Introduction: The androgen receptor (AR) is expressed in ~90% of ER+ BC. Androgen-based therapies have demonstrated response rates from 20-25% in advanced/metastatic breast cancer (mBC). RAD140 is an oral nonsteroidal SARM with tissue-selective AR agonist activity in BC cells but attenuated activity in other androgen-responsive tissues. In in vivo and in vitro models recapitulating various stages of AR/ER+ BCs, RAD140 exhibited potent anti-tumor activity as a single agent and in combination with inhibitors (i) of CDK4/6 or mTOR. Methods: This is a first-in-human, phase 1 dose escalation study with a 3+3 design and pharmacokinetic (PK) expansion cohort. The primary endpoint is safety, tolerability, and to establish the maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints are PK and antitumor activity by RECIST. In the dose escalation phase, patients (pts) were treated with RAD140 once daily (QD) in 28-day cycles. In the subsequent PK expansion (PKE) cohort, pts were treated with a single dose of 100 mg followed by 1 wk of PK sampling before entering continuous 28-day treatment cycles with 100 mg QD dosing. Dose-limiting toxicity (DLT) was assessed during the first 28-day cycle. Key eligibility criteria included: ER+/HER2- and inoperable/mBC, post-menopausal, and ineligible for standard therapy. Archival tumor samples within 2 years or fresh tumor biopsies collected at the time of enrollment were analyzed retrospectively by immunohistochemistry (IHC) for AR, ER, progesterone receptor (PR), HER2 and Ki67. Serum sex hormone-binding globulin (SHBG) and prostate specific antigen (PSA) were used to assess AR engagement. Results: Dose escalation and PKE enrollment (n=22) is complete. Median age = 60 years, 100% stage IV, 86% visceral disease, 95% AR+, 91% AR+/ER+, and 82% AR+/ER+/HER2-. Median number of prior lines of therapy for mBC = 4; prior fulvestrant 86%, aromatase inhibitor 96%, CDK4/6i 91%, mTORi/PI3Ki 46%, chemotherapy 91%. Starting dose levels were 50 mg (n=6), 100 mg (n=13), and 150 mg (n=3) QD. Median time on treatment = 9 wk (range <1-32+ wk). Most frequent (>30%) treatment-emergent adverse events were elevated AST (27% grade [G] 1; 9% G2; 18% G3; 5% G4) and elevated ALT (18% G1; 23% G3). DLTs at 150 mg were hypophosphatemia (n=2). DLTs at 100 mg were hypophosphatemia (n=1), elevated ALT (n=3), and elevated AST (n=1). All DLTs were grade 3 and reversible. No drug-related deaths occurred. PK samples collected for 144 hrs after the 100 mg single dose showed variable absorption with a half-life of approximately 60 hrs. The observed human steady-state PK exposure at 100 mg exceeds the PK exposure of the efficacious dose in mouse of 10 mg/kg. Of 9 evaluable pts at the MTD of 100 mg, there was 1 partial response (PR; ORR=11%) and 3 pts (33%) with stable disease ≥12 wk. Time to PR was 15.9 wk with duration 18.6+ wk. Three pts remain on treatment. SHBG decreased in 18/18 pts and PSA increased in 15/20 pts with paired samples available, indicative of AR target engagement, most notably in the pt with PR. In 1 pt with paired pre- and on-treatment tumor biopsies, a strong induction of AR by IHC, predominantly in the nucleus was seen, further suggesting AR activation by RAD140 at the tissue level. Conclusions: The MTD and recommended dose for RAD140 is 100 mg QD. RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+ mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity. This study is ongoing. NCT03088527

Citation Format: Erika Hamilton, Patricia LoRusso, Cynthia Ma, Neelima Vidula, Rebecca G Bagley, Steven Troy, Miriam Annett, Ziyang Yu, Aaron Weitzman, Maureen G Conlan, Amy Weise. Phase 1 dose escalation study of a novel selective androgen receptor modulator (SARM), RAD140, in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-01.