Fulvestrant prolonged PFS compared with anastrozole among women with hormone receptor– positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy, according to a phase 3, randomized, double blind trial published in The Lancet.
“The primary endpoint of this phase 3 study was met, with patients receiving fulvestrant having a significantly longer PFS than patients receiving anastrozole,” John F.R. Robertson, MD, a professor at University of Nottingham Medical School and Royal Derby Hospital Centre in Derby, United Kingdom, and colleagues wrote. “This represents a meaningful and relevant finding for which clinical data are limited.”
John F.R. Robertson
Fulvestrant (Faslodex, AstraZeneca) blocks ER function by inducing ER degradation; it is approved for postmenopausal women with hormone receptor–positive advanced breast cancer and disease progression after antiestrogen therapy. Anastrozole — a third-generation aromatase inhibitor — has been a standard of care for first-line treatment of hormone receptor–positive advanced breast cancer.
Researchers evaluated data from 462 patients from 113 academic hospitals and community centers in 20 countries in Asia, Europe, North America, South America and South Africa. Eligible patients had not received endocrine therapy and had WHO performance status of 0 to 2 with at least one measurable or nonmeasurable lesion.
Researchers randomly assigned patients to fulvestrant (n = 230; median age, 64 years; dose, 500 mg intramuscular injection on days 0, 14, 28 and every 28 days thereafter) or anastrozole (n = 232; median age, 62 years; dose, 1 mg orally daily) from Oct. 17, 2012, to July 11, 2014.
PFS served as the primary endpoint. Secondary endpoints included objective response rate and duration of response. The researchers assessed safety outcomes in all patients who received at least one dose of randomized treatment, including placebo.
Women assigned fulvestrant showed a significantly longer PFS compared with anastrozole (HR = 0.79; 95% CI, 0.63-0.99). Median PFS was 16.6 months (95% CI, 13.83-20.99) in the fulvestrant group compared with 13.8 months (95% CI, 11.99-16.59) in the anastrozole group.
In patients with measurable disease, women assigned fulvestrant showed an ORR comparable to those assigned anastrozole (46% vs. 45%), but a longer median duration of response (20 months; 95% CI, 15.9-27.63 vs. 13.2 months; 95% CI, 10.64-16.72). Expected duration of response had been 11.4 months in the fulvestrant group and 7.5 months in the anastrozole group.
Women with nonvisceral disease showed a median PFS of 22.3 months with fulvestrant vs. 13.8 months with anastrozole (HR = 0.59; 95% CI, 0.42-0.84). In the visceral disease subgroup, the median PFS for women on fulvestrant was 13.8 months compared with 15.9 months for the anastrozole group (HR = 0.99; 95% CI, 0.74-1.33).
The most common adverse events were arthralgia (fulvestrant, n = 38 vs. anastrozole, n = 24) and hot flashes (n = 26 vs. n = 24).
Seven percent (n = 16 of 228) of evaluable patients discontinued fulvestrant because of adverse events, and 5% (n = 11) of patients discontinued anastrozole.
“Patients who achieved clinical response to fulvestrant had a longer duration of response compared with anastrozole,” Robertson and colleagues wrote. “Thus, patients with endocrine-sensitive disease might not always require a combination treatment that is associated with greater toxicity.”
The marked improvement in patients with nonvisceral metastasis compared with patients with visceral metastasis is intriguing, Massimo Cristofanilli, MD, associate director of translational research and precision medicine at Robert H. Lurie Comprehensive Cancer Center, wrote in an accompanying editorial.
Cristofanilli acknowledged the trial enrolled only endocrine therapy–naive patients who are presumably endocrine sensitive. Therefore, the results of the study might not necessarily be applicable to a standard metastatic breast cancer population, who could also be offered a combination of endocrine drugs with a CDK4 or CDK6 inhibitor.
“The results of the FALCON study suggest that individuals with de-novo stage 4 disease are particularly sensitive to fulvestrant, but we should use caution in interpreting the data, because this study was not powered to assess this question,” Cristofanilli wrote. “It is possible that the presence of additional (visceral) metastasis indicated not only a more aggressive disease but also a larger tumor burden and heterogeneous estrogen sensitivity, and for patients with visceral metastasis, a combination of fulvestrant and anastrozole might also be appropriate.
“Besides the clinical criteria, several additional factors should be considered when selecting the appropriate endocrine therapy, including the access to novel drugs based on regional regulatory availability, and the additional toxicity and higher costs typically associated with the combination regimens,” Cristofanilli added. – by Chuck Gormley
Disclosures: Robertson reports a consultant role with and honoraria or research funding from AstraZeneca, Bayer AG and Novartis; has provided expert testimony for AstraZeneca; and holds stocks or other ownership with Carrick Therapeutics and Oncimmune. Please see the full study for a list of all other researchers’ relevant financial disclosures. Cristofanilli reports honoraria from Pfizer.