John F. R. Robertson, MD
Graduate Entry Medicine and Health School
University of Nottingham Royal Derby Hospital
Matthew J. Ellis, MB BChir, PhD
Washington University School of Medicine
Siteman Cancer Center Breast Cancer Program
St. Louis, MO
The question of whether fulvestrant (Faslodex) should be moved forward in the treatment timeline for postmenopausal women with advanced, hormone receptor (HR)-positive breast cancer is being evaluated in an international, randomized phase III trial.1
The FALCON trial aims to confirm that 500-mg fulvestrant is more effective than 1-mg anastrozole (Arimidex) as first-line hormonal therapy for patients with locally advanced or metastatic disease, according to John F. R. Robertson, MD, co-principal investigator for the study. Robertson is a professor of Surgery at the Graduate Entry Medicine and Health School, University of Nottingham at Royal Derby Hospital, England.
Fulvestrant, an estrogen receptor (ER) antagonist, is approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer with disease progression following antiestrogen therapy, but has shown to be efficacious in the first line. Anastrozole,a nonsteroidal aromatase inhibitor (AI), is indicated as a first-line treatment in this setting, as well as for the adjuvant treatment of HR-positive early breast cancer and advanced breast cancer after progression following tamoxifen therapy.
“The clinical problem the FALCON study addresses is that while AIs are potent hormonal agents, breast cancers still become resistant to these AIs and so better hormonal agents are required to improve outcomes for patients,” said Robertson in an interview.
Launched in October 2012, the FALCON trial seeks to recruit 450 women at more than 150 research sites throughout the world, including the United States, South America, Europe, and China. Participants will be randomized to receive either fulvestrant plus placebo or anastrozole plus placebo (Figure
The design of the FALCON trial is based on safety and efficacy results from the phase II FIRST trial. The FIRST trial demonstrated that first-line high-dose fulvestrant (500 mg/mo plus 500 mg on day 14 of month 1) was at least as effective as 1 mg/d anastrozole in terms of clinical benefit rate and objective response rate.2
Fulvestrant was also associated with significantly longer time to progression in the FIRST trial.
In addition to those findings, 500-mg fulvestrant has demonstrated superiority to 250-mg fulvestrant in two additional studies, Robertson said. The 500-mg fulvestrant dosage has been tolerated as well as 250- mg fulvestrant and 1-mg anastrozole.
Robertson said that while the results of the FIRST trial showed the significant benefits of fulvestrant, phase II trials are not generally accepted by the FDA for a drug’s approval in a specific indication such as firstline endocrine therapy. The FALCON trial is a registration study to confirm the results of the FIRST trial in patients who have not had prior hormonal therapy.
Robertson said there are several clinical scenarios to explain why HR-positive patients would not have received prior hormonal therapy:
A patient was treated for primary breast cancer in the late 1980s or early 1990s, before adjuvant endocrine therapy was fully introduced and only now has developed recurrence of breast cancer;
A patient was treated after the early 1990s but her primary breast cancer was low-risk and it was decided that the risks of treatment outweighed potential benefits;
A patient now presents with HR-positive advanced breast cancer for the first time.
As a hormonal therapy, fulvestrant prevents estrogen receptor pathway activation and also promotes the degradation of the estrogen receptor. It is believed that this mechanism makes it more difficult for (or at least delays) other proteins in the cell to cause resistance to occur to fulvestrant, said Robertson.