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
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.
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).
Single group
Darolutamide
DrugDarolutamide 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.
Pembrolizumab
DrugAdministered 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
Lupron
DrugAndrogen 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).
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.
Complete pathological response (pCR)
Complete pathological response (pCR) is defined as the absence of viable tumor in post treatment prostatectomy specimens). pCR is typically determined by examining the radical prostatectomy specimen after surgery.
Proportion of patients who had had their tumor downstaged
Proportion of patients who had had their tumor downstaged due to neoadjuvant Pembrolizumab, Darolutamide and ADT at the time of surgery. Downstaging will be determined using MRI and pathology separately.
Adverse events assessed by NCI CTCAE (v.5.0).
Adverse events assessed by NCI CTCAE (v.5.0). Incidence of AEs will be reported for the first cycle of neoadjuvant therapy, for the entire neoadjuvant treatment phase, and for the adjuvant treatment phase.
Biochemical progression free survival bPES
bPFS is defined as the time from baseline to first evidence of biochemical progression based on PSA level or death, whichever occurs first.
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Icahn School of Medicine at Mount Sinai
Lead sponsor
Merck Sharp & Dohme LLC
Collaborator
Bayer
Collaborator
