Results of a phase 1 study of vosilasarm (EP0062), a first-in-class oral selective androgen receptor modulator (SARM) in patients with advanced or metastatic AR+/ER+/HER-2- breast cancer.

Abstract

1057 Background: Vosilasarm (EP0062) is an oral, nonsteroidal, Selective Androgen Receptor Modulator (SARM). Initially developed under the code RAD140, EP0062 has been reformulated with markedly improved bioavailability and pharmacokinetics. Preclinically, vosilasarm has been shown to act as a potent tissue-selective AR agonist, suppressing growth and proliferation of multiple AR+/ER+/HER-2- breast cancer cell lines and patient-derived xenograft models, as monotherapy or in combination with standard of care (SoC) regimens (Clin Can Res 2017 23(24); SABCS 2019 P5-05-01). Here we report results from the dose finding and optimization cohorts of an ongoing phase 1/2 study (NCT05573126) in patients (pts) with advanced AR+/ER+/HER-2- breast cancer. Methods: The study recruited post-menopausal women with locally advanced or metastatic AR+/ ER+/HER-2- breast cancer, ≥ 18 years of age, with endocrine sensitive disease. AR+ defined as ≥ 10% AR nuclei staining by IHC. Primary objectives were to evaluate safety and determine the optimal dose for evaluation in future combination cohorts. Other endpoints included PK, ORR, DOR, CBR ≥6 months and genomic analysis (biopsy- or ctDNA-based NGS). Results: A total of 20 pts (Median age 59.5 y, PS 0/1 [70/30%]) were treated across 4 dose cohorts: 20mg QD (n = 2), 10mg BID (n = 10), 10mg QD (n = 5), 15mg BID (n = 3). The 10mg BID cohort was expanded for dose optimization. All pts received prior CDK4/6i and AI and/or SERD with a median of 4 prior lines (in any setting). CtDNA analysis showed genomic heterogeneity at baseline, with ESR1 mutations (8/19 pts) and TP53 mutations (9/19 pts) the most frequent. No DLTs were observed. 89% of all TEAEs were G1 or G2 with most common being increase in LFTs (55% of pts), nausea (40% of pts) and anemia (25% of pts). The LFT increases were transient, asymptomatic and generally occurred in cycle 1, with 2 pts requiring a dose interruption followed by reduction. Most common ≥ G3 TEAEs were ALT increase in 4 pts (20%). No treatment related deaths were observed. 19 pts were evaluable for efficacy. For 11/ 19 (58%) pts the best response was stable disease. 4/19 (21%) pts had clinical benefit with CBR ≥6 mo, corresponding with marked suppression of CA15-3 in 5/19 (26%) patients. Vosilasarm has a favorable PK profile with good bioavailability and no accumulation. Full data will be reported. 10 mg BID was selected as the optimal dose for Phase 2. Conclusions: Vosilasarm has promising clinical benefit, safety and tolerability in this heterogeneous, heavily pre-treated population. This confirms the potential of vosilasarm, a first in class SARM, as a new treatment strategy for AR+/ ER+/HER-2- breast cancer. The study is continuing with evaluation of vosilasarm in combination with SoC therapies including oral SERD, mTOR inhibitor and CDK4/6 inhibitors. Clinical trial information: NCT05573126 .