Neoadjuvant Leuprolide Acetate and Darolutamide with Pembrolizumab, Followed by Adjuvant Pembrolizumab for the Treatment of Intermediate or High-Risk Localized and Locally Advanced Prostate Adenocarcinoma

Inclusion Criteria

• Male age ≥ 18 years at the time of consent
• Subjects must have histopathologically confirmed adenocarcinoma of the prostate
• Subject must have unfavorable intermediate and high-risk localized or locally advanced prostate cancer (Gleason score ≥ 7 (4+3) and absence of distant metastasis (confirmed by PSMA PET scan) or non-regional nodal involvement
• Subjects must be risk-stratified at biopsy and their cancer should have all three molecular features given below at baseline * Decipher genomic classifier ≥ 0.45 (interpreted from decipher report) and/ or * Luminal B subtype (interpreted from decipher report)
• The subject must have a performance status of 0-1 as determined by criteria set forward by the Eastern Cooperative Oncology Group
• Subjects with prior neoadjuvant hormonal therapy are allowed if they meet the following criteria * Have completed all treatments ≥ 12, months ago * Recovered from all adverse events (AEs) due to previous therapies
• If subject has had a major surgery, he should have recovered from all complications and toxicities prior to enrolling in the study
• Absolute neutrophil count (ANC) ≥ 1,500/mcL
• Platelets ≥ 100,000/mcl
• Hemoglobin (Hb) ≥ 9 g/dL
• Total bilirubin ≤ 1.5 mg/dl (except in patients with Gilbert syndrome who can have total bilirubin < 3.0 mg/dl)
• Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN
• Creatinine ≤ 1.5 ULN OR * Calculated clearance ≥ 30 ml/min
• Men must agree to use a condom and not father a child or donate sperm for the duration of the study and for 90 days after completion of therapy. Subject must agree to partner use of an additional contraceptive method when having intercourse with women of childbearing potential (WOCBP)
• Ability to understand and the willingness to sign a written informed consent
• Participants who are hepatitis B virus surface antigen (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 randomization * Note: Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention * Hepatitis B screening tests are not required unless: ** Known history of HBV infection ** As mandated by local health authority
• Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening * Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization * Hepatitis C screening tests are not required unless: ** Known history of HCV infection ** As mandated by local health authority
• Participants with a known history of human immunodeficiency virus (HIV) infection are eligible as long as they have an undetectable viral. HIV positive participants must be taking stable antiretroviral therapy (ART) for ≥ 12 weeks, and have an undetectable HIV viral load within 28 days before enrollment. Minor fluctuations up to 200 copies/mL are acceptable

Exclusion Criteria

• Subjects with metastatic disease
• Subjects with Gleason score ≤ 7 (3+4)
• Subjects with biopsy decipher score ≤ 0.45
• Subjects have had prior hormonal therapy (please see inclusion criteria for exceptions)
• Subjects have had prior radiation therapy or chemotherapy for prostate cancer
• Subjects with active cardiac disease defined as having any of the following within 6 months prior to the start of treatment: * Myocardial infarction * Severe/unstable angina pectoris * Congestive heart failure * Hospitalization for any cardiac event
• Subject has active gastrointestinal (GI) disorder that will interfere with absorption of study drug darolutamide
• Subject has prior treatment with androgen receptor inhibitors, such as apalutamide, darolutamide, enzalutamide, abiraterone acetate or other investigational cytochrome P450 (CYP)17 inhibitor
• Inability to swallow oral medications
• Subject has active infection requiring systemic therapy within 7 days of week 1
• Subject has received prior therapy with anti-PD1, anti-PDL1, anti-PDL2 or with other checkpoint inhibitors or T-cell costimulatory/inhibitory agents (e.g., CD137, OX-40, CTLA4)
• Subject with an active viral hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive or detectable [qualitative] hepatitis b virus [HBV] deoxyribonucleic acid [DNA] or defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected), known human immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver disease with a need of treatment
• Subject has a known active or known history of TB (Bacillus tuberculosis) or active history of non-infectious pneumonitis
• Subjects who are immunodeficient or are receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days of study intervention. Topical or inhaled steroids are permitted in absence of immunodeficiency or autoimmune disease
• Subjects have active auto-immune disease that has required systemic therapy (use of disease modifying agents, corticosteroids, or immunosuppressive drugs) in the past 2 years. However, subjects receiving replacement therapy (e.g., insulin, thyroxine, or physiological corticosteroid replacement therapy for adrenal and pituitary insufficiency) are eligible
• Has history or current evidence of any condition, therapy that might confound results of the study
• Has known psychiatric, epileptic or substance abuse history or disorder that would interfere with participant’s ability to cooperate with the requirements of the study
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
• Known history of allergic reactions attributed to compounds of similar chemical or biologic composition to agent(s) or other agents used in study