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Fulvestrant delays disease progression in women with endocrine-therapy naïve advanced hormone-receptor positive breast cancer

Results of the phase III FALCON trial, evaluating fulvestrant in patients with estrogen- and progesterone receptor-positive, locally advanced or metastatic breast cancer who had not received prior hormonal therapy, demonstrated that fulvestrant significantly delays disease progression as compared to anastrozole. Interestingly, this benefit of fulvestrant was most pronounced in the subgroup of patients without visceral metastases. As such, these data suggest a potential benefit of using fulvestrant earlier in a patient’s treatment than what is currently the case.

The current first-line treatment recommendations for patients with hormone-receptor positive (HR+), advanced or metastatic breast cancer include endocrine therapy with a third-generation aromatase inhibitor (e.g. anastrozole) or tamoxifen. Fulvestrant is a selective estrogen receptor degrader that targets the function of the hormone receptor. As such, it does not directly interfere with estrogen levels, which is different from what is seen with other aromatase inhibitors like anastrozole. Fulvestrant is currently approved for the treatment of patients with HR+ advanced breast cancer who progress after anti-estrogen therapy. However, in the phase II FIRST trial, fulvestrant was shown to be as least as effective as anastrozole in the first-line treatment of advanced HR+ breast cancer. This formed the basis for the phase III FALCON study.

The presented randomized, double-blind, multi-center phase III trial enrolled a total of 462 women with inoperable locally-advanced or metastatic ER-positive, HER-negative breast cancer, who had not received prior hormone therapy. Patients in the study were randomly assigned to receive either fulvestrant (500mg intramuscular injections on days 0, 14, 28, then every 28 days) (N=230), or anastrozole (daily dose of 1mg) (N=232). The primary endpoint of the trial was progression-free survival (PFS), while secondary objectives included overall survival (OS); objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR: CR, PR or stable disease ≥24 weeks), duration of clinical benefit (DoCB); health-related quality of life (HRQoL) and safety.

After a median follow-up of 25 months, patients treated with fulvestrant had a borderline significant 21% improvement in PFS as compared to those treated with anastrozole (median PFS 16.6 versus 13.8 months, HR[95%CI]: 0.797[0.637-0.999]; p = 0.048). However, a subgroup analysis showed an even greater impact on PFS in patients whose disease had not spread to the liver or lungs at baseline (non-visceral disease) (median PFS: 22.3 versus 13.8 months; HR[95%CI]: 0.59[0.42-0.84]; p< 0.01). In patients with visceral disease, a similar PFS was seen with fulvestrant and anastrozole (median PFS 13.8 versus 15.9 months; HR[95%CI]: 0.99[0.74-1.33]). An overview of the secondary endpoints of the trial is depicted in slide 4 attached to this report.

Both groups in the study showed a similar health-related quality of life. The most commonly observed adverse events were arthralgia (joint pain) (16.7% versus 10.3%) and hot flushes (11.4% versus 10.3%) for fulvestrant and anastrozole, respectively. The rate of serious adverse events was comparable for both treatment arms )13.2% with fulvestrant and 13.4% with anastrozole’. The rate of grade 3 or higher adverse events was 22.4% with fulvestrant and 17.7% with anastrozole. This translated into a treatment discontinuation rate of 7% with fulvestrant and 4.7% with anastrozole.

In summary, FALCON met its primary endpoint with a significantly better PFS for fulvestrant than with anastrozole. Interestingly, this benefit was most pronounced in patients with non-visceral disease. As such, 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 become the new standard of care. Interestingly, fulvestrant is well tolerated, with a better toxicity profile than other drugs that could potentially be used in this setting (chemotherapy, CDK4 inhibitors). Two factors however complicate moving this new finding into routine clinical practice. First of all, the study only included patients without prior hormone treatment, while many patients presenting with advanced breast cancer have previously been treated for the primary breast cancer. Secondly, 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 US, in combination with an aromatase inhibitor, for the same group of patients. As such, further studies are needed to define the most optimal sequence of therapy for women with advanced breast cancer.


Ellis M, 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 ESMO 2016; Abstract LBA14_PR.

Speaker Matthew Ellis


Prof. Matthew J. Ellis, MD, PhD,
Lester and Sue Smith Breast Center, Baylor College of Medicine in Houston, Texas, USA


See: Keyslides

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