Pembrolizumab Plus 177Lu-PSMA-617 in Patients With Castration Resistant Prostate Cancer

This is a single-center, open-label, study of Prostate-Specific Membrane Antigen (PSMA)-targeted radionuclide therapy with 177Lu-PSMA-617 in combination with pembrolizumab in participants with metastatic castrate-resistant prostate cancer (mCRPC) who have previously progressed on at least one prior androgen pathway inhibitor (e.g., abiraterone, enzalutamide, apalutamide).

Inclusion Criteria: 1. Male participants who are at least 18 years of age on the day of signing informed consent. 2. Histologically confirmed prostate adenocarcinoma that is progressive metastatic castration-resistant prostate cancer by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria at the time of study entry. 3. Castrate level of serum testosterone at study entry (\< 50 ng/dL). Note: Participants without prior bilateral orchiectomy are required to remain on Luteinizing hormone-releasing hormone (LHRH) analogue treatment for duration of study. 4. At least one Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) (PSMA PET) avid lesion on screening PSMA PET. A positive lesion is defined as uptake above background liver. 5. Prior progression on at least one second generation androgen signaling inhibitor including abiraterone, apalutamide, darolutamide, and/or enzalutamide. 6. Adverse events related to prior anti-cancer treatment (excluding LHRH analogs) must have recovered to Grade \ 9.0 g/dL 2. Adequate hepatic function: * total bilirubin \ 10 mg daily or other form of immunosuppressive therapy within 7 days prior to first dose of study drug. 12. Has a history of (non-infectious) ≥ grade 2 pneumonitis/interstitial lung disease that required steroids within past 2 years or has current ≥ grade 1 pneumonitis/ interstitial lung disease at the time of study enrollment. 13. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug on C1D1. Note-Administration of a killed vaccine is allowed. 14. Patients who because of age, general medical or psychiatric condition, or physiologic status cannot give valid informed consent. 15. Has clinically significant cardiovascular disease including, but not limited to: 1. Uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure. 2. Uncontrolled angina, history of myocardial infarction, unstable angina, or stroke within 6 months before study entry. 3. Clinically significant arrhythmias not controlled by medication. Note: Chronic rate controlled, or paroxysmal atrial fibrillation/flutter is not an exclusion to study participation. 16. Prior external beam radiation involving \> 25 percent (%) of bone marrow or within 14 days of start of protocol therapy on C1D1. 17. Major surgery within 28 days of study treatment. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment on C1D1. Minor procedures (e.g., biopsy, cataract surgery, stent placement, endoscopy) are not considered major surgery. 18. Has an active infection requiring intravenous antibiotics within 7 days prior to C1D1. 19. HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease 20. Has a known history of Hepatitis B infection (defined as Hepatitis B surface antigen (HBsAg) reactive) or known active Hepatitis C virus infection (defined as (HCV RNA) \[qualitative\] detected, with the following exceptions: 1. Participants who are HbsAg positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to study entry 2. Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening. Participants must have completed curative anti-viral therapy at least 4 weeks prior to study entry. 21. Has a known history of active Bacillus Tuberculosis (TB). 22. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 23. History of bleeding diathesis and currently on anti-coagulation therapy that cannot be safely discontinued for the tumor biopsy procedure. 24. Any condition that, in the opinion of the Principal Investigator, would impair the participant's ability to comply with study procedures.