Phase 3 OMAHA-004 study of CYP11A1 inhibitor opevesostat versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after 1 prior NHA.

TPS301 Background: Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies (ADT) in mCRPC. Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. By blocking the first step of the enzymatic pathway, opevesostat has the potential to inhibit all steroid hormones involved in AR signaling activation. In the phase 1/2 CYPIDES study, opevesostat had antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations (1). The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in patients with molecularly unselected mCRPC previously treated with 1 prior NHA. Methods: Eligible patients have mCRPC that progressed during ADT ≤6 months before screening and during/after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. Approximately 1500 patients (375 with, 1125 without AR-LBD mutations) will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Primary endpoints are radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR) and overall survival in AR-LBD mutation–positive and –negative disease, separately. Secondary endpoints include time to initiation of first subsequent anticancer therapy or death; objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR; and safety. Recruitment is ongoing. 1. Fizazi et al. NEJM Evid. 2024. Clinical trial information: NCT06136650 .