Study Evaluating the Addition of Pembrolizumab to Radium-223 in mCRPC

Inclusion Criteria

• Histologically confirmed adenocarcinoma of the prostate
• Castration-resistant prostate cancer requires the following 3 criteria:
• Progression after surgical castration or on GnRH agonist or antagonist
• A castrate level of testosterone ( 1.5 X institutional ULN
• Hepatic
• Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels > 1.5 institutional ULN
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN
• Albumin > 2.5 mg/dL
• Coagulation

--International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Creatinine clearance should be calculated per institutional standard.
• The effects of radium-223 and pembrolizumab on the developing human fetus are unknown. For this reason, men must agree to use adequate contraception. Specifically, they must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 120 days (4 months) following the last dose of study drug. They must also agree not to donate sperm during the study and for 4 months after receiving the last dose of study drug.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

• Pathology consistent with majority of specimen having small cell carcinoma of the prostate (prostate cancer with other neuroendocrine features is acceptable).
• Prior treatment with radium-223
• Prior treatment with a PD-1, PD-L1, or PD-L2 blocking therapy
• Evidence of nodal disease greater than or equal to 15 mm in short axis as these findings are concerning for metastases that would not be targeted with radium-223 alone (Arm B). However, lymph nodes with short axis measurements between 1.5-3cm that have not enlarged more than 5mm (to account for reader variability) over the last 6 months and which are not inducing symptoms, causing obstruction, or in the opinion of the investigator pose a risk of impending obstruction of any structures, will be allowed.
• Pulmonary nodules >10 mm

--Pulmonary nodules >10mm that have been stable for >6 months and are not clearly metastatic disease per the treating investigator are permitted

• Soft tissue components of bone metastases ≥ 1.0 cm in longest axis

--Soft tissue components of bone metastases 6 months (must not have enlarged > 5mm) are permitted

• Soft tissue lesions ≥ 1.0 cm in longest axis

--Soft tissue lesions 6 months (must not have enlarged > 5mm) are permitted.

• If present, primary disease in the prostate must be stable for > 6 months (defined as no growth > 5mm)
• Evidence of local recurrence in the prostate bed
• Evidence of liver metastases or visceral disease
• Has a diagnosis of immunodeficiency
• Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., limited low-dose dexamethasone for nausea, multiple doses for contrast allergy) may be enrolled in the study and would not require a 7 day washout.
• Has a known history of active TB (Bacillus Tuberculosis)
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior systemic therapy (exception: GnRH agonist or antagonist) or radiation ther