Enzalutamide for the Treatment of Androgen Receptor–Expressing Triple-Negative Breast Cancer

Abstract

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.

Differences in molecular features of triple‐negative breast cancers based on the age at diagnosis

“…The AR is the focus of therapeutic targets in adjuvant and neoadjuvant setting in recent and ongoing clinical trials. 23, 24 AR is not among the genes included in PAM50 and we did not have access to tissue blocks to perform immunohistochemistry for AR to test if the increase in HER2-encriched subtype in older patients correlates with LAR subtype.…”

A magic drug target: Androgen receptor

“…A series of clinical trials which test the efficacy of marketed AR antagonists such as bicalutamide and enzalutamide to treat AR + TNBC have been started (eg, NCT02353988, NCT00468715, and NCT01889238) . For locally advanced or metastatic AR + TNBC, the treatment by enzalutamide showed 25% clinical benefit rate at 16 weeks, 2.9 months of median progression‐free survival, and 12.7 months of median overall survival, demonstrating the clinical activity of AR antagonists in the difficult‐to‐treat BrCa …”

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

“…Despite the reported association of AR with a better outcome in this disease context, there has been much enthusiasm for therapeutic targeting of AR, particularly in TNBC, as there are currently no targeted therapies for the treatment of this aggressive disease subtype. The mainstream clinical approach has been AR antagonism based on in vitro and in vivo preclinical studies, suggesting that AR has oncogenic activity in some ERa-negative breast cancer models (18)(19)(20)(21)(22)(23)(24)57), and two clinical trials of women with advanced TNBC have reported efficacy with this approach (58,59). However, in vitro studies have demonstrated dichotomous proliferative effects of androgens in different AR-positive ERa-negative breast cancer cell lines (15,(20)(21)(22), other AR-positive ERa-negative breast cancer cell lines (MFM-223 and CAL-148) are inhibited (25,60).…”