Fulvestrant Bests Anastrozole in Phase III Breast Cancer Study

Matthew J.C. Ellis, MB BChir, PhD

First-line treatment with fulvestrant (Faslodex) led to significantly better progression-free survival (PFS) compared with anastrozole for patients with hormone receptor (HR)-positive advanced breast cancer, according to findings from the phase III FALCON trial reported at the 2016 ESMO Congress.

Confirming results of an earlier phase II study, the FALCON trial yielded a median PFS of 16.6 months with fulvestrant versus 13.8 months with anastrozole. Moreover, a consistent advantage favoring fulvestrant emerged from a subgroup analysis. The overall advantage appeared to be driven by a substantial difference in PFS among patients without visceral metastases treated with fulvestrant.

“These results are consistent with data from the FIRST study and confirm that fulvestrant is more efficacious than anastrozole in postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer who have not received prior endocrine therapy,” said Matthew Ellis, MD, PhD, director of the Smith Breast Center at Baylor College of Medicine in Houston.

For postmenopausal women with HR-positive advanced or metastatic breast cancer, recommended first-line treatment includes endocrine therapy with an aromatase inhibitor or tamoxifen. Fulvestrant is a selective estrogen receptor degrader approved for treatment of advanced HR-positive breast cancer that has progressed following anti-estrogen therapy.

In the phase II FIRST study, first-line treatment of locally advanced/metastatic HR-positive breast cancer with fulvestrant led to outcomes similar to that achieved with the aromatase inhibitor anastrozole. The primary endpoint of clinical benefit rate did not differ significantly between treatment groups. Analysis of time to progression and overall survival showed significant advantages for patients treated with fulvestrant.

Investigation of fulvestrant’s potential as first-line therapy in locally advanced/metastatic breast cancer continued in the randomized, phase III FALCON trial, which compared fulvestrant and anastrozole. The principal objective was to confirm the observations of he FIRST trial, said Ellis. The trial randomized 462 patients to receive fulvestrant at 500 mg on days 0, 14, 28 (n = 230) or anastrozole at 1 mg daily (n = 232).

The primary endpoint was PFS, and secondary endpoints included overall survival, objective response rate, clinical benefit rate, duration of response, health-related quality of life, and safety.

Data analysis included 462 patients who had a median age of 63 to 64 years. Three fourths of the patients tested positive for both estrogen- and progesterone-receptor expression. About 87% of the patients had metastatic disease, as opposed to locally advanced breast cancer. Rates of visceral metastasis were 58.7% in the fulvestrant arm and 51.3% in the anastrozole arm.

The analysis confirmed results of the FIRST trial, showing almost a 3-month improvement in PFS with fulvestrant in the intention-to-treat population (HR, 0.797, P = .0486). Analysis of multiple prespecified subgroups showed a consistent benefit in favor of fulvestrant.

The one subgroup that stood out was patients without visceral metastases, who benefited substantially more from fulvestrant than with anastrozole. The median PFS in patients without visceral metastases was 22.3 months with fulvestrant and 13.8 months with anastrozole. Patients with visceral metastases had similar PFS with fulvestrant (13.8 months) or anastrozole (15.9 months).

“For patients with non-visceral disease whose life isn’t immediately threatened by breast cancer — a group for whom physicians would typically choose endocrine therapy as a first approach – it looks like fulvestrant could be a new standard of care compared to anastrozole,” said Ellis.

Overall survival data remain immature, but a preliminary analysis showed no difference between treatment groups.

Overall response rate and clinical benefit rate did not differ significantly between groups. Fulvestrant resulted in a median duration of response of 20.0 months as compared with 13.2 months with anastrozole. Median duration of clinical benefit was 22.1 months with fulvestrant and 19.1 months with anastrozole. Expected duration of response also favored fulvestrant (11.4 vs 7.5 months; P = .001), as did expected duration of clinical benefit (21.9 vs 17.5 months; P = .001).

Rates of adverse events, serious adverse events, and adverse events leading to discontinuation were similar between treatment groups. The most commonly reported adverse events with fulvestrant and anastrozole, respectively, were arthralgia (16.7% vs 10.3%), hot flashes (11.4% vs 10.3%), and nausea (10.5% vs 10.3%).

“It’s tolerated as well as anastrozole, and better than other drugs that could potentially be used in this setting, such as chemotherapy or CDK4/6 inhibitors,” Ellis said. “In patients for whom you are looking for a low toxicity approach, such as older patients or those with low volume disease, it looks like a good option.”

The study was designed and initiated in 2012, before frontline treatment with CDK4/6 inhibitors, such as palbociclib (Ibrance), became the standard of care for patients with HR-positive, HER2-negative advanced breast cancer. Palbociclib is approved in the second-line setting for use with fulvestrant; however, it remains unclear whether this combination would make an ideal frontline therapy. Experts at the meeting believed that further sequencing studies were required to help answer this question.

Ellis MJ, Bondarenko I, Trishkina E, et al. FALCON: a phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA14.

“Since the design of the study, the standard of care for these women has moved on, with the CDK4/6 inhibitor palbociclib now licensed in the US, in combination with an aromatase inhibitor, for the same group of patients," Nicholas Turner, MD, team leader at the Institute of Cancer Research and Medical Oncologist at the Royal Marsden, London, UK, said in a statement from ESMO. "Further studies will help define the most optimal sequence of therapy for women with advanced breast cancer.”

Investigators in the multicenter FALCON trial enrolled postmenopausal women with locally advanced or metastatic breast cancer that tested positive for expression of estrogen receptor or progesterone receptor and was HER2 negative. Eligible patients had received no prior endocrine therapy, although treatment with 1 prior chemotherapy regimen was permitted. Patients were randomized to fulvestrant or anastrozole and followed until disease progression or discontinuation for adverse events.