A Study of Opevesostat (MK-5684) Versus Alternative Next-generation Hormonal Agent (NHA) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Post One NHA (MK-5684-004)

Inclusion Criteria:

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

• Have histologically or cytologically confirmed adenocarcinoma of the prostatewithout small cell histology

• Has prostate cancer progression while receiving androgen deprivation therapy (ADT) (or post bilateral orchiectomy) within 6 months before screening

• Has current evidence of distant metastatic disease (M1 disease) documented by eitherbone lesions on bone scan and/or soft tissue disease shown by computed tomography (CT)/magnetic resonance imaging (MRI)

• Has disease that progressed during or after treatment with one next-generationhormonal agent (NHA) for hormone sensitive prostate cancer (HSPC) (metastatichormone-sensitive prostate cancer [mHSPC] or non-metastatic hormone-sensitiveprostate cancer [nmHSPC]), or castration-resistant prostate cancer (CRPC) (metastatic castration-resistant prostate cancer [mCRPC] or non-metastaticcastration-resistant prostate cancer [nmCRPC]), for at least 8 weeks of NHAtreatment (at least 14 weeks of NHA treatment for participants with boneprogression). Note: Participants may have received abiraterone acetate and docetaxelor darolutamide and docetaxel for HSPC. However, participants must have received nomore than 6 cycles of docetaxel and had no radiographic disease progression whilereceiving docetaxel

• Has had prior treatment with poly (ADP-ribose) polymerase inhibitor (PARPi) or weredeemed ineligible to receive treatment by the investigator or have refused PARPitreatment

• Has ongoing androgen deprivation therapy (ADT) with serum testosterone <50 ng/dL (<1.7 nM)

• Has an eastern clinical oncology group (ECOG) performance status of 0 or 1 assessedwithin 10 days before randomization

• Has adequate organ function

• Has provided tumor tissue from a fresh core or excisional biopsy from soft tissuenot previously irradiated. Samples from tumors progressing at a prior site ofradiation are allowed

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible ifthey have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeksand have undetectable HBV viral load before randomization

• Participants with history of hepatitis C virus (HCV) infection are eligible if HCVviral load is undetectable at screening

• Participants who have adverse event (AEs) due to previous anticancer therapies musthave recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs whoare adequately treated with hormone replacement therapy (HRT) or participants whohave ≤Grade 2 neuropathy or ≤Grade 2 osteopenia/osteoporosis are eligible

• Human immunodeficiency virus (HIV)-infected participants must have well controlledHIV on antiretroviral therapy (ART)

Exclusion Criteria:

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

• Has presence of gastrointestinal condition

• Is unable to swallow capsules/tablets

• Has history of pituitary dysfunction

• Has poorly controlled diabetes mellitus

• Has clinically significant abnormal serum potassium or sodium level

• Has any of the following at screening visit: Hypotension: systolic blood pressure (BP) <110 mmHg, or uncontrolled hypertension: systolic BP ≥160mmHg or diastolicblood BP ≥90 mmHg, in 2 out of the 3 recordings with optimized antihypertensivetherapy

• Has a history of active or unstable cardio/cerebrovascular disease, includingthromboembolic events

• History or family history of long QTc syndrome

• Has a history of seizure(s) within 6 months before providing documented informedconsent (IC) or has any condition that may predispose to seizure within 12 monthsprior to the date of enrollment

• Has a history of clinically significant ventricular arrhythmias or Mobitz II seconddegree or third-degree heart block without a permanent pacemaker in place

• Has received a taxane-based chemotherapy for metastatic castration-resistantprostate cancer (mCRPC)

• Has not adequately recovered from major surgery or have ongoing surgicalcomplications

• Is currently being treated with Cytochrome P450 (CYP450)-inducing antiepilepticdrugs for seizures

• Participants on an unstable dose of thyroid hormone therapy, as judged by theinvestigator, within 6 months before the start of the study intervention

• Receives prior radiotherapy within 2 weeks before the first dose of studyintervention, or radiation-related toxicities, requiring corticosteroids

• Receives prior systemic anticancer therapy including investigational agents within 4weeks before the first dose of study intervention

• Has systemic use of strong Cytochrome P450 3A4 (CYP3A4) inducers and P-glycoprotein (P-gp) inhibitors within 2 weeks before the first dose of study intervention

• Has received prior targeted small molecule therapy or NHA treatment within 4 weeksbefore the first dose of study intervention

• Received a live or live-attenuated vaccine within 30 days before the first dose ofstudy intervention

• Has received an investigational agent or has used an investigational device within 4weeks prior to study intervention administration

• Has known hypersensitivity to the components or excipients in abiraterone acetate,prednisone or prednisolone, enzalutamide, fludrocortisone, dexamethasone, oropevesostat

• Has a "superscan" bone scan defined as an intense symmetric activity in the bonesand diminished renal parenchymal activity on baseline bone scan such that thepresence of additional metastases in the future could not be evaluated

• Has known additional malignancy that is progressing or has required active treatmentwithin the past 3 years

• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (indosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior the first dose of study medication

• Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Participants with previously treated brain metastases may participateprovided they are radiologically stable, (ie, without evidence of progression) forat least 4 weeks as confirmed by repeat imaging performed during study screening,are clinically stable and have not required steroid treatment for at least 14 daysprior to the first dose of study intervention

• Has active autoimmune disease that has required systemic treatment in the past 2years. Replacement therapy is allowed

• Active infection requiring systemic therapy

• Has concurrent active Hepatitis B virus and Hepatitis C virus infection