Phase 3 Trial For Opevesostat A CYP11A1 Inhibitor in mCRPC

Opevesostat, a first-in-class CYP11A1 inhibitor, blocks the first step of steroid hormone production, eliminating all ligands that activate mutant androgen receptors in metastatic castration-resistant prostate cancer (mCRPC). The Phase 3 MK-5684-004 trial tests it against standard next-generation hormonal agents (NHAs, like abiraterone, enzalutamide, …) switching in 1,500 patients progressed on one prior NHA, with rPFS and OS endpoints stratified by AR-LBD mutation status.
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Phase 1/2 CYPIDES data showed 73.7% PSA50 responses in AR-LBD+ patients vs 8.7% in wildtype, confirming biomarker specificity in heavily pretreated mCRPC (median 3+ prior lines).

Pharmacodynamic confirmation was unequivocal: testosterone became undetectable in 87% of patients by week 1, alongside suppression of pregnenolone, androstenedione, DHEAS, cortisol, aldosterone, and 11-ketotestosterone. Reversibility upon discontinuation further affirmed the drug’s clean profile.

Adrenal insufficiency occurred in 13.3% (manageable with hydrocortisone); other AEs were anemia (38%), fatigue (30-38%). Median imaging PFS was 5 months; 70% disease control rate.
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If AR-LBD+ patients show superior OS vs NHA switching, opevesostat becomes precision therapy for 20-25% of post-NHA mCRPC.

Clinical trial.