Phase 1/2 OMAHA-01A substudy of oral CYP11A1 inhibitor opevesostat alone or in combination with other therapies for metastatic castration-resistant prostate cancer (mCRPC).

TPS300 Background: Current treatments for mCRPC are associated with hormone dependence and the development of resistance. Therapeutic agents with novel mechanisms of action are needed for this patient population. 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. In the phase 1/2 CYPIDES study, opevesostat demonstrated antitumor activity in patients with heavily pretreated mCRPC (1). OMAHA-U01 is an adaptive, open-label, rolling-arm, multicenter, phase 1/2 umbrella study that will evaluate the safety and efficacy of opevesostat-based investigational therapies in prostate cancer. Substudy 01A (NCT06353386) will evaluate opevesostat alone or in combination with other therapies in patients with previously treated mCRPC. Methods: Eligible patients have mCRPC that progressed during ADT ≤6 months before screening, and on/after 1-2 NHAs for metastatic or nonmetastatic hormone-sensitive prostate cancer and nonmetastatic or mCRPC. Prior treatment with ≤1 taxane for mCRPC is allowed. A safety lead-in phase for all opevesostat-based experimental combinations (~10 patients in each arm) will establish the recommended phase 2 dose (RP2D), followed by an efficacy phase (opevesostat alone, ≤100 patients; opevesostat-based combinations, ~40 patients each). Patients will be randomly assigned 1:1:1:1 to opevesostat 5 mg PO BID, opevesostat 5 mg PO BID + olaparib (RP2D), opevesostat 5 mg PO BID + docetaxel (RP2D), and opevesostat 5 mg PO BID + cabazitaxel (RP2D). The primary endpoint for the safety lead-in phase is safety and tolerability. Primary endpoints for the efficacy phase are safety and prostate-specific antigen response rate per Prostate Cancer Working Group criteria. 1. Fizazi et al. NEJM Evid. 2024. Clinical trial information: NCT06353386 .