FACT: An Open-Label Randomized Phase III Study of Fulvestrant and Anastrozole in Combination Compared With Anastrozole Alone as First-Line Therapy for Patients With Receptor-Positive Postmenopausal Breast Cancer
Bergh J, Jönsson PE, Lidbrink EK, et al
J Clin Oncol. 2012;30:1919-1925
Study Summary
Bergh and colleagues compared the effectiveness of anastrozole vs polyendocrine therapy (using a combination of fulvestrant and anastrozole) as first-line treatment for women with postmenopausal hormone-receptor positive breast cancer. They enrolled 514 postmenopausal women and premenopausal women on ovarian-suppressive therapy at first relapse in this open-label phase 3 study. The dose of fulvestrant was 250 mg/mo, and the primary endpoint was time to progression (TTP).
Two thirds of the study sample were women who had already received adjuvant endocrine therapy (most with tamoxifen). Median TTP was 10.8 months in the experimental group vs 10.2 months in the standard treatment group, thus showing no difference in outcome. The investigators concluded that the addition of fulvestrant offered no advantage over standard therapy with aromatase inhibition alone.
This study was conducted between 2004 and 2008 and recruited patients from 11 countries and 77 centers, at a time when enthusiasm for combined endocrine therapy was emerging from preclinical mouse models. About one third of patients had endocrine-naive disease. Previous chemotherapy had been given in the adjuvant setting in about one half of the cases.
Treatment was relatively well tolerated, with no significant observed differences in reported serious adverse events. The incidence of hot flashes, however, was greater in the patients receiving combination therapy. Few patients withdrew from the study because of adverse effects.
Viewpoint
How can we understand the failure of this treatment? Perhaps the dose of fulvestrant was suboptimal, although it was considered standard at the time of the study design and accrual. Di Leo and colleagues published results of the CONFIRM trial in 2010, which showed superiority of a schedule of 500 mg of fulvestrant compared with 250 mg.
Another possible explanation for the observed lack of superiority of polyendocrine therapy is endocrine resistance. Mehta and colleagues presented the results of a similar phase 3 trial on behalf of SWOG (formerly the Southwest Oncology Group) at the 2011 Annual Meeting of the San Antonio Breast Cancer Symposium (SABCS).In that study, postmenopausal women with estrogen receptor-positive breast cancer were treated with either first-line anastrozole or anastrozole and fulvestrant; both regimens were given according to the same dose and schedule as in the FACT trial. Progression-free survival and overall survival favored the combination treatment, both statistically and clinically. In the SWOG trial, almost two thirds of the patients were naive to tamoxifen, compared with one third of patients in the FACT trial.
As we continue to learn more about endocrine resistance, I imagine that our analyses will become increasingly more sophisticated. At this point, polyendocrine therapy remains a fascinating concept but to date has very limited clinical applicability.
Abstract