VOLUME

26

NUMBER

10

APRIL

2008

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

From the Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada; Division of Hematology and Medical Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL; Department of Medical Oncology, Institut Bergonie , Bordeaux; Department of Medical Oncology, CRLC Val d AurellePaul Lamarque, Montpellier, France; Medical Oncology, Instituto National de Cancer, Rio de Janeiro; Departmento de Radiologia, Faculdade de Medicina da USP, University of Sa o Paulo, Sa o Paulo, Brazil; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven; Medicine Department, Jules Bordet Institute, Brussels, Belgium; Investigacio n Cl nica, Centro Oncologico de Rosario, Rosario, Argentina; The M.D. Anderson Cancer Center, University of Texas, Houston, TX; Professorial Unit of Surgery, Nottingham City Hospital, Nottingham; Clinical Development, AstraZeneca Pharmaceuticals, Maccleseld, Cheshire, United Kingdom; Division of Hematology/ Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Oncology and Haematology, Charite Campus Mitte, Universitatsmedizin, Berlin, Germany; and Clinical Development, AstraZeneca Pharmaceuticals, Wilmington, DE. Submitted July 26, 2007; accepted December 5, 2007; published online ahead of print at www.jco.org on March 3, 2008. Presented in part at the 29th Annual San Antonio Breast Cancer Symposium December 14-17, 2006, San Antonio, Texas. Authors disclosures of potential conicts of interest and author contributions are found at the end of this article. Corresponding author: Stephen Chia, MD, Division of Medical Oncology, British Columbia Cancer Agency, University of British Columbia, 600 West 10th Avenue, Vancouver, B.C. Canada, V5Z 4E6; e-mail: [email protected]. 2008 by American Society of Clinical Oncology 0732-183X/08/2610-1664/$20.00 DOI: 10.1200/JCO.2007.13.5822

Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Aromatase Inhibitor Therapy in Postmenopausal Women With Hormone ReceptorPositive, Advanced Breast Cancer: Results From EFECT
Stephen Chia, William Gradishar, Louis Mauriac, Jose Bines, Frederic Amant, Miriam Federico, Luis Fein, Gilles Romieu, Aman Buzdar, John F.R. Robertson, Adam Brufsky, Kurt Possinger, Pamela Rennie, Francisco Sapunar, Elizabeth Lowe, and Martine Piccart
A B S T R A C T

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and rst-line advanced therapy for postmenopausal, hormone receptorpositive (HR) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efcacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n 351) or exemestane (n 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups (hazard ratio 0.963; 95% CI, 0.819 to 1.133; P .6531). The overall response rate (7.4% v 6.7%; P .736) and clinical benet rate (32.2% v 31.5%; P .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benet was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no signicant differences in the incidence of adverse events or quality of life. Pharmacokinetic data conrm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI. J Clin Oncol 26:1664-1670. 2008 by American Society of Clinical Oncology

INTRODUCTION

Hormone receptorpositive (HR) breast cancer is the most common presentation of breast cancer today.1 In postmenopausal HR breast cancer, there are several hormonal therapeutic options available, of which the classes of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have been studied extensively and are standard therapeutic options in breast cancer.

The third-generation AIs consists of both nonsteroidal (anastrozole, letrozole) and steroidal (exemestane) inhibitors. The nonsteroidal inhibitors block the peripheral conversion of androgens to estrogens by inhibiting the heme porphyrin portion of aromatase. In contrast, the steroidal AIs act by binding irreversibly to the androgen binding site and are structurally different from the nonsteroidal AIs. As rst-line therapy in HR, postmenopausal advanced breast cancer (ABC),

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Randomized Trial of Fulvestrant v Exemestane in Advanced Breast Cancer

the AIs have demonstrated superiority to tamoxifen for response rates and time to progression.2-4 Furthermore, the AIs, either up front or after tamoxifen, have been clearly established as adjuvant hormonal options in early-stage HR postmenopausal breast cancer.5-10 Unfortunately, the vast majority of patients diagnosed with ABC will eventually progress during treatment with a specic therapy, and a signicant proportion of patients with early stage-breast cancers will relapse. Thus, additional therapeutic agents are required to continue to treat the disease at time of progression/relapse. Fulvestrant is a novel estrogen-receptor (ER) antagonist that, unlike tamoxifen, is devoid of any agonist activity.11 On binding to the ER, fulvestrant induces a rapid degradation and loss of ER and the progesterone receptor (PgR).12-13 Several large phase III trials have demonstrated signicant activity for fulvestrant in the treatment of HR ABC, with similar efcacy to that of anastrozole and tamoxifen.14-16 Furthermore, activity has been seen in phase II trials of fulvestrant after progression during treatment with a nonsteroidal AI, with clinical benet rates (CBRs) of 30% to 35%.17-18 Exemestane is a steroidal-based AI, with modest androgenic activity.19 Exemestane has been studied in a phase II trial after documented progression during treatment with a nonsteroidal AI, and showed a 20% clinical benet rate.20 Because of the lack of randomized clinical trial data and the prevalence of patients exposed to nonsteroidal AIs, the Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was undertaken to address this specic question of which hormonal agent to consider rst after progression during treatment with a nonsteroidal AI.

All women provided written informed consent before registration on trial. The study was conducted in accordance with the ethical principles that originated in the Declaration of Helsinki and with local Research Ethics Board approval at each participating center. Trial Treatments Fulvestrant 250 mg/5 mL (2) as an intramuscular injection or a matching 5 mL (2) oily excipient placebo was injected into each buttock (500 mg or matching placebo) on day 1, followed by a single injection of 250 mg fulvestrant/placebo at day 14 and again on day 28. Treatment after day 28 was every 28 days ( 3 days) thereafter. Exemestane 25 mg and a matching placebo were to be taken orally once daily. Patients continued treatment until objective disease progression or other events that required withdrawal. There was no built in crossover design in this trial. Thereafter, patients were followed up until death. Patients who withdrew from trial treatment before progression were followed up for response until progression and death. All patients were seen by a physician monthly until month 6, and every 3 months thereafter. Tumor assessment was performed every 8 weeks from baseline until month 6, and then every 3 months until disease progression. In a subset of 60 patients (30 in each treatment group) pharmacokinetic samples were collected at specied time intervals to conrm whether the LD regimen would achieve steady-state earlier than that seen previously with a dose of fulvestrant 250 mg every 28 days. Statistical Analysis The primary end point of the study was time to disease progression (TTP). Secondary end points included objective response (OR) rate, CBR, duration of response, time to response, overall survival, and tolerability. The trial was designed to detect superiority of fulvestrant compared with exemestane in terms of TTP. The nal analysis was scheduled to take place when 580 progression events (ie, objective disease progression or death) had occurred across both treatment groups. This would provide 90% power to detect a hazard ratio of 1.31 or greater, or of 0.76 or less for fulvestrant treatment compared with exemestane treatment, at a two-sided signicance level of 5%. To achieve the required number of events, it was planned to recruit 660 patients (330 in each treatment group). Data for the efcacy parameters were analyzed and summarized on an intention-to-treat basis. TTP TTP was dened as the number of days from the date of random assignment until the date of objective disease progression, as per RECIST criteria. If the patient died without documented disease progression, and the date of death was no more than 6 months from the last disease assessment per RECIST, then death was regarded as a progression event. For patients who had not experienced disease progression at the time of data cutoff, data were right censored to the date of the last RECIST assessment. The primary analysis for TTP was the unstratied log-rank test. The secondary analysis used the Cox proportional hazards regression model and included the following six baseline covariates: age ( 65 v 65 years), number of prior hormonal therapies (1 v 2), receptor status (both ER and PgR v only one receptor positive), visceral involvement (yes v no), presence of measurable disease compared with nonmeasurable disease, and AI sensitive versus AI resistant. The treatment effect was estimated using the hazard ratio of fulvestrant to exemestane, together with the 95% CI and P value. A global interaction test using a 1% signicance level was performed to determine whether the overall treatment benet was consistent across each of the six covariates. TTP was also summarized using Kaplan-Meier curves for each treatment group and the median TTP was calculated. Overall Survival Time to death was to be analyzed when more than 50% of the patients had died across both treatment groups. At the time of data analysis, only 34% of patients had died, and therefore no formal statistical analyses were conducted. Best OR and CBR An OR was dened as a patient having a best overall response of either CR or PR with conrmation criteria as per RECIST. A patient with clinical
2008 by American Society of Clinical Oncology

MATERIALS AND METHODS

Study Design EFECT is a randomized, double blind, double-dummy, phase III international trial designed to compare the efcacy and tolerability of a loadingdose (LD) schedule of fulvestrant to exemestane in postmenopausal women with HR ABC with disease progression after prior nonsteroidal AI therapy. Patient Population All patients were postmenopausal women with incurable locally advanced or metastatic breast cancer whose disease had relapsed during treatment with (or within 6 months of discontinuation of) an adjuvant nonsteroidal AI, or whose advanced disease progressed during treatment with a nonsteroidal AI. Patients were categorized as AI sensitive if the investigator determined that the patient had a complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months during treatment with the AI for ABC. All other patients, including all those who received the AI as adjuvant therapy, were dened as AI resistant. Inclusion onto the trial required women to be postmenopausal ( 60 years old, or age 45 years with amenorrhea for 12 months or follicle stimulating hormone levels within postmenopausal range, or prior bilateral oophorectomy). Other inclusion criteria included HR (ER and/or PgR) disease as determined locally, WHO performance status of 0 to 2, life expectancy of at least 3 months and the presence of at least one measurable or assessable (nonmeasurable) lesion. Initially, the protocol required that all patients have at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, but subsequently the protocol was amended to include patients with bone only (lytic or mixed) metastatic lesions. Up to one prior chemotherapy regimen for the treatment of ABC was allowed. Exclusion criteria included life threatening metastatic visceral disease, brain or leptomeningeal metastases, prior exposure to either fulvestrant or exemestane, extensive radiation or cytotoxic therapy within the last 4 weeks, or a history of bleeding diathesis or need for long-term anticoagulation.
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Chia et al

benet (CB) was dened as a patient having a best overall response of a CR, PR, or SD for at least 24 weeks. SD was dened, as per RECIST criteria, as neither achieving a PR nor progressive disease at week 24 or later. Duration of Response Duration of response (DOR) was evaluated only for patients who had an OR, and was dened as the number of days from date of random assignment until the day on which disease progression or death resulting from any cause was rst observed. Quality of Life Quality of life (QOL) was assessed using the Functional Assessment of Cancer TherapyEndocrine Symptom (FACT-ES) instrument. The analysis was undertaken using both the FACT-ES and Trial Outcome Index (TOI). The difference between the two treatment groups in FACT-ES and TOI over time was compared using a generalized linear mixed model, with the Restricted Maximum Likelihood option, including the same six covariates as for TTP. Tolerability All safety data were listed and summarized according to the treatment received. Adverse events (AEs) were presented using MedDRA terminology. Eight AE categories considered relevant to endocrine therapy were predened for statistical analysis. The analysis of the predened AEs was performed using a two-sided Fishers exact test at the 5% signicance level.

exemestane arms, respectively (odds ratio 1.03; 95% CI, 0.72 to 1.487; P .853). Of note, in the cohort of patients with visceral involvement, the CBR was 29% and 27% in the fulvestrant and exemestane arms, respectively. The median DOR, as measured from the date of random assignment, was 13.5 months in the fulvestrant group and 9.8 months in the exemestane group (Fig 3); median DOR as measured from the date of rst response was 7.5 months for fulvestrant compared with 5.5 months for exemestane. Pharmacokinetics The pharmacokinetic (PK) substudy results mirrored those from modeling studies and demonstrated a much faster time to steady-state levels with the LD schedule of fulvestrant, compared to prior PK studies of the 250 mg monthly dose. Median time to steady state was achieved within 28 days with the LD regimen, compared with 3 to 6 months with the 250-mg monthly dose22 (Fig 4). Tolerability Both fulvestrant and exemestane were well tolerated in this study (Table 2), with only 2% of fulvestrant-treated patients and 2.6% of exemestane-treated patients withdrawing because of an adverse event (AE). Drug-related serious AEs (SAEs) were rare, occurring in 1.1% and 0.6% of each arm, respectively. No patient died as a result of a drug-related AE. The incidence of venous thromboembolic events in the fulvestrant and exemestane arms was 1.1% and 0.9%, respectively. QOL QOL was measured with two instruments in this study, the FACT-ES and TOI. A graph of the mean TOI over time is shown in Figure A2 (online only). The mean difference across both instruments was not signicant, demonstrating that QOL was not statistically different between either treatment arms.

RESULTS

Patients A total of 693 women across 138 centers worldwide were randomly assigned to either fulvestrant (n 351) or exemestane (n 342) from August 2003 to November 2005. The accountability of all patients randomly assigned is seen in Figure A1 (online only). Baseline characteristics between the two randomly assigned treatments are outlined in Table 1. Overall, the groups were well balanced, except that the fulvestrant cohort had a slightly greater number of women with ER and PgR tumors (67.5%) versus the exemestane cohort (56.4%). Approximately 60% of participants had two or more prior lines of hormonal therapy. Approximately 60% of patients in both groups had either a response (CR or PR) or SD lasting at least 6 months during treatment with the prior nonsteroidal AI for ABC (termed AI sensitive) as determined by the individual investigator. Only 10% of women enrolled received their previous AI as adjuvant therapy. The median follow-up for all patients alive is approximately 13 months. Efcacy The primary end point of this study was TTP. At the time of analysis, 82.1% (n 288) of the fulvestrant group and 87.4% (n 299) of the exemestane group had experienced a dened progression event. The median time to progression (Fig 1) in both groups was 3.7 months (P .65) with a hazard ratio of 0.93 (95% CI, 0.819 to 1.133). The adjusted hazard ratio for the specied covariates was 0.968 (P .70) with the 95% CI at 0.822 to 1.141. In an investigation of the consistency of treatment effect across the predened covariates, there were no statistically signicant differences (Fig 2). OR Rate and CBR A total of 540 patients (270 in each arm) had measurable disease by RECIST criteria at trial entry. Overall, 20 patients in the fulvestrant arm (7.4%) and 18 patients in the exemestane arm (6.7%) had a documented response (odds ratio 1.12; 95% CI, 0.578 to 2.186; P .736). The CBR was 32.2% and 31.5% in the fulvestrant and
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DISCUSSION

EFECT is not only one of the largest published trials to date comparing hormonal therapies in HR ABC, but also one of the rst to specically address the optimal agent to use in sequence immediately after progression of a nonsteroidal AI. EFECT conrmed efcacy for both fulvestrant and exemestane in this setting, with clinical benet rates of approximately 32% and a median TTP of 3.7 months for both agents. The observed durations of response with fulvestrant and exemestane (13.5 v 9.8 months, respectively) and durations of clinical benet (9.3 v 8.3 months, respectively), are encouraging for a population of patients with relapsed disease after AI treatment. Furthermore, results from EFECT support the concept that patients achieving SD lasting at least 24 weeks have similar outcomes compared with patients obtaining a response (Fig A3, online only), even in this previously hormonally treated population. It is interesting, that for more than 60% of women in EFECT, the treating oncologist identied the patient as AI sensitive, but this was neither conrmed centrally or by RECIST criteria. Yet by 6 months, approximately 70% of trial subjects had experienced disease progression. This indicates that approximately two thirds of patients did not benet from either hormonal agent, implying that the majority of
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Randomized Trial of Fulvestrant v Exemestane in Advanced Breast Cancer

Table 1. Baseline Patient and Disease Characteristics Fulvestrant (n 351) Characteristic Age, years Median Range Age group, years 65 (adult) 65 (elderly) Prior treatments Adjuvant endocrine therapy Endocrine therapy for advanced disease 1 prior endocrine therapy 1 prior endocrine therapy Adjuvant chemotherapy Chemotherapy for advanced disease Adjuvant radiotherapy Radiotherapy for advanced disease Other breast cancer treatment AI-sensitive disease AI-resistant disease Disease stage Locally advanced Metastatic Sites of metastases Bone Lung Liver Lymph nodes Skin/soft tissue Other Visceral involvement Yes No Hormone receptor status ER and/or PgR ER and PgR Other WHO performance status 0 (normal activity) 1 (restricted activity) 2 (in bed 50% of the time) Measurable disease Yes No No. 63 38-88 189 162 217 313 145 206 147 87 190 129 35 224 127 8 342 236 121 109 104 71 48 197 154 345 237 6 194 133 24 270 81 53.8 46.2 61.8 89.2 41.3 58.7 41.9 24.8 54.1 36.8 10.0 63.8 36.2 2.3 97.4 67.2 34.5 31.1 29.6 20.2 13.7 56.1 43.9 98.3 67.5 1.7 55.3 37.9 6.8 76.9 23.1 194 148 199 294 147 195 168 74 171 142 29 210 132 10 332 227 124 110 117 58 56 198 144 336 193 6 181 149 12 270 72 % No. 63 32-91 56.7 43.3 58.2 86.0 43.0 57.0 49.1 21.6 50.0 41.5 8.5 61.4 38.6 2.9 97.1 66.4 36.3 32.2 34.2 17.0 16.4 57.9 42.1 98.2 56.4 1.8 52.9 43.6 3.5 78.9 21.1 Exemestane (n 342) %

Abbreviations: ER, estrogen receptor; PgR, progesterone receptor; AI, aromatase inhibitor. Thirty-eight patients (10.8%) in the fulvestrant group and 48 (14.0%) patients in the exemestane group received their last non-steroidal AI therapy as adjuvant therapy. Three hundred ten patients (88.3%) in the fulvestrant group and 293 (85.7%) in the exemestane group received their last non-steroidal AI therapy for advanced disease. Disease stage was unknown in one patient in the fulvestrant group (patients subsequently classed as a violator). Patients could have 1 site of metastases. One patient in the fulvestrant group and ve patients in the exemestane group had no evidence of meeting the criterion for ER of PgR positivity at baseline and so were classed as violators. The remaining ve patients in the fulvestrant group and one patient in the exemestane group did not meet this criterion at baseline but met it previously and so werent considered violators.

patients enrolled on EFECT had hormone-insensitive disease. In addition, in close to 60% of women, the study hormonal agent was administered as third-line or greater therapy. All of these factors could have contributed to a less-than-optimal clinical efcacy than had been hoped for, and may have undermined the power of the study. Indeed, in a retrospective analysis looking at TTP in patients who received fulvestrant or exemestane as second-line treatment and were deemed to be sensitive to the prior nonsteroidal AI, the curves do appear to
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separate in favor of fulvestrant (hazard ratio 0.73; 99.8% CI, 0.45 to 1.19; Fig A4, online only). However, the number of patients contributing to this analysis is small (n 190), and the results are nonsignificant as well as being retrospectively derived. When used earlier in the hormonal treatment sequence of ER ABC, fulvestrant has demonstrated signicantly better clinical outcomes than those seen here. As rst line therapy fulvestrant was shown to be similar to tamoxifen, with a clinical benet rate of 57% and a
2008 by American Society of Clinical Oncology

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Chia et al

Table 2. Most Commonly Occurring Treatment-Related Adverse Events ( 2% incidence in either treatment group) Fulvestrant (n 351) Adverse Event Injection-site pain Hot ashes Nausea Fatigue Myalgia Arthralgia Diarrhea Asthenia Injection-site reaction Alopecia Headache Anorexia Dyspepsia Pain in extremity No. 33 31 24 22 14 13 12 11 8 8 7 7 3 1 % 9.4 8.8 6.8 6.3 4.0 3.7 3.4 3.1 2.3 2.3 2.0 2.0 0.9 0.3 Exemestane (n 340) No. 28 39 27 34 14 19 10 7 7 5 10 7 7 8 % 8.2 11.5 7.9 10.0 4.1 5.6 2.9 2.1 2.1 1.5 2.9 2.1 2.1 2.4

Receptor status Visceral involvement AI sensitive/resistant Measurable disease Age No. of prior hormonals All patients

ER+/PgR+ Not ER+/PgR+ With Without Sensitive Resistant Yes No < 65 years 65 years 1 prior 2 prior

0.40

0.60

0.80

1.25 1.5 1.75

Hazard ratio (fulvestrant v exemestane) and 95% CI

Fig 2. Forest plot of effect of predened covariates on time to progression. ER, estrogen receptor; PgR, progesterone receptor.

median TTP of 8.2 months.16 In a combined analysis of two multicenter trials as either rst- or second-line therapy in ABC compared with anastrozole, fulvestrant demonstrated a clinical benet rate of 43.5% and a median TTP of 5.5 months.21 Interestingly in a relatively small phase II trial of fulvestrant administered immediately after progression during treatment with an AI, in the subset of patients whose only prior hormonal therapy was an AI, the clinical benet rate was 52.4% (95% CI, 32.8% to 71.4%).17 Of note, in EFECT, there was no difference in either CBR or median TTP between the predened subgroup of patients exposed to only one prior hormonal agent or two or more prior hormonal agents. As a pure ER antagonist, fulvestrant is in a distinct class of its own in regard to its mechanism of action. When fulvestrant binds to the

ER, it results in reduced nuclear uptake of the ER-fulvestrant complex, prevention of the ER binding to the estrogen-responsive genes, and, ultimately, downregulation of ER levels.23-27 Given a distinctly different mechanism of action, it was rational to assume that a substantial degree of clinical activity would be seen with fulvestrant in this setting. The clinical activity seen with fulvestrant in EFECT is similar to those in a previously published experience.18,28-30 What perhaps was surprising from this study was the clinical activity seen with exemestane in this setting: The CBR of 31.5% was higher than the 20% CBR reported in a phase II trial, even though the median TTP was similar.20 EFECT reinforces the notion of incomplete resistance between the nonsteroidal and steroidal AIs. This incomplete cross-resistance is likely not a result of differences in the degree of aromatase inhibition between the AIs.31-32 It may be caused by the androgenic effects of exemestane.19-20 Some questions still remain unanswered today in regard to the optimal use of fulvestrant in the treatment of breast cancer. A higher dose is currently being investigated in several trials. The combination

Proportion of Patients Progression-Free

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 100 200 300 400 500 600 700 800

Proportion of Patients Responding

Fulvestrant Exemestane

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 100 200 300 400 500 600 700 800
Fulvestrant Exemestane

Time to Progression (days)

Days Fulvestrant at risk 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 351 301 191 127 89 67 46 29 23 13 10 4 4 2 0 37 24 21 13 10 8 8 6 2

Duration of Response (days)

Days Fulvestrant at risk Exemestane at risk 0 20 18 50 100 150 200 250 300 350 400 450 500 550 600 650 700 20 20 20 15 13 10 9 8 3 1 0 0 0 0 18 18 17 15 12 9 5 5 4 3 3 3 3 2

Exemestane at risk 342 305 184 130 86 56

Fig 1. Kaplan-Meier estimates for time to progression (TTP). Estimated median TTP for patients receiving fulvestrant was 3.7 months, compared with 3.7 months for patients receiving exemestane (hazard ratio 0.963; 95% CI, 0.819 to 1.133; P .6531). 1668
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Fig 3. Kaplan-Meier estimates for duration of response (DOR; from random assignment). Estimated median DOR for patients receiving fulvestrant was 13.5 months, compared with 9.8 months for patients receiving exemestane.
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Randomized Trial of Fulvestrant v Exemestane in Advanced Breast Cancer

40 35 30 25 20 15 10 5 0 28 56 84 112 140 168 196 224

Population predicted Observed

Time (days)
Fig 4. Observed and population-predicted pharmacokinetic prole for the fulvestrant loading-dose regimen (500 mg day 0, 250 mg day 14, 250 mg day 28, and then 250 mg/month thereafter).

of fulvestrant and an AI compared with an AI alone is another approach being studied in several clinical trials. The premise for the combination is that fulvestrant may be more effective in a lowestrogen environment, which is supported by preclinical data.33 In conclusion, EFECT has demonstrated clinical activity for both LD fulvestrant and exemestane in a meaningful proportion of postmenopausal HR ABC after progression during treatment with a nonsteroidal AI. Both agents were well tolerated, with a similar incidence of reported adverse events and quality of life. There were also no apparent preliminary differences in the proportion of women receiving chemotherapy (approximately 50%) as the rst subsequent systemic therapy after trial treatment failure. The pros and cons of these two agents with their different mechanisms of action, costs, and modes of delivery should be discussed with patients because there are preferences to both intramuscular and oral agents.34
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked

with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: Pamela Rennie, AstraZeneca (C); Francisco Sapunar, AstraZeneca (C); Elizabeth Lowe, AstraZeneca (C) Consultant or Advisory Role: Stephen Chia, Advisory board for Astra Zeneca (C); William Gradishar, AstraZeneca (C), Pzer (C); Louis Mauriac, Novartis (C), AstraZeneca (C); John F.R. Robertson, AstraZeneca (C), Pzer (C); Martine Piccart, AstraZeneca (C), Pzer (C), Novartis (C) Stock Ownership: Pamela Rennie, AstraZeneca; Francisco Sapunar, AstraZeneca; Elizabeth Lowe, AstraZeneca Honoraria: Stephen Chia, Honoraria for CME talks by Astra Zeneca; Louis Mauriac, Novartis, AstraZeneca; Jose Bines, AstraZeneca; Aman Buzdar, AstraZeneca, Eli Lilly, Roche, Genetech, Pzer, Taiho; John F.R. Robertson, AstraZeneca; Adam Brufsky, AstraZeneca; Kurt Possinger, AstraZeneca Research Funding: Stephen Chia, Investigator initiated funding with Astra Zeneca; William Gradishar, AstraZeneca; John F.R. Robertson, AstraZeneca; Martine Piccart, Novartis, Pzer Expert Testimony: None Other Remuneration: John F.R. Robertson, AstraZeneca, Pzer; Kurt Possinger, AstraZeneca

Predicted Concentration (ng/mL)

AUTHOR CONTRIBUTIONS
Conception and design: Stephen Chia, Aman Buzdar, Pamela Rennie, Francisco Sapunar Provision of study materials or patients: Stephen Chia, William Gradishar, Louis Mauriac, Jose Bines, Frederic Amant, Miriam Federico, Luis Fein, Gilles Romieu, Aman Buzdar, John F.R. Robertson, Adam Brufsky, Kurt Possinger, Martine Piccart Collection and assembly of data: Stephen Chia, William Gradishar, Louis Mauriac, Frederic Amant, John F.R. Robertson, Adam Brufsky, Pamela Rennie, Elizabeth Lowe Data analysis and interpretation: Stephen Chia, William Gradishar, Aman Buzdar, John F.R. Robertson, Adam Brufsky, Pamela Rennie, Francisco Sapunar, Elizabeth Lowe, Martine Piccart Manuscript writing: Stephen Chia, William Gradishar, Frederic Amant, Aman Buzdar, John F.R. Robertson, Adam Brufsky, Pamela Rennie, Elizabeth Lowe Final approval of manuscript: Stephen Chia, William Gradishar, Louis Mauriac, Jose Bines, Frederic Amant, Miriam Federico, Luis Fein, Gilles Romieu, Aman Buzdar, John F.R. Robertson, Adam Brufsky, Kurt Possinger, Pamela Rennie, Francisco Sapunar, Elizabeth Lowe, Martine Piccart
8. Jakesz R, Jonat W, Gnant M, et al: Switching of postmenopausal women with endocrine responsive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005 9. Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after ve years of tamoxifen therapy for early stage breast cancer. N Engl J Med 349:1793-1802, 2003 10. Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment of the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005 11. Wakeling AE, Dukes M, and Bowler J: A potent specic pure antiestrogen with clinical potential. Cancer Res 51:3867-3873, 1991

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