There is growing interest in targeting the androgen receptor (AR) in advanced/metastatic breast cancer. It has been recently demonstrated preclinically that AR activation, rather than AR suppression, exerts potent antitumor activity across a number of ER+/AR+ breast tumors, including those resistant to standard-of-care endocrine therapy and CDK4/6 inhibitors (Hickey et al, Nature Medicine 2021 27: 310-320). Mechanistically, agonist activation of AR altered the genomic distribution of ER and essential co-activators resulting in repression of ER-regulated cell cycle genes and upregulation of AR target genes, including known tumor suppressors. EP0062 is an oral, non-steroidal, SARM currently being developed for the treatment of AR+/HER2-/ER+ advanced breast cancer. The efficacy and safety of EP0062 has previously been investigated in a Phase 1 clinical trial of AR+/HER2–/ER+ advanced breast cancer, and demonstrated that EP0062 has acceptable tolerability with evidence of clinical efficacy (LoRusso et al. Clinical Breast Cancer 2022 22;1 67-77). This new study is designed to further extend the evaluation of EP0062 as a potential therapy for AR+/HER2–/ER+ advanced breast cancer. The primary aim of the study is to assess tolerability and identify an optimal RP2D dose. The study will also explore the relationship between efficacy of EP0062 and AR expression, to establish a threshold for future patient selection, and undertake an initial evaluation of the safety and efficacy of EP0062 in combination with established standard of care therapies. The study will recruit up to 128 patients with AR+/HER2-/ER+ advanced breast cancer. Module A is a dose finding cohort to investigate safety, tolerability, PK and PD and to define the maximum tolerated dose (MTD) and/or Recommended Phase II Dose (RP2D). Dose finding will be based on a 3+3 design and is expected to recruit up to 32 patients. Once potential recommended doses are identified, approximately 60 evaluable patients will be randomised to two different dose cohorts in Module B in order to further optimise the RP2D dose, by further evaluation of safety and tolerability, as well as prospectively evaluate the relationship between efficacy and AR expression. In Module C, EP0062 will be combined with select standard of care targeted therapies in patients with relapsed AR+/HER2-/ER+ advanced breast cancer to confirm safety and explore efficacy. This will include approximately 36 patients across a number of single arm expansion cohorts. The key inclusion criteria are as follows: • Post-menopausal women, ≥18 years • ECOG performance status of 0 to 1 • Locally advanced or metastatic breast cancer • ER+, HER2- as per ASCO CAP guidelines • AR+, as defined as ≥ 10% AR nuclei staining by IHC • Endocrine-sensitive defined as greater than 3 years endocrine treatment prior to recurrence if recurrence occurred in the adjuvant setting, or ≥ 6 months treatment and response if recurrence occurred from primary treatment in the advanced setting • Relapsed, defined as clear and documented evidence of disease progression following ≥ 1 lines and ≤2 prior lines of previous endocrine therapy and ≤ 2 lines of chemotherapy in the advanced/metastatic setting • Measurable disease defined by RECIST version 1.1, or measurable bone-only disease EP0062 will be dosed to progression. Endpoints include incidence of DLTs during Cycle 1 of EP0062 treatment (28 days), MTD, RP2D (Module A), incidence and severity of AEs and SAEs, plasma PK parameters, Clinical Benefit Rate (complete response, partial response, or stable disease) at 24 weeks, ORR, duration of response, PFS, OS and quality of life. Clinic follow-up will be at 2 and 4 weeks, then every 4 weeks until disease progression. Recruitment is scheduled to initiate in Q4 2022.

Citation Format: Elgene Lim, Erika Hamilton, Carlo Palmieri, Hendrik-Tobias Arkenau, Sue Brook, Geoff Fisher, Andrew Mazur. A phase 1/2 study to evaluate the safety and efficacy of EP0062, an oral Selective Androgen Receptor Modulator (SARM), for the treatment of AR+/HER2-/ER+ advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-02-02.