The purpose of this study is to assess the efficacy and safety of opevesostat in the treatment of Japanese men with metastatic castration-resistant prostate cancer (mCRPC) previously treated with Next Generation Hormonal Agent (NHA) and taxane-based chemotherapy.

After approval of Protocol amendment 03, participants in the survival follow-up phase will have a final survival contact and then be discontinued from the study.

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
• Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI)
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nmol/L)
• Participants receiving bone anti-resorptive therapy (including, but not limited to bisphosphonate or denosumab) must have been on stable doses for ≥4 weeks prior to the start of study intervention.
• Has progressed on or after treatment with at least 1 line of NHAs in metastatic hormone-sensitive prostate cancer (mHSPC) or in castration-resistant prostate cancer (CRPC) for a minimum of 12 weeks (e.g. abiraterone, enzalutamide, darolutamide, apalutamide), and with at least 1 line of taxane-based chemotherapy in mHSPC or in CRPC, or ineligibility for chemotherapy
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 10 days prior to allocation
• If capable of producing sperm, participant must agree to the following during the study treatment period and for at least 7 days after the last dose of opevesostat: Refrain from donating sperm, plus EITHER be abstinent OR must agree to use male condom.

Exclusion Criteria:

• Has a history of pituitary dysfunction
• Has brain metastases
• History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 3 years
• Has an active or uncontrolled autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
• Has an active infection or other medical condition that would make corticosteroid contraindicated
• Has serious persistent infection within 2 weeks prior to the start of the study intervention
• Participants on an unstable dose of thyroid hormone therapy within 6 months prior to the start of the study intervention
• Has poorly controlled diabetes mellitus
• Hypotension: systolic blood pressure (BP) < 110 mmHg, or uncontrolled hypertension: systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg, in 2 out of 3 recordings with optimized antihypertensive therapy
• Has active or unstable cardio/cerebro-vascular disease, including thromboembolic event
• Is unable to swallow orally administered medication or known gastrointestinal (GI) disease or GI procedure that may interfere with absorption of study intervention
• Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to the start of the study intervention and not adequately recovered from the toxicities and/or complications
• Has received aldosterone antagonist (e.g. spironolactone, eplerenone) and phenytoin within 4 weeks prior to the start of the study intervention
• Has received radiotherapy within 4 weeks prior to the start of the study intervention, or radiation related toxicities, requiring corticosteroids
• Has received chemotherapy within the last 4 weeks (2 weeks for oral or weekly chemotherapy; 6 weeks for nitrosoureas and mitomycin C) prior to the start of the study intervention
• Has received prior enzalutamide and apalutamide within 3 weeks, or abiraterone and darolutamide within 2 weeks prior to the start of the study intervention
• Systemic use of the following medications within 2 weeks prior to the start of study intervention: strong cytochrome P450 (CYP)3A4 inducers: e.g., carbamazepine, rifampicin, phenobarbital, phenytoin, St John's Wort) and strong CYP3A4 inhibitors: e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, grapefruit juice
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
• Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto) within 4 weeks prior to the start of the study intervention
• Has received treatment with 5-α reductase inhibitors (eg, finasteride or dutasteride), estrogens, and/or cyproterone within 4 weeks prior to the start of the study intervention
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
• History of human immunodeficiency virus (HIV) infection
• Has a history of Hepatitis B or active Hepatitis C virus
• Has a "superscan" bone scan
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the start of the study intervention

https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf