Final Overall Survival: Fulvestrant 500 mg vs 250 mg in the Randomized CONFIRM Trial Reply
Authors: Matthew R Cooperberg, Janet E Cowan, Peter R Carroll
Journal: JNCI Journal of the National Cancer Institute (2014)

DOI:10.1093/jnci/djt337 Advance Access publication December 7, 2013 Article © The Author 2013. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Final Overall Survival: Fulvestrant 500 mg vs 250 mg in the Randomized CONFIRM Trial Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka, Roberto Torres, Igor N. Bondarenko, Rustem Khasanov, Didier Verhoeven, Jose L. Pedrini, Iya Smirnova, Mikhail R. Lichinitser, Kelly Pendergrass, Luca Malorni, Sally Garnett, Yuri Rukazenkov, Miguel Martin Manuscript received May 15, 2013; revised October 7, 2013; accepted October 18, 2013. Correspondence to: Angelo Di Leo, MD, PhD, “Sandro Pitigliani” Medical Oncology Unit, Hospital of Prato, Piazza dell Ospedale 2, 59100 Prato, Italy (e-mail: adileo@usl4.toscana.it). 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 500 mg (n = 362) or 250 mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg (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 cluster- ing 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. C onclusions In patients with locally advanced or metastatic estrogen receptor–positive breast cancer, fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulves- trant 250 mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified. JNCI J Natl Cancer Inst (2014) 106(1): djt337 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 250 mg compared with anastrozole (1,5), fulvestrant 250 mg was approved as treat- ment in postmenopausal women with advanced hormone recep- tor–positive breast cancer that had progressed or recurred after prior antiestrogen therapy. However, previous preoperative stud- ies 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 250 mg. Other phase I and phase III stud- ies 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 (250 mg every 28 days) with a higher-dose regimen (500 mg every 28 days plus an additional 500 mg on day 14 of the first month only) in postmenopausal women jnci.oxfordjournals.org with locally advanced or metastatic ER-positive breast cancer that had recurred or progressed after prior endocrine therapy. The ini- tial results showed that fulvestrant 500 mg 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 fulves- trant 250 mg (9). Based on these data, the 500-mg dose of fulves- trant 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 effi- cacy 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 500 mg over 250 mg, it was agreed to perform a final sur- vival analysis after 75% of patients had died. Here we report the results of this final OS analysis. JNCI | Article 1 of 7