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Advances in mCRPC

CE / CME

Advances in Metastatic Castration-Resistant Prostate Cancer: Biomarker-Driven Treatment Strategies and Emerging Therapeutic Approaches

ABIM MOC: maximum of 0.50 Medical Knowledge MOC point

Physicians: Maximum of 0.50 AMA PRA Category 1 Credit™

Released: July 20, 2026

Expiration: January 19, 2027

Neal D. Shore
Neal D. Shore, MD, FACS
CME/CE Information

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Opevesostat: Mechanism of Action

Opevesostat inhibits steroidogenesis upstream of abiraterone by targeting CYP11A1, the first step in adrenal steroid hormone synthesis. Because this mechanism can suppress glucocorticoid and mineralocorticoid production, clinical trials administer opevesostat with replacement therapy, typically dexamethasone and fludrocortisone acetate, to reduce the risk of adrenal insufficiency.

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CYPIDES Phase II Trial of Opevesostat in mCRPC:​ Unconfirmed Best PSA Change

The phase II CYPIDES trial of opevesostat in mCRPC showed very pronounced declines in PSA, particularly in patients who had mutations in the AR-LBD. These waterfall plots illustrate marked differences in PSA decreases between patients with and without mutations in the AR-LBD. Treatment with Opevesostat led to PSA50 responses in 53.0% and 14.7% of patients and PSA30 responses in 68.2% and 29.4% of patients with and without mutations in the AR-LBD, respectively.27

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CYPIDES Phase II Trial of Opevesostat in mCRPC: Safety

Opevesostat produces profound suppression of adrenal steroidogenesis, which necessitates hormone replacement and can lead to adrenal insufficiency. Beyond this expected mechanism-related toxicity, most reported adverse events in the phase II experience were grade 1 or 2, and grade 3/4 events were less common.27

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Key Ongoing Phase III Trials of Opevesostat in mCRPC

There are 2 ongoing phase III trials of opevesostat in mCRPC: OMAHA-003 and OMAHA-004. OMAHA-003 is looking at men with prostate adenocarcinoma with no neuroendocrine features. Participants will be randomized to opevesostat with dexamethasone and fludrocortisone acetate or abiraterone acetate with prednisone or enzalutamide. Essentially, patients will undergo ARPI sequencing. These are patients with mCRPC who have progressed on 1 novel hormonal therapy and received 1-2 prior lines of chemotherapy for mCRPC. Coprimary endpoints are OS in the AR-LBD–mutant and wild-type populations. 

The OMAHA-004 trial is enrolling patients with mCRPC previously treated with 1 next-generation hormonal agent. This trial is designed as a direct head-to-head comparison between opevesostat and standard approved ARPIs, such as abiraterone acetate or enzalutamide, to determine whether this oral therapy provides greater clinical benefit. The primary endpoint is rPFS.

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