Opevesostat (MK-5684/ODM-208): A Comprehensive Clinical and Scientific Review of a First-in-Class CYP11A1 Inhibitor for Hormone-Dependent Cancers

1.0 Introduction to Opevesostat

Opevesostat is an investigational, orally bioavailable, non-steroidal new drug representing a first-in-class therapeutic agent designed as a selective inhibitor of the cytochrome P450 11A1 (CYP11A1) enzyme.[1] Also known as the cholesterol side-chain cleavage enzyme, CYP11A1 is the critical gatekeeper for the entire steroid biosynthesis pathway. By targeting this initial, rate-limiting step, opevesostat offers a novel and potentially more profound mechanism for suppressing the production of all steroid hormones and their precursors.[2]

The primary therapeutic rationale for opevesostat is centered on the treatment of hormone-dependent malignancies, with the most advanced clinical program focused on metastatic castration-resistant prostate cancer (mCRPC).[1] In mCRPC, the androgen receptor (AR) signaling pathway remains a fundamental driver of tumor progression, even in the castrate setting where testicular androgen production is suppressed.[4] Resistance to standard-of-care androgen receptor pathway inhibitors (ARPIs) often involves mechanisms that reactivate AR signaling, such as mutations in the AR ligand-binding domain (AR-LBD) that allow activation by alternative steroid ligands.[4] Opevesostat's mechanism of action is hypothesized to overcome this resistance by eliminating the entire pool of potential steroid ligands—both androgens and their precursors—that could promiscuously activate wild-type or mutated ARs.[4]