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

NCT07027124 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: STUDY-23-01400
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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. 1.Decipher Genomic classifier, GC\>0.6
2. 2.AR activity score/AR-output gene signature (ARoS)\>11.0
3. 3.High Luminal B score/ PAM50 subtype signature

Conditions

Prostate Cancer; High-risk Prostate Cancer

Keywords

Prostate Cancer; Immunotherapy; Pembrolizumab; Darolutamide; ADT

Outcome Measures

Primary Outcomes (1)

• Proportion of patients who achieve Minimal residual disease (MRD)

  MRD is defined as residual cancer burden (RCB) ≤0.25cm³ at final pathology, where RCB is calculated by multiplying the residual tumor volume with the tumor cellularity. The proportion of patients who achieve MRD will be collected at the time of surgery.

  at time of surgery (At Week 17)

Secondary Outcomes (9)

• Complete pathological response (pCR)

  After Week 17

• Proportion of patients who had had their tumor downstaged

  at time of surgery (At Week 17)

• Adverse events assessed by NCI CTCAE (v.5.0).

  Week 1 to Week 16, Week 19 to Week 52

• Biochemical progression free survival bPES

  Week 22 and until 5 years after Week 17

• Metastasis free survival (MFS)

  Week 17 and until 5 years after Week 17

Study Arms (1)

Participants with Prostate Cancer

EXPERIMENTAL

Neoadjuvant ADT plus AR- antagonist, Darolutamide plus Pembrolizumab (5 cycles) prior to radical prostatectomy (RP) in a stratified high-risk localized prostate cancer cohort, followed by adjuvant treatment with Pembrolizumab (12 cycles) post-RP.

Drug: Darolutamide; Drug: Pembrolizumab; Drug: Lupron

Interventions

Darolutamide DRUG

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg for 16 weeks prior to RP.

Also known as: Nubeqa

Participants with Prostate Cancer

Pembrolizumab DRUG

Administered at the dose of 200 mg intravenously, every 3 weeks, for a total of 5 cycles prior to RP (Neoadjuvant phase, study weeks 1, 4, 7, 10, 13 \& 16), and every 3 weeks, for a total of 12 cycles post-RP (Adjuvant phase, study weeks, 19, 22, 25, 28, 31, 34, 37, 40 43, 46, 49, \& 52). Total Pembrolizumab cycles=17

Also known as: Keytruda

Participants with Prostate Cancer

Lupron DRUG

Androgen deprivation, GnRH agonist Leuprolide will be administered at a dose of 22.5 mg SQ (Eligard)/IM Lupron every 12 weeks prior to RP (Study weeks, 1 and 13).

Also known as: Leuprolide

Participants with Prostate Cancer

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Prostate Cancer Patients
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Patients with metastatic disease
• Patients with Gleason score \<8
• Patients with Biopsy Decipher score ≤0.6.
• Patients have had prior radiation therapy or chemotherapy for prostate cancer.
• Patients 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
• Patients 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.
• Patients has active infection requiring systemic therapy within 7 days of Week 1.
• Patients 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).
• Patients 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.
• Patients has a known active or known history of TB (Bacillus tuberculosis) or active history of non-infectious pneumonitis.

Sponsors & Collaborators

• Bayer: collaborator
• Icahn School of Medicine at Mount Sinai: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 10028, United States

RECRUITING

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

darolutamide; pembrolizumab; Leuprolide

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Ashutosh K Tewari, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

• Dimple Chakravarty, PhD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Daniela Delbeau- Zagelbaum, RN, NP

CONTACT

212 241 2066; daniela.delbeau-zagelbaum@mssm.edu

Monali Fatterpekar, PhD

CONTACT

212 241 0751; monali.fatterpekar@mountsinai.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Urology Chair

Study Record Dates

• First Submitted: June 10, 2025
• First Posted: June 18, 2025
• Study Start: March 19, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): May 2, 2031
• Last Updated: March 19, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Access Criteria: Investigators whose proposed use of the data has been approved by an independent review committee ('learned intermediary') identified for this purpose. For individual participant data meta-analysis. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in ISMMS data warehouse but without investigator support other than deposited metadata. Information regarding submitting proposals and accessing data may be found at (Link to be determined).

Locations

US (1)