Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies in metastatic castration-resistant prostate cancer (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 trial, opevesostat had antitumor activity in participants with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations (Fizazi K et al. NEJM Evid. 2024;3:EVIDoa2300171). The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in participants with molecularly unselected mCRPC previously treated with 1 prior NHA.

Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening and during or after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. Participants 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 Clinical Trials 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. Planned enrollment is approximately 1500 participants.

Recruitment is ongoing in Australia, Brazil, Canada, Chile, China, Colombia, Costa Rica, Czech Republic, Estonia, France, Germany, Greece, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Lativa, Lithuania, Malaysia, Mexico, New Zealand, Peru, Portugal, Puerto Rico, Romania, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, the United Kingdom, the United States, and Turkey.

Results from the OMAHA-004 trial will elucidate the efficacy and safety of opevesostat versus NHA switch in AR-LBD mutation–positive and –negative participants after 1 prior NHA. ©2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was previously presented at the 2024 ASCO Annual Meeting. All rights reserved.