Targeting the Androgen Receptor in Breast Cancer

Recent studies have shown that the androgen receptor (AR) is a tumor suppressor and AR agonists can lead to AR activation and antitumor activity in estrogen receptor (ER)–positive breast cancer (Nat Med 2021; 27:310). Selective AR modulators (SARMs) selectively bind to the AR without causing the virilizing effects associated with androgen therapy and AR antagonists. Enobosarm is an oral SARM that has demonstrated in vivo antitumor activity in ER-positive and ER-resistant disease.

In a multinational, randomized, open-label, phase 2 trial, researchers assessed the effects of enobosarm at two dose levels (9 mg or 18 mg daily) in 136 postmenopausal patients with ER-positive/AR-positive metastatic breast cancer. The median age was 60.5 years and 62.5 years in the 9 mg and 18 mg groups, respectively. Overall, 92% of patients had received prior chemotherapy and 82% had received endocrine therapy (median, two lines) in the metastatic disease setting. Median follow-up was 7.5 months. The clinical benefit rate at 24 weeks, the primary outcome, was 32% in the 9-mg group and 29% in the 18-mg group. Most treatment-related toxicity was grade 1 or 2. Grade 3 or 4 treatment-related toxicity occurred in 8% of the 9-mg group and 16% of the 18-mg group, most commonly elevated hepatic transaminases, hypercalcemia, and fatigue.