Abstract PD8-10: Efficacy and safety of enobosarm, a selective androgen receptor modulator, to target AR in women with advanced ER+/AR+ breast cancer - final results from an international Phase 2 randomized study
Authors: Palmieri Carlo , Linden Hannah , Birrell Stephen , Lim Elgene , Schwartzberg Lee S , Rugo Hope S , Cobb Patrick , Jain Kirti , Vogel Charles , O’Shaughnessy Joyce A , Getzenberg Robert H , Steiner Mitchell S , Brufsky Adam , Overmoyer Beth 
Published: February 2021

Abstract
Introduction: Hormonal agents remain the most effective therapies for estrogen receptor positive (ER+) HER2- breast cancer. The androgen receptor (AR) is the most highly expressed steroid receptor found in up to 95% of ER+ breast cancer patients. Androgen agonists have antiproliferative activity in ER+ breast cancer and have been used in treatment, however their lack of availability and virilizing side effects have limited their use. Enobosarm is a non-steroidal tissue-selective AR modulator that that is being developed for AR targeted treatment of ER+/AR+ breast cancer.
Methods: An international, Phase 2, open label, parallel design, randomized study was conducted in 136 patients (pts) to investigate the efficacy and safety of enobosarm in postmenopausal women with metastatic ER+/AR+ breast cancer that progressed on previous endocrine therapy. Pts were randomized to receive 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. The primary endpoint was clinical benefit rate (CBR) at 24 weeks (defined as CR, PR or SD) by RECIST 1.1. Secondary endpoints included objective response rate, best overall response rate (BOR), progression free survival (PFS), duration of clinical benefit.
Results: The study population consisted of heavily pre-treated pts with a mean of 4 (range 1-6) prior hormone therapies and &gt;90% receiving one prior course of chemotherapy. Median age was 60.8 years (35-83) for 9 mg and 62.1 (42-81) for the 18 mg cohort. AR positivity was centrally confirmed in 73.6% and 81.2% in the 9 and 18 mg cohorts, respectively. Efficacy: In the evaluable pts, 50 in the 9 mg arm and 52 in the 18 mg arm (AR confirmed), 32% of the 9mg cohort met the primary endpoint of CBR at 24 weeks (95% CI, 19.5%; 46.7%) and 29% (95% CI, 17.1%; 43.1%) in the 18 mg cohort. The BOR was 2 CRs, 10 PRs in the 9 mg and 3 CRs,7 PRs in the 18 mg group by central review. Median PFS was 5.6 (2.9 to 27.5) and 4.2 (2.8 to 11) months (mo) in the 9 mg and 18 mg groups. The median duration of treatment was 4.0 months (0.23-30.3 months) in the 9 mg group and 3.8 months (0.5-16.7 months) in the 18 mg group. At the time the study was terminated, the median duration of clinical benefit was not reached (NR) in the 9 mg group (range 8.2 mo to NR) and 14.1 mo (range 11.0 to 16.5) in the 18 mg group.
QOL: Using a standardized instrument of generic health status (EQ-5D), a significant percentage of pts reported improvement in measurements including mobility (40%, 50%), anxiety/depression (50%, 29%) and pain discomfort (50%, 31%) for the 9 and 18 mg groups, respectively. Drug related severe adverse events (SAEs) (Grades 3-4) were observed in 6 (8.0%) at the 9 mg and 10 (16.4%) at the 18 mg dose. The SAEs (Grade 3-4) attributed to the study drug by the site investigator were for the 9 mg group: fatigue (1), elevated transaminases (2), headache (1), hypercalcemia (2) and anemia (1). For the 18 mg group the drug attributable SAEs (Grade 3-4) were: dry mouth (1), increased aminotransferase (2), decreased white blood cell count (1), fatigue (2), hypercalcemia (1), decreased appetite (1), headache (1), tumor flare (2), agitation (1), lymphadenopathy (1) and acute kidney injury (1).
Conclusions: In this Phase 2 parallel design study, enobosarm (9 mg and 18 mg) has significant clinical activity and was well tolerated in heavily pretreated patients with ER+/AR+ metastatic breast cancer. Given the limited options of hormonal therapy for metastatic ER+ breast cancer, enobosarm merits further clinical development in a Phase 3 clinical program as an AR targeted treatment for metastatic ER+AR+ breast cancer.
Citation Format: Carlo Palmieri, Hannah Linden, Stephen Birrell, Elgene Lim, Lee S Schwartzberg, Hope S Rugo, Patrick Cobb, Kirti Jain, Charles Vogel, Joyce A O’Shaughnessy, Robert H Getzenberg, Mitchell S Steiner, Adam Brufsky, Beth Overmoyer. Efficacy and safety of enobosarm, a selective androgen receptor modulator, to target AR in women with advanced ER+/AR+ breast cancer - final results from an international Phase 2 randomized study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-10.