First Results from FACT – An Open-Label, Randomized Phase III Study Investigating Loading Dose of Fulvestrant Combined with Anastrozole Versus Anastrozole at First Relapse in Hormone Receptor Positive Breast Cancer.
Authors: Bergh J. , Jönsson P. , Lidbrink E. , Trudeau M. , Eiermann W. , Brattström D. , Lindemann J. , Wiklund F. , Henriksson R. 
Published: December 2010

Background:Although aromatase inhibitors, including anastrozole (A) have been shown to be effective for treatment of hormone-dependent postmenopausal breast cancer, many patients with advanced disease will develop resistance. Fulvestrant (F) down regulates estrogen receptors in human breast cancer and has similar single agent activity as A and tamoxifen. Fulvestrant demonstrates a dose-response effect and the present standard dosing strategy takes 3-6 months to reach pharmokinetically sufficient drug levels. Combining A with F might counteract resistance by increasing estrogen blockade through different, yet synergistic modes of action A lowering estrogen levels and F antagonizing and down-regulating the estrogen receptor. Here, the combination of F+A vs A was investigated at first relapse in hormone receptor positive breast cancer in the phase III FACT study, by using a loading dose (LD) schedule followed by monthly injections of F, with the aim to overcome some endocrine resistance mechanisms by maximal estrogen blockade and to use F more optimally.Methods:Postmenopausal women, or premenopausal women receiving a GnRH agonist, with ER+ and/or PgR+ disease at first relapse following primary treatment of localized disease, were randomized to F LD (500 mg i.m. day 0, 250 mg day 14 and 28, then 250mg monthly thereafter) + 1 mg A daily, or 1 mg A daily alone at first relapse. The primary endpoint was time to progression (TTP). Secondary endpoints included objective response rate (ORR), clinical benefit rate (ORR + stable disease ≥24 weeks) (CBR), overall survival (OS) and tolerability. With 512 patients, approximately 380 events were required to detect a 3 month increase in TTP (5% two-sided significance level with 80% power).Results:514 patients, 256 in A alone group and 258 in F+A group, were randomized and approximately 2/3 of the full analysis set were either endocrine-naïve patients or patients with recurrence ≥12 month's gap following completion of adjuvant endocrine therapy. The study is mature while disease progression was demonstrated in 78.1% in the A alone group and 77.5% in the F+A combination group (HR 0.99; CI 95% 0.81-1.20, p-value 0.91). Investigator assessed ORR using the RECIST criteria on patients with measurable disease was 33.6% for the A alone group (38/113), and 31.8% for the F+A combination group (41/129) (odds ratio (OR) 0.92; 95% CI 0.54-1.58), respectively. The CBR rates were 55.1% for A and 55.0% for the F+A combination, respectively. F+A is a well-tolerated combination, but with an increased incidence of hot flushes over A alone. A total of 156 patients (61.4%) in the A alone group and 155 (60.5%) in the F+A combination group reported AEs. AEs for both groups were predominantly mild or moderate in intensity, whereas AEs CTC 3 or higher occurred in 16.9% vs 16.4%. 11 deaths due to side effects were recorded in the F+A arm and 5 in the A alone arm. In the investigator&s opinion, none of these AEs were causally related to study treatment.Discussion:Despite convincing preclinical data supporting the combined therapy strategy of fulvestrant plus an aromatase inhibitor, the present prospective, randomized study did not demonstrate any advantage by adding fulvestrant to anastrozole.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 23.