FALCON Trial Compares Two Types of Endocrine Therapy

John F. R. Robertson, MD

Professor, Surgery

Graduate Entry Medicine and Health School

University of Nottingham Royal Derby Hospital

Nottingham, England

Matthew J. Ellis, MB BChir, PhD

DProfessor, Medicine

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.

By contrast, AIs inhibit the aromatase enzyme that promotes the production of estrone and estradiol, thereby lowering serum estradiol concentrations. “The long-term problem is that other proteins in the cell can eventually take over the stimulation of the estrogen receptor in the absence of estrogen—that is one way that the cancer cell can become resistant to AIs,” said Robertson. “Another is that the cancer cells can become hypersensitive to these very low levels of estradiol, which can end up stimulating the tumor.”

In addition to increased efficacy compared with anastrozole, fulvestrant could be used in combination therapy in the future, said Matthew J. Ellis, MB BChir, PhD, who also is co-principal investigator on the study. Ellis is a professor of Medicine at the Washington University School of Medicine and Siteman Cancer Center Breast Cancer Program in St. Louis, Missouri.

“[There are studies looking at] combinations of endocrine therapy and a second drug designed to enhance the efficacy of the endocrine approach,” said Ellis. “We might see an increasing trend for those endocrine drugs [and] for fulvestrant to be the favored combination partner.”

AstraZeneca, which markets both fulvestrant and anastrozole, is sponsoring the FALCON trial.

Figure. Phase III FALCON Trial

^aEstimated enrollment CBR indicates clinical benefit rate;

DoR, duration of response; ER, estrogen receptor; ORR, objective response rate;

OS, overall survival; PFS, progression-free survival; PgR, progesterone receptor.

Source: NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01602380.

References

1. A global study to compare the effects of Fulvestrant and Arimidex in a subset of patients with breast cancer (FALCON). NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01602380. Updated November 6, 2013. Accessed November 10, 2013.
2. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study [published online ahead of print August 24, 2009]. J Clin Oncol. 2009;27(27):4530-4535.