Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg.

Background: The COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial (NCT00099437 ) compared fulvestrant 500 mg with fulvestrant 250 mg in postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer who had recurred or progressed following prior endocrine therapy. Fulvestrant 500 mg was associated with a statistically significant increase in progression-free survival compared with fulvestrant 250 mg (Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600). At the time of the primary analysis approximately 50% of patients had died. Median overall survival was 25.1 months and 22.8 months for fulvestrant 500 mg and 250 mg, respectively (hazard ratio [HR] 0.84; 95% confidence interval [CI] 0.69, 1.03; p = 0.091). A follow-up analysis of overall survival was subsequently planned for when 75% of patients had died and the results are presented here. Methods: CONFIRM was a randomized, double-blind, parallel-group, multicenter, Phase III study. Patients were randomized 1:1 to either fulvestrant 500 mg (500 mg i.m. on Days 0, 14 and 28 and every 28 days thereafter) or fulvestrant 250 mg (250 mg i.m. every 28 days). After the primary analysis, patients on fulvestrant 250 mg were permitted to switch to 500 mg and all patients were followed up for overall survival, regardless of treatment discontinuation, unless consent was withdrawn. Overall survival was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) were also reported. Results: In total, 736 women (median age 61.0 years) were randomized between February 2005 and August 2007 from 128 centers in 17 countries (fulvestrant 500 mg: n=362; fulvestrant 250 mg: n=374). At time of follow-up analysis, 63 (9.0%) patients were lost to follow-up, 16 (2.2%) patients had withdrawn consent, 103 (14.0%) patients were still ongoing (21 [2.9%] on treatment and 82 [11.1%] not on treatment), and 554 (75.3%) patients had died. Eight (2.1%) patients crossed over from fulvestrant 250 mg to 500 mg. Median overall survival was 26.4 months for fulvestrant 500 mg and 22.3 months for fulvestrant 250 mg (HR 0.81; 95% CI, 0.69, 0.96; nominal p = 0.016). During the treatment period, a total of 32 (8.9%) patients had at least one SAE in the fulvestrant 500 mg and 25 (6.7%) patients in the fulvestrant 250 mg groups, and SAEs that were causally related to study treatment were reported for 6 (1.7%) and 3 (0.8%) patients, respectively. SAEs with an outcome of death were reported for 5 (1.4%) and 6 (1.6%) patients, respectively, during the treatment period. Overall, there were no clinically important differences in the profiles of SAEs between the treatment groups and no clustering of SAEs could be detected in either treatment group. Conclusions: Overall survival data from CONFIRM demonstrate that, in patients with locally advanced or metastatic ER positive breast cancer, fulvestrant 500 mg is associated with a clinically relevant 4.1 month difference in median overall survival and 19% reduction in risk of death compared with fulvestrant 250 mg. There were no new safety concerns associated with the use of fulvestrant 500 mg. [ABSTRACT FROM AUTHOR]