Adding Pembrolizumab with or without Olaparib to Radiation and Androgen Deprivation Therapy for the Treatment of Localized High Risk Prostate Cancer

Inclusion Criteria

• Male participants with histologically confirmed adenocarcinoma of the prostate without histological variants comprising > 50% of the sample (including neuroendocrine differentiation, small cell, sarcomatoid, ductal adenocarcinoma, squamous or transitional cell carcinoma)
• High-risk / very high-risk status per National Comprehensive Cancer Network (NCCN) guidelines, defined by the presence of at least one of the following four high-risk features: * Clinical T3a, T3b or T4 * N1 disease * Gleason grade group 4 or 5 * PSA > 20ng/dl
• Regional nodes are allowed with no size limit
• Prior pharmacologic androgen ablation for prostate cancer is allowed if the onset of androgen ablation is =< 90 days prior to the date of registration
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1
• Agree to use contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period. Your partners of child-bearing potential have to agree to use contraception as well
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L
• Estimated creatinine clearance (CrCl) using the Cockcroft-Gault equation or a 24-hour urine test >= 50 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN) * For patients with Gilbert syndrome =< 3 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• Ability to understand and the willingness to sign a written informed consent document
• International normalized ratio (INR) OR prothrombin time (PT) and activated partial thromboplastin time (aPTT) Patient is considered eligible for study enrollment as long as PT/INR and aPTT are within the therapeutic range of the intended use of anticoagulants (If patient is on anti-coagulation prior to study enrollment)

Exclusion Criteria

• Prior hormonal therapy with luteinizing hormone-releasing hormone (LHRH) agonists (e.g., Lupron) and LHRH antagonists (e.g., Degarelix) for prostate cancer continuously for more than 90-days prior to study enrollment
• Prior radiation to the prostate or pelvic nodes radiation except treating radiation oncologists feel safe to receive addition standard of care radiation for treatment of high-risk or very high risk prostate cancer
• Previous major surgery (For example: colorectal anastomosis, total cystectomy, etc.)
• Concurrent active, additional malignancy in the last 2 years * Note: Exceptions include indolent malignancies such as basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, that have undergone potentially curative therapy, indolent follicular lymphoma, chronic lymphocytic leukemia (CLL) not on any therapy, Ta urothelial carcinoma etc. These exceptions are not excluded. Consult with principal investigator (PI) and get approval if needed
• Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization
• Patients with distant metastases
• History of ulcerative proctitis
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug Note: Current use of immunosuppressive medication is also not allowed except for the following: the use of steroids for physiologic replacement, intranasal, inhaled, topical, local steroid injection, and/or premedication for hypersensitivity reactions (use of these specific medications is allowed)
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent per treating physician’s clinical judgment and/or consult with PI. * Note: Exceptions include but are not limited to diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment
• Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Active infection requiring systemic therapy
• Known history of human immunodeficiency virus (HIV) infection * Note: No HIV testing is required unless mandated by local health authority
• Active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active untreated hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] 15 to 100,000,000 IU/mL is detected) infection. * Note: no testing for hepatitis B/C is required unless mandated by local health authority
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has had an allogenic tissue/solid organ transplant
• Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) or with features suggestive of MDS/AML
• Persistent toxicities (≥ grade 2 Common Terminology Criteria for Adverse Events [CTCAE]) caused by previous cancer therapy, unless determined not clinically significant by the principal investigator, excluding alopecia, hot flash, sexual dysfunction, fatigue from standard hormonal therapy
• Received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention
• Considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
• Presence of uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 ms, electrolyte disturbances, etc.), or participant has congenital long QT syndrome
• Unable to swallow orally administered medication or has gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption)
• Prior therapy with olaparib or with any other PARP inhibitor
• Prior therapy with an anti-PD-1, anti-PD-L1, or an anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Known hypersensitivity to the components or excipients of compounds of olaparib
• Severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• Currently receiving either strong (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks * Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
• Currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (e.g., bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents * Note: a current list of strong/moderate inducers of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
• Received a whole blood transfusion in the last 120 days prior to entry to signing consent. Packed red blood cells and platelet transfusions are acceptable if not performed within 28 days of the first dose of study intervention. Note: This criterion is only required for studies that prospectively test for BRCA or HRRM status
• Received a live vaccine within 30-days prior to the first dose of pembrolizumab * Note: Killed vaccines are allowed