Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)

Inclusion Criteria:

• For Cohorts A, B, C, D, E, G, J: Has histologically- or cytologically-confirmedadenocarcinoma of the prostate without small cell histology

• For Cohorts F, H, I: Has t-NE or de novo metastatic prostate cancer defined by ≥1% neuroendocrine cells that are located in discrete regions of a recentbiopsy specimen from a metastasis as determined by the investigational site andconfirmed by central histology review prior to enrollment. Epstein criteria ofneuroendocrine differentiation in prostate cancer is used for eligibility.Specimens must have one of the morphologies of Small cell carcinoma or Largecell neuroendocrine carcinoma (LCNEC) or Mixed (small or large cell) NEcarcinoma - acinar adenocarcinoma with positive IHC confirmed by centralpathology review

• Is able to provide tumor tissue from a site not previously irradiated as follows:Cohorts A, E, G and J: must provide a core or excisional biopsy from soft tissue orbone biopsy within 1 year of screening and after developing mCRPC; Cohort B: mustprovide an archival tumor tissue sample or tumor tissue from a newly obtained coreor excisional biopsy from soft tissue if the lesion is clinically accessible;Cohorts C and D with soft tissue disease: must provide a core or excisional biopsyfrom a soft tissue lesion if clinically accessible within 1 year of screening andafter developing mCRPC and an archival specimen if available; and Cohorts F, H, andI must provide a core or excisional biopsy from soft tissue or a bone biopsy. For denovo metastatic neuroendocrine prostate participants, biopsies must be performedwithin 1 year of screening. Participants with bone metastasis only must provide anarchival tumor tissue specimen

• Has prostate cancer progression within 6 months prior to screening, as determined bythe investigator, by means of one of the following: PSA progression as defined by aminimum of 2 rising PSA levels with an interval of ≥1 week between each assessmentwhere the PSA value at screening should be ≥2 ng/mL; radiographic diseaseprogression in soft tissue based on Response Evaluation Criteria In Solid TumorsVersion 1.1 criteria with or without PSA progression; radiographic diseaseprogression in bone defined as the appearance of 2 or more new bone lesions on bonescan with or without PSA progression. Participants with de novo neuroendocrineprostate cancer will not need to provide evidence of progression within 6 months

• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM).Treatment with luteinizing hormone-releasing hormone agonists or antagonists for allcohorts must have been initiated ≥4 weeks prior to first dose of study therapy andmust be continued throughout the study. Participants with de novo metastatic NEprostate cancer will not be required to have been previously treated with androgendeprivation therapy (ADT). ADT must be started in these participants by the time oftreatment allocation/randomization

• Participants receiving bone resorptive therapy (including, but not limited tobisphosphonate or receptor activator of nuclear factor kappa-β ligand inhibitor)must be on stable doses for ≥4 weeks prior to first dose of study therapy

• Must be abstinent from heterosexual intercourse, refrain from donating sperm, oragree to use contraception (unless confirmed to be azoospermic) during theintervention period starting with the first dose of study therapy. The length oftime required to continue contraception after the last dose of study interventionfor each study intervention is as follows: 7 days for abiraterone acetate andlenvatinib; 30 days for enzalutamide; and 95 days for olaparib, docetaxel, andcarboplatin/etoposide. No contraception measures are required during and after theintervention period for pembrolizumab/vibostolimab coformulation

• Has a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale for Cohorts A and C and a performance status of 0 or 1 forCohorts B, D, E, F, G, H, I and J within 10 days of study start

• For Cohort A: Has received docetaxel for mCRPC. Prior treatment with 1 otherchemotherapy for mCRPC is allowed. Up to 2 second-generation hormonal manipulations (e.g., abiraterone acetate and/or enzalutamide) are allowed. Prior docetaxel formetastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks have elapsedfrom the last dose of docetaxel prior to day 1 of Cycle 1

• For Cohort B: Has received prior treatment with either abiraterone acetate orenzalutamide (but not both) in the prechemotherapy mCRPC state. Participants inCohort B must have received at least 4 weeks of either abiraterone or enzalutamidetreatment (but not both) who failed treatment or became intolerant of the drug

• For Cohort C: Has received prior treatment with abiraterone acetate in thepre-chemotherapy mCRPC state without prior enzalutamide. Participants in Cohort Cmust have received at least 4 weeks of abiraterone treatment who failed treatment orbecome intolerant of the drug. Participants who received abiraterone acetate in thehormone-sensitive state will not be eligible

• For Cohort D: Has not received chemotherapy for mCRPC and has either not had priorsecond generation hormonal manipulation for mCRPC OR has previously been treatedwith enzalutamide for mCRPC and failed treatment or has become intolerant of thedrug. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks have elapsed from the last dose of docetaxel. Prior treatment withabiraterone acetate in the hormone-sensitive metastatic setting is allowed as longas there was no progression on this agent and abiraterone acetate was notdiscontinued due to adverse events (AEs)

• For Cohorts E, G and J: Has received docetaxel for mCRPC. Prior treatment with 1other chemotherapy for mCRPC is allowed. Up to 2 second-generation hormonalmanipulations (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide orother next-generation hormonal agents [NHA]) are allowed. Participants who receivedprior ketoconazole for metastatic disease may be enrolled. If docetaxel chemotherapyis used more than once (eg, once for metastatic hormone-sensitive and once formCRPC), it will be considered as 1 therapy. Prior docetaxel for metastatichormone-sensitive prostate cancer (mHSPC) is allowed if ≥4 weeks have elapsed fromthe last dose of docetaxel prior to Day 1 of Cycle 1

• For Cohort F, H, and I: Participants must have received prior treatment withandrogen deprivation therapy (ADT) for metastatic disease. Prior treatment with upto a total of 2 chemotherapies for mCRPC is allowed, as well as up to 2second-generation hormonal manipulations for mCRPC. Participants who received priorketoconazole for metastatic disease may be enrolled. Docetaxel for mHSPC is allowedin addition to docetaxel for mCRPC. If docetaxel chemotherapy is used more than once (eg, once for metastatic hormone-sensitive and once for mCRPC), it will beconsidered as 1 therapy

Exclusion Criteria:

• Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to firstdose study therapy or who has not recovered (i.e., Grade ≤1 or at baseline) from AEsdue to mAbs administered >4 weeks earlier

• Has had prior chemotherapy, targeted small molecule therapy abiraterone treatment,enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose ofstudy therapy or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due toa previously administered agent

• Is currently participating in and receiving study therapy or has participated in astudy of an investigational agent and received study drug or used an investigationaldevice within 4 weeks of treatment allocation/randomization

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to treatmentallocation/randomization

• Has had prior treatment with therapeutic radiopharmaceuticals for prostate cancer,such as Radium-223 or Leutitium-177, within 4 weeks prior to the first dose of trialtreatment

• Has an active autoimmune disease that has required systemic treatment in past 2years

• Has a history of (noninfectious) pneumonitis/interstitial lung disease that requiredsteroids or current pneumonitis/interstitial lung disease

• Has previously participated in any other pembrolizumab trial, or received priortherapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell deathligand 1 (anti-PD-L1), and anti-programmed cell death ligand 1 (anti-PD-L2)

• Has a known history of Human Immunodeficiency Virus (HIV)

• Has known active Hepatitis B or Hepatitis C

• Has received a live vaccine or live-attenuated vaccine within 30 days of the firstdose of study therapy

• Has known active central nervous system metastases and/or carcinomatous meningitis

• 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 had prior solid, organ or bone marrow transplant

• For Cohort A: Has experienced a seizure or seizures within 6 months of study startor is currently being treated with cytochrome P450 enzyme (CYP) inducinganti-epileptic drugs for seizures

• For Cohort A: Is currently receiving strong or moderate inhibitors of CYP3A4including azole antifungals; macrolide antibiotics; or protease inhibitors

• For Cohort A: Is currently receiving strong or moderate inducers of CYP3A4

• For Cohort A: Has myelodysplastic syndrome

• For Cohort A: Has symptomatic congestive heart failure (New York Heart AssociationClass III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, oruncontrolled hypertension

• For Cohort B: Has received prior treatment with docetaxel or another chemotherapyagent for metastatic prostate cancer

• For Cohort B: Has peripheral neuropathy Common Terminology Criteria for AdverseEvents ≥2 except due to trauma

• For Cohort B: Has ascites and/or clinically significant pleural effusion

• For Cohort B:Has symptomatic congestive heart failure (New York Heart AssociationClass III or IV heart disease)

• For Cohort B: Is currently receiving any of the following classes of inhibitors ofCYP3A4: azole antifungals; macrolide antibiotics; or protease inhibitors

• For Cohort C: Has received prior chemotherapy for mCRPC. Prior docetaxel formetastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks elapsed fromlast dose of docetaxel. Participants who received abiraterone acetate in thehormone-sensitive state will not be eligible

• For Cohort C: Has a history of seizure or any condition that may predispose toseizure (including, but not limited to prior cerebrovascular accident, transientischemic attack, or brain arteriovenous malformation; or intracranial masses such asa schwannoma or meningioma that is causing edema or mass effect)

• For Cohort C:Has known or suspected brain metastasis or leptomeningealcarcinomatosis

• For Cohort C: Has a history of loss of consciousness within 12 months of thescreening visit

• For Cohort C: Has hypotension (systolic blood pressure <86 millimeters of mercury [mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolicblood pressure >105 mmHg) at the screening visit

• For Cohort C: Has received treatment with 5-α reductase inhibitors (e.g.,finasteride, dutasteride), estrogens, and/or cyproterone within 4 weeks prior toCycle 1

• For Cohort C: Has a history of prostate cancer progression on ketoconazole

• For Cohort D: Has received prior treatment with docetaxel or another chemotherapyagent for metastatic prostate cancer

• For Cohort D: Has progressed on prior abiraterone acetate for treatment ofcastration sensitive or resistant metastatic prostate cancer

• For Cohort D: Has discontinued prior treatment with abiraterone acetate due to AEs

• For Cohort D: Has previously been treated with ketoconazole for prostate cancer for >7 days

• For Cohort D: Has received prior systemic treatment with an azole drug (eg,fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1

• For Cohort D: Has uncontrolled hypertension (systolic BP ≥ 160 mm Hg or diastolic BP ≥ 95 mm Hg)

• For Cohort D: Has a history of pituitary or adrenal dysfunction

• For Cohort D: Has clinically significant heart disease as evidenced by myocardialinfarction, or arterial thrombotic events in the past 6 months, severe or unstableangina, or New York Heart Association Class II-IV heart disease or cardiac ejectionfraction measurement of <50% at baseline

• For Cohort D: Has atrial fibrillation, or other cardiac arrhythmia requiring therapy

• For Cohort D: Has a history of chronic liver disease

• For Cohort D: Is currently receiving strong CYP3A4 inducers (eg, phenytoin,carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abirateroneacetate treatment, CYP2D6 substrates with a narrow therapeutic index (for examplethioridazine), or CYP2C8 substrates with a narrow therapeutic index (for examplepioglitazone)

• For Cohorts E and F: Has a left ventricular ejection fraction (LVEF) below theinstitutional (or local laboratory) normal range, as determined by multigatedacquisition (MUGA) or echocardiogram (ECHO)

• For Cohorts E and F: Has radiographic evidence of encasement or invasion of a majorblood vessel, or of intratumoral cavitation

• For Cohorts E and F: Has prolongation of QT interval by Fredericia (QTcF) intervalto >480 milliseconds

• For Cohorts E and F: Has had major surgery within 3 weeks prior to first dose ofstudy interventions

• For Cohorts E and F: Has pre-existing ≥Grade 3 gastrointestinal ornon-gastrointestinal fistula

• For Cohorts E and F: Has had significant cardiovascular impairment within 12 monthsof the first dose of study intervention, such as history of New York HeartAssociation >Class II congestive heart failure, unstable angina, myocardialinfarction, or cerebrovascular accident (CVA)/stroke, cardiac revascularizationprocedure, or cardiac arrhythmia associated with hemodynamic instability

• For Cohorts E and F: Has active hemoptysis (bright red blood of at least 0.5teaspoon) within 3 weeks prior to the first dose of lenvatinib

• For Cohorts E and F: Has gastrointestinal malabsorption or any other condition thatmight affect the absorption of lenvatinib

• For Cohorts G, H, and I: Has had a severe hypersensitivity reaction to treatmentwith another monoclonal antibody

• For Cohorts G, H, and I: Has symptomatic ascites or pleural effusion

• For Cohort I: Has clinically active diverticulitis, intra-abdominal abscess,gastrointestinal obstruction, and/or abdominal carcinomatosis

• For Cohort I: Has received previous treatment for prostate cancer withplatinum-containing compounds