A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer

Abstract

Lessons Learned The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor‐targeted therapy in combination with immune checkpoint inhibitors are warranted. Background Luminal androgen receptor is a distinct molecular subtype of triple‐negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR‐targeted therapy has shown modest activity in AR‐positive (AR+) TNBC. Enobosarm (GTx‐024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). Methods This study was an open‐label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis. Results The trial was stopped early because of the withdrawal of GTx‐024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36–81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow‐up was 24.9 months (95% confidence interval [CI], 17.5–30.9). Progression‐free survival (PFS) was 2.6 months (95% CI, 1.9–3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4–not reached [NR]). Conclusion The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand‐1 (PD‐L1). Future clinical trials combining AR‐targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

“…However, not all combinations of drugs and checkpoint inhibitors were proved to be successful. Although the co-administration of pembrolizumab and enobosarm, a selective androgen receptor modulator, in the androgen receptor-positive subtype of TNBC, showed only a modest antitumor response [ 92 ], it still warrants further studies exploring the use of the checkpoint inhibitors. Moreover, to increase the expression of the target checkpoints, a broad range of drugs is constantly investigated, including the classical ones.…”

Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth

“…GTX-024 and a related SARM, GTX-027, suppressed the growth of triple-negative breast cancer (TNBC) xenografts without adverse effects on animal health (34). GTX-024 has been evaluated in phase II clinical trials of AR-positive breast cancer (NCT02971761; NCT02368691), with no reported adverse safety signals (35). SARM-2F was shown to support muscle, prostate, and seminal vesicle mass in rats following castration and improved outcomes in a model of cancer cachexia (23).…”

Identifying High-Risk Triple-Negative Breast Cancer Patients by Molecular Subtyping

“…In a phase I/II study, metastasized patients with a positive androgen receptor status at mRNA level benefited from anti-androgen receptor-hormonal therapy, so that may be an option to bypass chemoresistance and to de-escalate chemotherapy [36]. Considering the unfavorable prognosis of patients with LAR subtype, a combination of immune checkpoint inhibitors and androgen receptor-inhibiting treatment should also be studied [43].…”