for 89Sr on clinical PFS (HR, 0.85; 95% CI, 0.73–0.99; P = .03). For
large metastatic burden and visceral disease.809 Those with initial Grade secondary outcomes, zoledronic acid improved the SRE-free interval (HR,
Group 5 are especially at risk. Biopsy of accessible metastatic lesions 0.78; 95% CI, 0.65–0.95; P = .01) and decreased the total SREs (424 vs.
should be considered to identify patients with small cell/neuroendocrine 605) compared with docetaxel alone.
histomorphologic features in patients with visceral metastases.810
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Denosumab was compared to zoledronic acid in a randomized, double- D are recommended to prevent hypocalcemia in patients receiving either
blind, placebo-controlled study in patients with CRPC.817 The absolute denosumab or zoledronic acid.
incidence of SREs was similar in the two groups; however, the median
time to first SRE was delayed by 3.6 months by denosumab compared to Monitoring of creatinine clearance is required to guide dosing of zoledronic
zoledronic acid (20.7 vs. 17.1 months; P = .0002 for non-inferiority, P = acid. Zoledronic acid should be dose reduced in patients with impaired
.008 for superiority). The rates of important SREs with denosumab were renal function (estimated creatinine clearance 30–60 mL/min), and held for
similar to zoledronic acid and included spinal cord compression (3% vs. creatinine clearance <30 mL/min.821 Denosumab may be administered to
4%), need for radiation (19% vs. 21%), and pathologic fracture (14% vs. patients with impaired renal function or even patients on hemodialysis;
15%). however, the risk for severe hypocalcemia and hypophosphatemia is
greater, and the dose, schedule, and safety of denosumab have not yet
Treatment-related toxicities reported for zoledronic acid and denosumab been defined. A single study of 55 patients with creatinine clearance <30
were similar and included hypocalcemia (more common with denosumab mL/min or on hemodialysis evaluated the use of 60-mg-dose
13% vs. 6%), arthralgias, and osteonecrosis of the jaw (ONJ, 1%–2% denosumab.822 Hypocalcemia should be corrected before starting
incidence). Most, but not all, patients who develop ONJ have preexisting denosumab, and serum calcium monitoring is required for denosumab and
dental problems.818 recommended for zoledronic acid, with repletion as needed.
Therefore, denosumab every 4 weeks (category 1) or zoledronic acid Radium-223 is a category 1 option to treat symptomatic bone metastases
every 3 to 4 weeks is recommended for patients with CRPC and bone without visceral metastases, and the use of palliative, systemic radiation
metastases to prevent or delay disease-associated SREs. SREs include with either 89Sr or 153Sm (see Radium-223 and Other
pathologic fractures, spinal cord compression, operation, or EBRT to Radiopharmaceuticals, above).
bone. The optimal duration of zoledronic acid or denosumab in patients
with CRPC and bone metastases remains unclear. A multi-institutional, Clinical research continues on the prevention or delay of disease spread
open-label, randomized trial in 1822 patients with bone-metastatic prostate to bone. A phase 3 randomized trial of 1432 patients with non-metastatic
cancer, breast cancer, or multiple myeloma found that zoledronic acid CRPC at high risk of bone involvement showed that denosumab delayed
every 12 weeks was non-inferior to zoledronic acid every 4 weeks.819 In bone metastasis by 4 months compared to placebo.823 OS was not
the every-12-weeks and every-4-weeks arms, 28.6% and 29.5% improved, and the FDA did not approve this indication for denosumab.
experienced at least 1 SRE within 2 years of randomization, respectively.
Visceral Metastases
Oral hygiene, baseline dental evaluation for high-risk individuals, and The panel defines visceral metastases as those occurring in the liver, lung,
avoidance of invasive dental surgery during therapy are recommended to adrenal gland, peritoneum, or brain. Soft tissue/lymph node sites are not
reduce the risk of ONJ.820 If invasive dental surgery is necessary, therapy considered visceral metastases. In general, there are less data on
should be deferred until the dentist confirms that the patient has healed treatment of patients with CRPC and visceral metastases than for those
completely from the dental procedure. Supplemental calcium and vitamin without visceral metastases. This is especially true in patients who have
Version 2.2023 © 2023 National Comprehensive Cancer Network© ©
(NCCN ), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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already received docetaxel and a novel hormone therapy, where all disease progression on enzalutamide or abiraterone, is associated with
systemic therapies are given a category 2B recommendation. detection of AR-V7 mRNA in CTCs using an RNA-based polymerase
chain reaction (PCR) assay.841 AR-V7 presence did not preclude clinical
Sequencing of Therapy in CRPC benefit from taxane chemotherapies (docetaxel and cabazitaxel).842 While
No chemotherapy regimen has demonstrated improved survival or QOL other mechanisms of cross-resistance clearly exist, patients with AR-V7–
after cabazitaxel, although several systemic agents other than positive CTCs exhibited superior PFS with taxanes compared to novel
mitoxantrone have shown palliative and radiographic response benefits in hormonal therapies (abiraterone and enzalutamide); the two classes of
clinical trials (ie, carboplatin, cyclophosphamide, doxorubicin, vinorelbine, agents resulted in comparable PFS in patients with AR-V7–negative
carboplatin/etoposide, docetaxel/carboplatin, gemcitabine/oxaliplatin, CTCs. A confirmatory study used a different CTC assay that detected
paclitaxel/carboplatin824-833). Prednisone or dexamethasone at low doses nuclear-localized AR-V7 protein using immunofluorescence. Patients with
may provide palliative benefits in the chemotherapy-refractory setting.834 AR-V7–positive CTCs had superior OS with taxanes versus abiraterone or
No survival benefit for combination regimens over sequential single-agent enzalutamide, whereas OS was not different between the two classes of
regimens has been demonstrated, and toxicity is higher with combination agents among patients with AR-V7–negative CTCs.843
regimens. Treatment with these agents could be considered after an
informed discussion between the physician and an individual patient about A blinded, correlative study at three cancer centers assessed the
treatment goals and risks/side effects and alternatives, which must include correlation between AR-V7 results before second-line treatment and OS in
best supportive care. Participation in a clinical trial is encouraged. patients with metastatic CRPC.844 Approximately half of the validation
cohort received taxane therapy in first line, whereas half received an
No randomized trials that compare taxane chemotherapies versus novel androgen receptor signaling inhibitor. In a high-risk subset of this cohort,
hormonal therapies in patients who previously had abiraterone or patients negative for AR-V7 had superior OS if they were treated with an
enzalutamide have been reported, and some data suggest cross- androgen receptor signaling inhibitor than if they were treated with a
resistance between abiraterone and enzalutamide.835-838 One molecular taxane (median OS, 19.8 vs. 12.8 months; HR, 1.67; 95% CI, 1.00–2.81;
biomarker that may aid appropriate selection of therapy after progression P = .05).
on abiraterone or enzalutamide is the presence of AR-V7 in CTCs (See
AR-V7 Testing, below).839 Results of a randomized, open-label, phase 2, PROPHECY was a prospective multicenter validation study, which
crossover trial suggest that the sequence of abiraterone followed by enrolled 118 patients with metastatic CRPC who were starting abiraterone
enzalutamide is more efficacious than the reverse.840 or enzalutamide.845 The primary endpoint was to validate the prognostic
significance of baseline AR-V7 in CTCs on radiographic or clinical PFS.
AR-V7 Testing Secondary endpoints included OS. Prior exposure to enzalutamide or
Cross resistance between novel androgen receptor pathway inhibitors is abiraterone was permitted if the alternative hormonal therapy was
common with sequential therapy. This lack of response of patients with planned. After adjusting for CTC number and clinical prognostic factors,
metastatic CRPC to abiraterone and enzalutamide, particularly after the detection of AR-V7 was associated with a shorter PFS (HR, 1.9 [P =
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Prostate Cancer
.032] or 2.4 [P = .020], depending on the test used) and OS (HR, 4.2 [95%
CI, 2.1–8.5] or 3.5 [95% CI, 1.6–8.1], depending on the test used)
regardless of first- or second-line AR inhibitor use. In the updated final
analyses, CTC AR-V7 was confirmed to be independently a poor
prognostic factor for AR therapy, but was not significantly predictive of the
benefits of docetaxel nor cabazitaxel, where outcomes were similar
regardless of AR-V7 status.846
These clinical experiences suggest that AR-V7 assays may be a useful

predictor of abiraterone and enzalutamide resistance in patients with
metastatic CRPC particularly following progression on prior enzalutamide
or abiraterone. The prevalence of AR-V7 positivity is only 3% in patients
prior to treatment with enzalutamide, abiraterone, and taxanes,843 so the
Panel believes AR-V7 detection would not be useful to inform treatment
decisions before these treatments are given. On the other hand, the
prevalence of AR-V7 positivity is higher after progression on abiraterone
or enzalutamide (19%–39%841), but data have already shown that
abiraterone/enzalutamide crossover therapy is rarely effective long-term,
and taxanes are more effective in this setting. The Panel recommends that
use of AR-V7 tests can be considered to help guide selection of therapy in
the post-abiraterone/enzalutamide metastatic CRPC setting.
Summary
The intention of these guidelines is to provide a framework on which to
base treatment decisions. Prostate cancer is a complex disease, with
many controversial aspects of management and with a dearth of sound
data to support many treatment recommendations. Several variables
(including adjusted life expectancy, disease characteristics, predicted
outcomes, and patient preferences) must be considered by the patient and
physician to tailor prostate cancer therapy for the individual patient.
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Table 1. Available Tissue-Based Tests for Prostate Cancer Risk Stratification/Prognosis

Populations Outcome(s) Reported Selected Molecular Diagnostic Services Program (MolDX)
Test Platform
Studied (Test independently predicts) References Recommendations
Decipher Whole-transcriptome Post radical prostatectomy • Metastasis 155,158,159,582,8 Cover post-biopsy for NCCN very-low-, low-risk,
1.4M RNA (RP), adverse pathology/high- • Prostate cancer-specific mortality 47-860 favorable intermediate, and unfavorable intermediate
expression (46,050 risk features risk prostate cancer in patients with at least 10 years
• Postoperative radiation sensitivity (PORTOS)
genes and noncoding life expectancy who have not received treatment for
RNA) oligonucleotide Post RP, biochemical • Metastasis prostate cancer and are candidates for active
microarray optimized recurrence/PSA persistence • Prostate cancer-specific mortality surveillance or definitive therapy
for FFPE tissue • PORTOS
Post RP, adjuvant, or post- • Metastasis Cover post-RP for 1) pT2 with positive margins; 2)
recurrence radiation any pT3 disease; 3) rising PSA (above nadir)
• Prostate cancer-specific mortality
• PORTOS
Biopsy, localized prostate • Non-organ confined (pT3) or grade group 3
cancer post RP or EBRT disease at RP
• Lymph node metastasis
• Biochemical failure/recurrence
• Metastasis
• Grade Group ≥4 disease at RP
M0 CRPC • Metastasis-free survival
Ki-67 IHC Biopsy, conservatively • Prostate cancer-specific mortality 861-864 Not recommended
managed (active surveillance)
Biopsy, low- to intermediate- • Non-organ-confined pT3 or Grade Group ≥4
risk treated with RP disease on RP
Oncotype Quantitative RT-PCR Biopsy, very low- to high-risk • Non-organ-confined pT3 or Grade Group 4 157,865,866 Cover post-biopsy for NCCN very-low-, low-risk, and
DX for 12 prostate treated with RP disease on RP favorable intermediate-risk prostate cancer in patients
Prostate cancer-related genes • Biochemical recurrence with at least 10 years life expectancy who have not
and 5 housekeeping received treatment for prostate cancer and are
controls • Metastases candidates for active surveillance or definitive therapy
Prolaris Quantitative RT-PCR Biopsy, conservatively • Prostate cancer-specific mortality 150-153,867-869 Cover post-biopsy for NCCN very-low-, low-risk, and
for 31 cell cycle- managed (active surveillance) favorable intermediate-risk prostate cancer in patients
related genes and 15 Biopsy, localized prostate • Biochemical recurrence with at least 10 years life expectancy who have not
housekeeping cancer • Metastasis received treatment for prostate cancer and are
controls candidates for active surveillance or definitive therapy
Biopsy, intermediate-risk • Biochemical recurrence
treated with EBRT
RP, node-negative localized • Biochemical recurrence
prostate cancer
Biopsy, Gleason grade 3+3 or • Non–organ-confined pT3 or Grade Group ≥3
3+4 on RP
PTEN Fluorescence in situ Biopsy, Grade Group 1 • Upgrading to Grade Group ≥3 on RP 870-874 Not recommended
hybridization or IHC RP, high-risk localized disease • Biochemical recurrence
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Table 2. Summary of FDA-Cleared PET Imaging Tracers Studied in Prostate Cancer

Tracer Half-life Production Mechanism of Excretion Detection Rates* Panel Recommendation
(min) Action
Ga-68 68 Generator or Binds extracellular Renal 40% sensitivity and 95% specificity May be used for detection of disease
PSMA-11 Cyclotron epitope of PSMA to detect nodal involvement in at initial staging, biochemical
(PSMA- (Regional) primary staging of patients with recurrence, and progression of
HBED- intermediate-, high-, and very-high- disease in bone and soft tissues
CC)195,875 risk disease (See NCCN Guidelines algorithm for
92% patient-level PPV in BCR more details)
F-18 110 Cyclotron Binds extracellular Renal 31%–42% sensitivity and 96%99% May be used for detection of disease
piflufolastat epitope of PSMA specificity to detect nodal at initial staging, biochemical
(DCFPyL)198, (Regional) involvement in primary staging of recurrence, and progression of
876
patients with unfavorable disease in bone and soft tissues
intermediate-risk, high-risk, and (See NCCN Guidelines for more
very-high-risk disease details)
85%–87% patient-level CLR** in
BCR
C-11 20 Cyclotron Cellular uptake and Hepatic 53%–96% PPV in BCR May be used for detection of disease
choline877 (Onsite) incorporation into cell and renal at biochemical recurrence and
membrane/lipid progression of disease in bone and
synthesis soft tissues (See NCCN Guidelines
algorithm for more details)
F-18 110 Cyclotron Cellular uptake by Renal 87%–91% CLR** in BCR May be used for detection of disease
fluciclovine (Regional) amino acid at biochemical recurrence and
(FACBC)878 transporters ASCT2, progression of disease in bone and
LAT1, and SNAT2 soft tissues (See NCCN Guidelines
algorithm for more details)
F-18 NaF217 110 Cyclotron Adsorption to bone Renal 77%–94% sensitivity, 92%–99% May be used as an alternative to
(Regional) matrix by osteoblasts specificity, and 82%–97% PPV for bone scintigraphy
bone metastases
* Interpret with caution. Wherever possible, studies were included that used histopathologic confirmation, but not all studies used confirmatory
histology as gold standard. Values may vary depending upon the site of the lesion and phase of the disease process.
** CLR: Correct localization rate. Patient-level positive predictive value + anatomic lesion co-localization. Preferred over sensitivity and specificity in
analyses of patients with BCR.
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MS-133

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines for Patients® available at www.nccn.org/patients

*Edward M. Schaeffer, MD, PhD/Chair ω James A. Eastham, MD ω George Netto, MD ≠

ф Diagnostic/Interventional ¥ Patient advocate NCCN

INITIAL PROSTATE CANCER DIAGNOSISa,b,c WORKUP

• Perform physical exam

• Perform physical exam

Note: All recommendations are category 2A unless otherwise indicated.

Note: All recommendations are category 2A unless otherwise indicated.

>20 y External Beam Radiation Therapy (EBRT)p or brachytherapyp

<10 yf Observation r See Monitoring (PROS-9)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

≥10 y EBRTp or brachytherapyp

<10 yf Observation r See Monitoring (PROS-9)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

FAVORABLE INTERMEDIATE-RISK GROUP

Note: All recommendations are category 2A unless otherwise indicated.

UNFAVORABLE INTERMEDIATE-RISK GROUP

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

HIGH- OR VERY-HIGH-RISK GROUP

Observationr See Monitoring (PROS-9)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

REGIONAL RISK GROUP (ANY T, N1, M0)

See Footnotes for Risk Groups (PROS-8A).

Note: All recommendations are category 2A unless otherwise indicated.

Note: All recommendations are category 2A unless otherwise indicated.

MONITORING RECURRENCE See Radical

• Physical exam + PSA N1,M0 Systemic Therapy for

h See Principles of Imaging (PROS-E).

Note: All recommendations are category 2A unless otherwise indicated.

RADICAL PROSTATECTOMY PSA PERSISTENCE/RECURRENCE

Note: All recommendations are category 2A unless otherwise indicated.

RADIATION THERAPY RECURRENCE Biopsy

See footnotes (PROS-11A).

Note: All recommendations are category 2A unless otherwise indicated.

Note: All recommendations are category 2A unless otherwise indicated.

SYSTEMIC THERAPY FOR CASTRATION-SENSITIVE PROSTATE CANCERrr

See footnotes on PROS-12A

Note: All recommendations are category 2A unless otherwise indicated.

Note: All recommendations are category 2A unless otherwise indicated.

SYSTEMIC THERAPY FOR M0 CASTRATION-RESISTANT PROSTATE CANCER (CRPC)eee

ll Document castrate levels of testosterone if clinically indicated. Workup for

Note: All recommendations are category 2A unless otherwise indicated.

SYSTEMIC THERAPY FOR M1 CRPCeee

• Continue ADTu to maintain

c See Principles of Genetics and Molecular/Biomarker Analysis (PROS-C).

Note: All recommendations are category 2A unless otherwise indicated.

SYSTEMIC THERAPY FOR M1 CRPC: ADENOCARCINOMAiii,kkk,lll

See Footnotes for Systemic Therapy M1 CRPC (PROS-15A).

Note: All recommendations are category 2A unless otherwise indicated.

PRINCIPLES OF LIFE EXPECTANCY ESTIMATION

• Life expectancy can be estimated using:

Note: All recommendations are category 2A unless otherwise indicated.

PRINCIPLES OF QUALITY-OF-LIFE AND SHARED DECISION-MAKING

Note: All recommendations are category 2A unless otherwise indicated.

ll Document castrate levels of testosterone if clinically indicated. Workup for