OMAHA-004: Phase 3 trial of the steroidogenesis inhibitor opevesostat versus androgen receptor pathway inhibitor (ARPI) switch in participants with metastatic castration-resistant prostate cancer (mCRPC) after a prior ARPI.

TPS5135 Background: 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. Opevesostat showed antitumor activity in participants with heavily pretreated mCRPC in the phase 1/2 CYPIDES trial. The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) is designed to evaluate the efficacy and safety of opevesostat in participants with mCRPC after a prior ARPI. Methods: Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening and on or after 1 ARPI for metastatic or nonmetastatic hormone-sensitive prostate cancer (HSPC) or CRPC for ≥8 weeks (≥14 weeks with bone progression). Prior ARPI plus docetaxel for HSPC is permitted if participants received no more than 6 cycles of docetaxel without radiographic disease progression. Approximately 1314 participants will be randomized 1:1 to opevesostat 5 mg orally twice-daily plus dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily or abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily (if prior enzalutamide, darolutamide, or apalutamide) or enzalutamide 160 mg orally once-daily (if prior abiraterone). Stratification factors are metastatic site (bone only vs liver vs other), androgen receptor ligand binding mutation (AR-LBDm) status (positive vs negative), and prior docetaxel treatment for HSPC (yes vs no). Once the predefined enrollment threshold for participants with either mutation status (AR-LBDm-positive, ~400 participants or AR-LBDm-negative, ~914 participants) is met, no additional participants with that mutation status will be permitted to enroll. The protocol was amended to use radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR), analyzed separately in participants with AR-LBDm–positive and –negative disease, as the primary end point and overall survival as a key secondary end point. Other 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, time to pain progression; time to prostate-specific antigen (PSA) progression, PSA response rate, time to first symptomatic skeletal-related event, and safety and tolerability. Enrollment is ongoing. Clinical trial information: NCT06136650 .