The androgen receptor (AR) plays a pivotal role in prostate cancer pathogenesis, even after progression on AR-directed therapies. In patients with mCRPC, activation of AR ligand binding domain (AR-LBD) somatic point mutations is a common mechanism of resistance to AR-directed therapies. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. By inhibiting CYP11A1, opevesostat can suppress the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. In the phase 1/2 CYPIDES trial, opevesostat showed antitumor activity in participants with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC), and in those with AR-LBD mutations (Fizazi K et al. NEJM Evid. 2024;3:EVIDoa2300171). The randomized, open-label, phase 3 OMAHA-003 trial (NCT06136624) is evaluating the efficacy and safety of opevesostat versus NHA switch in participants with mCRPC who received NHA and taxane-based chemotherapy.

Eligible participants have mCRPC (unselected for AR-LBD mutations) that progressed on androgen deprivation therapy ≤6 months of screening and during or after treatment with 1 NHA or 1-2 taxane-based chemotherapies. Participants will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide). Primary end points 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 participants with AR-LBD mutation-positive and -negative disease, separately. Secondary end points 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 1200 participants.

Enrollment is ongoing in Argentina, Australia, Austria, Canada, Chile, China, Colombia, Czech Republic, Denmark, Finland, France, Germany, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Malaysia, Mexico, New Zealand, Norway, Peru, Poland, Puerto Rico, Singapore, South Korea, Spain, Sweden, Taiwan, Thailand, the Netherlands, the United Kingdom, the United States, and Turkey.

Results from the OMAHA-003 trial will elucidate the efficacy and safety of opevesostat versus NHA switch in participants with mCRPC previously treated with NHA and taxane-based chemotherapy. ©2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was previously presented at the 2024 ASCO Annual Meeting. All rights reserved.