Steroidogenesis inhibitor opevesostat (MK-5684) for metastatic castration-resistant prostate cancer: OMAHA-003 and OMAHA-004 trial designs.

Treatment options for metastatic castration-resistant prostate cancer (mCRPC) include androgen receptor pathway inhibitors (ARPIs), taxanes, radium-223, Lu-PSMA, poly (ADP-ribose) polymerase inhibitors, and immunotherapy in select patients. Resistance to ARPIs and hormone-based therapies has been associated with AR-ligand-binding domain mutations that can lead to promiscuous stimulation by other steroid hormones. There is a need to explore alternative targets and develop next-generation ARPIs or combination therapies that overcome this resistance. We describe the rationale and design of the randomized phase III trials OMAHA-003 (NCT06136624) and OMAHA-004 (NCT06136650), which will evaluate the efficacy and safety of opevesostat, a steroidogenesis inhibitor, versus ARPI switch in previously treated mCRPC. Results may support opevesostat as a potential new treatment option for mCRPC. www.clinicaltrials.gov identifiers are NCT06136624 and NCT06136650.