Phase 1/2 OMAHA-U01 substudy 01A: Oral steroidogenesis inhibitor opevesostat alone or in combination with other therapies in participants with metastatic castration-resistant prostate cancer (mCRPC).

TPS5140 Background: mCRPC remains an incurable disease and therapeutic agents with novel mechanisms of action are needed for this patient population. Opevesostat (MK-5684; ODM-208), an oral steroidogenesis inhibitor, selectively inhibits cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. In the phase 1/2 CYPIDES study, opevesostat showed antitumor activity in participants with heavily pretreated mCRPC. OMAHA-U01 is an adaptive, open-label, rolling-arm, multicenter, phase 1/2 umbrella study designed to evaluate opevesostat-based investigational therapies in participants with prostate cancer. Substudy 01A (NCT06353386) will evaluate the safety and efficacy of opevesostat alone or in combination with other therapies in participants with previously treated mCRPC. Methods: Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening, and on or after 1-2 androgen receptor pathway inhibitors for metastatic or nonmetastatic hormone-sensitive prostate cancer and nonmetastatic or mCRPC. Prior treatment with ≤1 taxane-based chemotherapy regimen for mCRPC is allowed. A safety lead-in phase for all opevesostat-based experimental combinations (~10 participants in each arm) will establish the recommended phase 2 dose (RP2D), followed by an efficacy phase (opevesostat alone, ≤100 participants; opevesostat-based combinations, ~40 participants each). Participants will be randomly assigned 1:1:1:1 to receive opevesostat 5 mg PO BID, opevesostat 5 mg PO BID plus olaparib (RP2D), opevesostat 5 mg PO BID plus docetaxel (RP2D), or opevesostat 5 mg PO BID plus cabazitaxel (RP2D). Randomization for the efficacy phase will be stratified according to AR-LBD mutation (AR-LBDm) status (positive or negative). The primary end point for the safety lead-in phase is safety and tolerability. Primary end points for the efficacy phase are safety and prostate-specific antigen response rate per Prostate Cancer Clinical Trials Working Group (PCWG) criteria. Secondary end points include objective response rate and radiographic progression-free survival per PCWG-modified RECIST v1.1 by blinded independent central review (BICR), overall survival, duration of response by BICR, time to first subsequent anticancer therapy, and time to pain progression. The predefined eligibility cap for pts with AR-LBDm-negative status has been reached, and the study is currently only enrolling pts with AR-LBDm-positive status. Clinical trial information: NCT06353386 .