Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer

Abstract

BACKGROUND The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)–positive metastatic breast cancer. METHODS Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progressionfree survival, with overall survival designated as a prespecified secondary outcome. RESULTS The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P = 0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P = 0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups. CONCLUSIONS The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard.

Use of anastrozole in the chemoprevention and treatment of breast cancer: A literature review

“…This study involved a large number of patients with recurrent metastasis who had not received previous endocrine therapy and who seemed to have more benefits from the combination of fulvestrant and anastrozole. 30 The Faslodex Versus Exemestane With/Without Arimidex (SoFEA) trial aimed to evaluate endocrine resistance in postmenopausal patients through the combination of fulvestrant and anastrozole versus fulvestrant versus exemestane, and did not demostrate any benefits to the groups of patients treated with fulvestrant and exemestane alone. These data suggest that treatment with fulvestrant combined with anastrozole may offer advantages to postmenopausal women with metastatic recurrence and there seems to be no significant benefit from the combination of fulvestrant and anastrozole in patients with endocrine resistance who had previously received endocrine therapy.…”

ABC3 Consensus Commented from the Perspective of the German Guidelines

“…The German experts thus agree with the close absolute majority vote of the ABC3 panelists (53.4%) not to use a combined endocrine first-line treatment with a non-steroidal aromatase inhibitor plus fulvestrant for postmenopausal patients without prior adjuvant endocrine treatment. The German experts refer to two randomised phase-III studies [13,14]: " In the SWOG study [13], however, first-line treatment consisting of a non-steroidal aromatase inhibitor plus fulvestrant (250 mg) showed a significant advantage for progression-free (PFS) and overall survival compared with monotherapy of an aromatase inhibitor. The subgroup analysis confirmed the advantage only for patients without adjuvant endocrine pretreatment (with tamoxifen) and a very long DFS (≥ 10 years). "…”

“…The German experts also indicate that in Germany, most patients with ER+/HER2 negative breast cancer receive endocrine adjuvant pre-treatment. Furthermore, in the SWOG study [13] there was no control arm with fulvestrant (500 mg) monotherapy. It is thus difficult to assess the significance of the combination (nonsteroidal aromatase inhibitor/fulvestrant 250).…”

Aromatase inhibitors of the third generation in endocrine therapy of breast cancer and endometrial cancer: the successes and failures of the combination therapy

“…2). В этом иссле-довании, включившем 707 больных, комбинация [38]. Однако опубликованные результаты похожего по дизайну исследования FACT (n = 514), сравнивав-шего терапию анастрозолом с или без добавления фулвестранта, не выявили различий не только в ОВ, но и в выживаемости без прогрессирования.…”