Pembro With Radiation With or Without Olaparib

Phase II Study of Pembrolizumab in Combination With Radiation With or Without Olaparib in Localized High-risk Prostate Cancer

This trial will evaluate whether the immune-sensitizing effects of immunotherapy (Pembrolizumab) and radiation with or without a PARP-inhibitor (Olaparib) will increase the effects of immunotherapy in men with high-risk localized prostate cancer.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Biological: Pembrolizumab; Drug: Olaparib; Drug: Androgen Deprivation Therapy; Radiation: Radiation Therapy

Detailed Description

Immunotherapy and PARP-inhibitor are known to have radio-sensitizing effects when combined with radiation therapy. In addition, the combination with PARP-inhibitor and radiation can increase neoantigen expression, cytotoxic lymphocyte infiltration within the tumor microenvironment and increased immune stimulating cytokine concentration. Thus, there is a potential synergy of combining immunotherapy and PARP-inhibitor.

This is a phase 2 randomized 1:1 study. Subjects will be randomized to one arm (pembro + PARPi + standard of care therapy which is definitive radiation therapy combined with hormonal therapy) vs. another arm (pembro + standard of care therapy). All subjects will receive adjuvant immunotherapy for one year once they are done with definitive radiation treatment.

Due to slow accrual and feasibility concerns, the protocol was modified to single arm phase II study. All patients will receive definitive radiation therapy combined with ADT per institutional standards. In addition to concurrent ADT and radiation therapy, patients on this trial will also receive as follow: Pembrolizumab (17 cycles) combined with olaparib (the first three cycles). The remaining patients will be enrolled to Arm 1 only (i.e., Arm 2 usual care is closed to accrual upon Amendment 5 protocol).

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bryan Courtney; Phone Number: 859-257-3379; Email: bryancourtney@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • University of Kentucky
      • Contact: Yvonne Taul, RN,CCRC; Phone Number: 859-323-2354; Email: yvonne.taul@uky.edu
      • Contact: Zin Myint, MD; Phone Number: 410236809; Email: zin.myint@uky.edu
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute
      • Contact: Benjamin Maughan, MD, PharmD; Phone Number: 801-581-2267; Email: benjamin.maughan@hci.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male participants with histologically confirmed adenocarcinoma of the prostate
• High-risk / very high-risk status per NCCN guidelines
• ECOG performance status 0 to 1
• Regional lymph nodes are allowed.
• Agree to use contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period.
• Ability to understand and the willingness to sign a written informed consent document.
• Adequate organ and marrow function
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation is ≤90 days prior to the date of registration
• Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.

Exclusion Criteria:

• Prior hormonal therapy with LHRH agonists (e.g., Lupron) and LHRH antagonists (e.g., Degarelix)for prostate cancer continuously for more than 90-days prior to study enrollment.
• Prior radiation to the prostate or pelvic nodes radiation.
• Previous or major surgery (colorectal anastomosis, total cystectomy, etc.).
• History of Ulcerative proctitis.
• Concurrent active, additional malignancy in the last 2 years.
• Prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization.
• Patients with M1 disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 - Pembrolizumab and Olaparib; Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab and Olaparib.	Biological: Pembrolizumab; Pembrolizumab will be delivered via IV at 200mg on day 1 of each 3-week cycle for approximately 12 months. Cycle 1 begins 21 days prior to radiation therapy and cycles 2-17 are administered during and after radiation therapy.; Other Names: Keytruda; Drug: Olaparib; 200mg Olaparib will be given twice daily for a total of 3 cycles. Cycle 1 begins 21-days prior to radiation therapy.; Other Names: Lynparza; Drug: Androgen Deprivation Therapy; Androgen Deprivation Therapy (either LHRH agonist or LHRH antagonist) as per treating physician choice will be allowed within 3 months prior to randomization. Duration is per institutional standards.; Radiation: Radiation Therapy; Definitive radiation (total dose and fractions) will be dosed per institutional standards. Definitive radiation may include external beam radiation therapy with or without brachytherapy, based on NCCN risk score and as per treating physicians.
Experimental: Arm 2 - Pembrolizumab; Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab.	Biological: Pembrolizumab; Pembrolizumab will be delivered via IV at 200mg on day 1 of each 3-week cycle for approximately 12 months. Cycle 1 begins 21 days prior to radiation therapy and cycles 2-17 are administered during and after radiation therapy.; Other Names: Keytruda; Drug: Androgen Deprivation Therapy; Androgen Deprivation Therapy (either LHRH agonist or LHRH antagonist) as per treating physician choice will be allowed within 3 months prior to randomization. Duration is per institutional standards.; Radiation: Radiation Therapy; Definitive radiation (total dose and fractions) will be dosed per institutional standards. Definitive radiation may include external beam radiation therapy with or without brachytherapy, based on NCCN risk score and as per treating physicians.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response Rate	The proportion of patients who achieve a PSA nadir level of ≤ 0.06ng/mL six months after completion of radiation therapy.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biochemical-Free Survival	Biochemical-free survival rate at 3 years as defined by Phoenix Criteria.	3 years
Metastasis-Free Survival	Metastasis-free survival rate at 3 years as defined by RECIST v1.1 criteria.	3 years
Time to Normalization of Serum Testosterone	Time from normalization is the date of first return to normal serum testosterone 270 ng/ml or greater after withdrawal of androgen deprivation therapy.	3 years
Molecular Alterations in Homologous Recombination Repair Genes	Molecular alterations in the homologous recombination repair (HHR) genes.	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA Progression-Free Survival	PSA progression-free survival (PSA-PFS) stratified by PDL1 immunohistochemistry expression on baseline or /archival biopsy tissue, if tissue is available.	3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)
Correlation between clinical outcome and immune cell subtype.	Correlation between the clinical outcomes and changes in immune cell subtype frequencies (% CD4 T cells, % CD8 T cells, % naïve, effector memory, and T regulatory cells) immune functions (T cell ability to induce cytokine following stimulation).	3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)
Correlation between clinical outcome and cytokine levels.	Correlation between the serum cytokines (IL2, IL-10, and INF-γ) and clinical outcomes.	3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)
Correlation between clinical outcomes and TCR repertories clonotypes.	Correlation between T cell receptor (TCR) repertories clonotypes and clinical outcomes.	3 years (Pre-treatment baseline, cycle 3, 6 months or at disease progression)
Percent changes in plasma circulating tumor DNA	Percent changes in plasma circulating tumor DNA (ctDNA).	Baseline and on-treatment (6 months)

Collaborators and Investigators

• Sponsor: Zin W Myint
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Zin W Myint, MD, University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2023
• Primary Completion (Estimated): July 2, 2026
• Study Completion (Estimated): July 2, 2029

Study Registration Dates

• First Submitted: September 29, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 5, 2022

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: immunotherapy; radiation; PD-1; ADT; PARP; androgen deprivation therapy
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Therapeutics; Pharmacologic Actions; Chemical Actions and Uses; Androgen Antagonists; Radiotherapy; pembrolizumab; olaparib
• Other Study ID Numbers: MCC-22-GU-80

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes