Abstract and Introduction
Abstract
Background At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died. A final analysis of OS was subsequently planned for when 75% of patients had died.
Methods Patients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (±3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (±3) days thereafter. OS was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy were also reported. All statistical tests were two-sided.
Results In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500mg (n = 362) or 250mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500mg and 22.3 months for 250mg (hazard ratio = 0.81; 95% confidence interval = 0.69–0.96; nominal P = .02). There were no clinically important differences in SAE profiles between the treatment groups; no clustering of SAEs could be detected in either treatment group. Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups.
Conclusions In patients with locally advanced or metastatic estrogen receptor–positive breast cancer, fulvestrant 500mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250mg. Fulvestrant 500mg was well tolerated, and no new safety concerns were identified.
Introduction
Fulvestrant is a pure estrogen receptor (ER) antagonist devoid of the agonistic properties displayed by tamoxifen in some tissues.[1–4] After phase III studies, which demonstrated similar efficacy and an acceptable safety profile for fulvestrant 250mg compared with anastrozole,[1,5] fulvestrant 250mg was approved as treatment in postmenopausal women with advanced hormone receptor–positive breast cancer that had progressed or recurred after prior antiestrogen therapy. However, previous preoperative studies showed that short-term exposure to fulvestrant was associated with a dose-dependent reduction in the levels of ER, progesterone receptor, and the cell proliferation–related antigen Ki67[6,7] for fulvestrant doses up to 250mg. Other phase I and phase III studies also suggested a dose–response effect for fulvestrant.[1,5,8]
The phase III Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial compared the then-approved dose and dosing schedule of fulvestrant (250mg every 28 days) with a higher-dose regimen (500mg every 28 days plus an additional 500mg on day 14 of the first month only) in postmenopausal women with locally advanced or metastatic ER-positive breast cancer that had recurred or progressed after prior endocrine therapy. The initial results showed that fulvestrant 500mg was associated with a statistically significant increase in progression-free survival (PFS) without increased toxicity, therefore corresponding to a clinically meaningful improvement in benefit vs risk compared with fulvestrant 250mg.[9] Based on these data, the 500-mg dose of fulvestrant is now the approved dose in the European Union (approved in March 2010), United States (approved in September 2010), Japan (approved in November 2011), and other countries worldwide.
In the CONFIRM study, the assessment of the therapeutic efficacy of both doses of fulvestrant was evaluated by several secondary outcome measures, including overall survival (OS). At the time of the initial analysis, approximately 50% of patients had died. After the reporting of the 50% survival data, which showed a trend in favor of 500mg over 250mg, it was agreed to perform a final survival analysis after 75% of patients had died. Here we report the results of this final OS analysis.
J Natl Cancer Inst. 2014;106(1) © 2014 Oxford University Press