Neoadjuvant ADT and Darolutamide With Pembrolizumab, Followed by Adjuvant Pembrolizumab in NCCN High-risk and Molecularly Stratified Prostate Cancer Patients
This is a single-arm, phase II study of neoadjuvant combination therapy of Androgen Deprivation Therapy (ADT), \[Gonadotropin-Releasing Hormone (GnRH) agonist Leuprolide\], androgen receptor (AR)-antagonist Darolutamide and Pembrolizumab in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-radical prostatectomy (RP). Patients with National Comprehensive Cancer Network (NCCN) high-risk non-metastatic prostate cancer (localized or locally advanced) (defined as Gleason ≥8, disease stage \>=cT3a, or PSA l \>20 ng/mL) will be risk-stratified at a biopsy using Decipher, a commercial standard-of-care diagnostic assay. Patients satisfying all three criteria of high-risk genomic characteristics listed below as per the Decipher grid results will be enrolled in the study: 1. Decipher Genomic classifier, GC\>0.6 2. AR activity score/AR-output gene signature (ARoS)\>11.0 3. High Luminal B score/ PAM50 subtype signature
• Male Age ≥ 18 years at the time of consent
• Patients must have histopathologically confirmed adenocarcinoma of the prostate
• Patients must have NCCN high-risk localized or locally advanced prostate cancer and absence of distant metastasis or nodal involvement defined as those having one of the following.
‣ Gleason score ≥ 8
⁃ PSA \> 20 ng/ml
⁃ Clinical stage \>cT2C (T3a and above)
• Patients must be risk-stratified at biopsy and their cancer should have all three molecular features given below at baseline.
‣ Decipher Genomic Classifier \>0.6 (interpreted from decipher report)
⁃ High AR activity/AR activity score \>11 (interpreted from decipher report)
⁃ Luminal B subtype (interpreted from decipher report)
• The patient must have a performance status of 0-1 as determined by criteria set forward by the eastern cooperative oncology group.
• Patients with prior neoadjuvant hormonal therapy are allowed if they meet the following criteria.
‣ have completed all treatments ≥ 12, months ago.
⁃ Recovered from all AEs due to previous therapies.
• If patient has had a major surgery, he should have recovered from all complications and toxicities prior to enrolling in the study.
• Adequate organ and marrow function as defined below:
‣ Hematological
⁃ Absolute neutrophil count (ANC) ≥ 1,500/mcL
⁃ Platelets ≥ 100,000/mcl
⁃ Hemoglobin (Hb) ≥ 9 g/dL Hepatic
⁃ 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 ULN
⁃ Alanine aminotransferase (ALT) ≤ 2.5 x ULN Renal
⁃ Creatinine OR Creatinine ≤ 1.5 ULN OR
⁃ Calculated creatinine clearance Creatinine 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 HBs Ag positive are eligible if they have received HBV anti-viral 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 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 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.