177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

Inclusion Criteria

• The subject is able and willing to comply with study procedures and provide signed and dated informed consent
• Histologically confirmed prostate adenocarcinoma. De novo small cell neuroendocrine prostate cancer will not be allowed due to putative lower PSMA expression in this tumor subtype. Treatment-emergent small cell neuroendocrine prostate cancer detected in metastatic tumor biopsy is not an exclusion
• A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with positive lesions defined as those with maximum standardized uptake value (SUVmax) values greater than liver.
• Progressive metastatic castration-resistant prostate cancer by Prostate Cancer Working Group (PCWG)3 criteria at the time of study entry
• Castrate level of serum testosterone at study entry ( 1.5 x 10^9/L
• Hemoglobin > 9.0 g/dL
• Platelet count > 100,000/microliter
• Serum creatinine = 50 ml/min by Cockcroft-Gault or 24 hour urine collection
• Total bilirubin = 24 consecutive months) or has not undergone successful surgical sterilization. Even women who use contraceptive hormones (oral, implanted, or injected), an intrauterine device, or barrier methods (diaphragms, condoms, spermicide) should be considered to be of childbearing potential
• Participants who have undergone vasectomy themselves should also be considered to be of childbearing potential
• Acceptable methods of contraception include continuous total abstinence, or double-barrier method of birth control (e.g. condoms used with spermicide, or condoms used with oral contraceptives). Periodic abstinence and withdrawal are not acceptable methods of contraception
• Participants must provide consent to comply to recommended radioprotection precautions during study
• Participants willing to undergo tumor biopsy and have at least one lesion safely accessible to tumor biopsy. Bone or soft tissue lesion is allowed
• Measurable disease by RECIST 1.1 criteria

Exclusion Criteria

• Untreated brain metastases at study entry. Participants with previously treated brain metastases are eligible provided the following criteria are all met:
• Last treatment was > 28 days prior to cycle 1 day 1 (C1D1)
• No evidence of new/progressive brain metastases is observed on magnetic resonance imaging (MRI) obtained during screening window
• Patient is clinically stable without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
• Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or antibody-drug conjugate)
• Prior enrollment on clinical study investigating Lu-PSMA-based radioligand therapy
• Prior treatment with radium-223 or other radioisotope for the treatment of prostate cancer
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (= 2 peripheral neuropathy at the time of study entry
• Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) or treatment with drugs (e.g. neomercazole, carbimazole, etc.) that function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g. in Graves? disease) is not considered a form of systemic treatment of an autoimmune disease
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a prednisone equivalent dose of > 10 mg daily or other form of immunosuppressive therapy within 7 days prior to first dose of study drug
• Has a history of (non-infectious) ≥ grade 2 pneu