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

Inclusion Criteria:

1. Histologically confirmed prostate adenocarcinoma that is progressive metastaticcastration-resistant prostate cancer by Prostate Cancer Clinical Trials WorkingGroup 3 (PCWG3) criteria at the time of study entry.

2. Male participants who are at least 18 years of age on the day of signing informedconsent.

3. Castrate level of serum testosterone at study entry (< 50 ng/dL). Note: Participantswithout prior bilateral orchiectomy are required to remain on Luteinizinghormone-releasing hormone (LHRH) analogue treatment for duration of study.

4. Prior progression on at least one second generation androgen signaling inhibitorincluding abiraterone, apalutamide, darolutamide, and/or enzalutamide.

5. Adverse events related to prior anti-cancer treatment (excluding LHRH analogs) musthave recovered to Grade <= 1 (except for any grade alopecia and grade <= 2neuropathy).

6. Prior radiotherapy is allowed if the last radiotherapy treatment was greater than 2weeks from start of study treatment on cycle 1, day 1 (C1D1). Note- Participantsmust have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (<=2 weeks of radiotherapy) to non-centralnervous system (CNS) disease.

7. 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 asuptake above background liver.

8. Eastern Cooperative Oncology Group (ECOG) performance status <= 1 (Karnofsky >= 70%).

9. Demonstrates adequate organ function as defined below:

10. Adequate bone marrow function:

• absolute neutrophil count >=1,500/microliter (mcL)
• platelets >=100,000/mcL
• hemoglobin > 9.0 g/dL

2. Adequate hepatic function:

• total bilirubin <= 1.5 x upper limit of normal (ULN). In patients withknown or suspected Gilbert's disease, direct bilirubin <= ULN
• aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) <= 2.5 x institutional ULN (<= 5 x ULN in patients with livermetastases)
• alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) <= 2.5 x institutional upper limit of normal (<= 5 x ULN in patients withliver metastases)

3. Adequate renal function:

• creatinine <= 1.5 x within institutional upper limit of normal OR
• creatinine clearance Glomerular filtration rate (GFR) >= 50 mL/min/1.73m^2, calculated using the Cockcroft-Gault equation or 24 hour urinecollection.

10. Participants must use appropriate methods of contraception during study treatmentand for at least 6 months after last study treatment. Patients who are sexuallyactive should consider their female partner to be of childbearing potential if shehas experienced menarche and is not postmenopausal (defined as amenorrhea > 24consecutive months) or has not undergone successful surgical sterilization. Evenwomen who use contraceptive hormones (oral, implanted, or injected), an intrauterinedevice, or barrier methods (diaphragms, condoms, spermicide) should be considered tobe of childbearing potential. Patients who have undergone vasectomy themselvesshould also be considered to be of childbearing potential. Acceptable methods ofcontraception include continuous total abstinence, or double-barrier method of birthcontrol (e.g., condoms used with spermicide, or condoms used with oralcontraceptives). Periodic abstinence and withdrawal are not acceptable methods ofcontraception.

11. Participants must provide consent to comply to recommended radioprotectionprecautions during study.

12. Participants willing to undergo a tumor biopsy. Bone or soft tissue lesion isallowed. Note: The biopsy can be waived if there is no safely accessible lesion inthe judgement of the treating investigator.

13. Participants with previously treated brain metastases are eligible provided thefollowing criteria are all met:

14. Last treatment was > 28 days prior to C1D1.

15. No evidence of new/progressive brain metastases is observed on magneticresonance imaging (MRI) obtained during screening window

16. Patient is clinically stable without requirement of steroid treatment for atleast 14 days prior to first dose of study treatment on C1D1.

17. Individuals with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

18. Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

1. De novo small cell neuroendocrine prostate cancer will not be allowed due toputative lower PSMA expression in this tumor subtype. Note-Treatment-emergent smallcell neuroendocrine prostate cancer detected in metastatic tumor biopsy is notexcluded.

2. Soft tissue lesions (lymph nodes > 1.5 centimeter (cm) in short axis, visceral/softtissue lesions > 1 cm) on screening Computerized tomography (CT) that are negativeon PSMA PET. Note: Negative lesions on PSMA PET are defined as those with uptakebelow the background liver.

3. Has received other systemic anti-cancer therapies administered within 14 days, or 5half-lives, whichever is shorter, prior to initiation of study treatment. Note: LHRHanalogues are the exception.

4. Untreated brain metastases at study entry.

5. Receipt of prior PSMA-directed treatment (e.g., radiotherapy, immunotherapy, orantibody-drug conjugate).

6. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-Programmed celldeath-ligand 2 (PD-L2) agent or with an agent directed to another stimulatory orco-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX 40, CD137).

7. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study treatment on C1D1. Note: Participants who have entered the follow-up phaseof an investigational study may participate as long as it has been 4 weeks after thelast dose of the previous investigational agent.

8. Receipt of > 2 lines of prior taxane-based chemotherapy.

9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

10. Has an active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) or treatment with drugs (e.g., neomercazole, carbimazole, etc.) thatfunction to decrease the generation of thyroid hormone by a hyper-functioningthyroid gland (e.g., in Graves' disease) is not considered a form of systemictreatment of an autoimmune disease.

11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at aprednisone equivalent dose of > 10 mg daily or other form of immunosuppressivetherapy within 7 days prior to first dose of study drug.

12. Has a history of (non-infectious) ≥ grade 2 pneumonitis/interstitial lung diseasethat 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 thefirst dose of study drug on C1D1. Note-Administration of a killed vaccine isallowed.

14. Patients who because of age, general medical or psychiatric condition, orphysiologic status cannot give valid informed consent.

15. Has clinically significant cardiovascular disease including, but not limited to:

16. Uncontrolled or any New York Heart Association Class 3 or 4 congestive heartfailure.

17. Uncontrolled angina, history of myocardial infarction, unstable angina, orstroke within 6 months before study entry.

18. Clinically significant arrhythmias not controlled by medication. Note: Chronicrate controlled, or paroxysmal atrial fibrillation/flutter is not an exclusionto study participation.

19. Prior external beam radiation involving > 25 percent (%) of bone marrow or within 14days of start of protocol therapy on C1D1.

20. Major surgery within 28 days of study treatment. Note: If participant received majorsurgery, they must have recovered adequately from the toxicity and/or complicationsfrom the intervention prior to starting study treatment on C1D1. Minor procedures (e.g., biopsy, cataract surgery, stent placement, endoscopy) are not consideredmajor surgery.

21. Has an active infection requiring intravenous antibiotics within 7 days prior toC1D1.

22. 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:

23. Participants who are HbsAg positive are eligible if they have receivedHepatitis B virus (HBV) antiviral therapy for at least 4 weeks and haveundetectable HBV viral load prior to study entry

24. Participants with history of Hepatitis C virus (HCV) infection are eligible ifHCV viral load is undetectable at screening. Participants must have completedcurative anti-viral therapy at least 4 weeks prior to study entry.

25. Has a known history of active Bacillus Tuberculosis (TB).

26. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

27. History of bleeding diathesis and currently on anti-coagulation therapy that cannotbe safely discontinued for the tumor biopsy procedure.

28. Any condition that, in the opinion of the Principal Investigator, would impair theparticipant's ability to comply with study procedures.