Neoadjuvant ADT + Darolutamide With Pembrolizumab, Followed by Adjuvant Pembrolizumab in Molecularly Stratified High-Risk Prostate Cancer

Recruiting now · Phase 2

Conditions studied: Prostate Cancer, High-risk Prostate Cancer

In brief

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

Key facts

Study ID

NCT07027124

Run by

Icahn School of Medicine at Mount Sinai

People needed

40

Starts

2026-05-21

Expected to finish

2031-05-02

Last updated by the study team

2026-06-16

Who can join

Age: 18 and older. Sex: male. Healthy volunteers: not accepted.

You may qualify if…

• Male Age ≥ 18 years at the time of consent
• Subjects must have histopathologically confirmed adenocarcinoma of the prostate
• Subjects must have unfavorable intermediate and high-risk localized or locally advanced prostate cancer (Gleason score ≥7 (4+3) and absence of distant metastasis or non-regional nodal involvement.
• Subjects must be risk-stratified at biopsy and their cancer should have all the 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 patient 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 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.
• 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.
• Subjects 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: Subjects should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.

You may not qualify if…

• 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 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 CYP17 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] DNA or defined as Hepatitis V 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.
• Subject 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.
• Subject 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.
• Subjects 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.

Where it is running

• Icahn School of Medicine at Mount Sinai — New York, New York, United States (enrolling)

Full record on ClinicalTrials.gov

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