A phase II trial has demonstrated that fulvestrant 500 mg provides a statistically significant overall survival (OS) benefit compared to anastrozole in the first-line treatment of postmenopausal women with estrogen receptor (ER)-positive advanced breast cancer. The study, known as the Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST), showed an approximately 6-month improvement in median OS with fulvestrant. This suggests a potential shift in the treatment paradigm for this patient population.
The FIRST trial was a randomized, open-label, multicenter study comparing fulvestrant 500 mg to anastrozole 1 mg in postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had not received prior systemic therapy for advanced disease. Patients were administered fulvestrant 500 mg intramuscularly on days 0, 14, 28, and every 28 days thereafter, or anastrozole 1 mg orally once daily. The primary endpoint was clinical benefit rate, while overall survival (OS) was a key secondary endpoint assessed in a follow-up analysis.
Survival Advantage with Fulvestrant
The follow-up analysis revealed that fulvestrant 500 mg was associated with a median OS of 54.1 months, compared to 48.4 months for anastrozole (HR 0.70, 95% CI 0.50-0.98; log-rank test P = 0.04). This translates to an approximate 30% reduction in the risk of mortality. At 3 years, 64% of patients in the fulvestrant arm were event-free compared to 58% in the anastrozole arm; at 5 years, these values were 47% and 38%, respectively.
Consistent Benefit Across Subgroups
Subgroup analyses indicated that the OS benefit with fulvestrant was generally consistent across various pre-specified patient subgroups, including age, ER and progesterone receptor (PgR) status, visceral involvement, prior chemotherapy, measurable disease, and prior endocrine therapy. This suggests that the survival advantage is not limited to a specific subset of patients.
Safety and Tolerability
No new safety or tolerability issues were identified during the OS follow-up phase of the study. The majority of serious adverse events (SAEs) were considered unrelated to treatment. Two SAEs were deemed treatment-related: one case of hypertension and one case of pulmonary embolism, both occurring in the fulvestrant 500 mg group.
Implications for Clinical Practice
"This study reports improved OS with fulvestrant 500 mg treatment compared with anastrozole in the first-line setting for ER-positive advanced breast cancer, with an approximately 30% reduction in mortality risk," the researchers noted in their publication. The findings suggest that fulvestrant 500 mg could be a valuable first-line treatment option, particularly in settings where access to newer therapies like CDK4/6 inhibitors is limited or cost is a significant concern.
Ongoing Research
The role of fulvestrant 500 mg as first-line therapy is being further investigated in the ongoing phase III FALCON trial (NCT01602380), which is comparing fulvestrant 500 mg versus anastrozole in women with locally advanced or metastatic breast cancer who have strict definitions of endocrine therapy-naïve disease. Results from this trial are expected to provide further clarity on the optimal use of fulvestrant in this setting.
