A Randomized Placebo-Controlled Phase 2 Trial Evaluating Exemestane With or Without Enzalutamide in Patients With Hormone Receptor-positive Breast Cancer.

Purpose Determine if the androgen receptor (AR) inhibitor enzalutamide improves effectiveness of endrocrine therapy (ET) in hormone receptor-positive (HR+) breast cancer. Methods In this phase 2 trial, patients with HR+/HER2-normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohor 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. Results Overall, 247 patients were randomized (cohort 1, n=127; cohort 2, n=120). PFS was not improved in either cohort of the ITT population (hazard ratio [HR] 0.82 [95% CI 0.54-1.26]; P=0.3631 for cohort 1; HR 1.02 [95% CI 0.66-1.59]; P=0.9212 for cohort 2). In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (interaction P=0.0048). This effect was particularly apparent in patients with both high AR mRNA and low levels of ESR1 mRNA (HR 0.24 [95% CI 0.10-0.60]; P=0.0011). The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Conclusions Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-native patients with high AR mRNA, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.