Final Overall Survival: Fulvestrant 500 mg vs 250 mg in the Randomized CONFIRM Trial

Abstract

BackgroundAt 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.MethodsPatients 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.ResultsIn 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.ConclusionsIn 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.

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…The poor pharmacokinetic properties of ICI 182,780 may limit its effectiveness in the clinic; indeed, increasing monthly intra-muscular injections of fulvestrant from 250 mg to 500 mg led to significant gains in overall survival in metastatic patients having recurred or progressed after prior endocrine therapy in the CONFIRM study and resulted in subsequent adoption of this regimen in the clinic (Di Leo et al . 2010, 2014, Robertson et al . 2014).…”

Hormone Therapy in Breast Cancer: Where do We Stand?

“…However, later it was realised that probably the actual dose of fulvestrant that is effective is 500 mg and not 250 mg. This was proven in the confirm trial, where fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified [18,50]. Fulvestrant was also shown to be beneficial compared to anastrozole other phase III randomised trials [51].…”

Therapeutic Place of Fulvestrant in the Management of Hormone-receptor Positive Breast Cancer

“…23 In the follow-up analyses, median OS was shown to be significantly longer with 500 mg of fulvestrant than with 250 mg (26.4 months versus 22.3 months; HR=0.81; p=0.016) ( Table 3). 24 Following the publication of these results, fulvestrant at 500 mg has become the standard dose for this drug. The fulvestrant 500 mg arm demonstrated a statistically significant increase in the median time to progression and median overall survival (see Table 4).…”