Pembro With Radiation With or Without Olaparib

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Biological: Pembrolizumab
* Drug: Olaparib
* Drug: Androgen Deprivation Therapy
* Radiation: Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
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 No pelvic nodes >2 cm in long axis as established by CT imaging 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 Prior 5-alpha reductase inhibitor (for example, finasteride) for prostatic hypertrophy is allowed if discontinued at least 60 days prior to 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: PSA > 150ng/ml 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. Previous pelvic RT or major surgery (colorectal anastomosis, total cystectomy, radical prostatectomy, TURP, 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 distant metastases

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 - Pembrolizumab and Olaparib<br>Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab and Olaparib. | Biological: Pembrolizumab<br>* 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.<br>* Other names: Keytruda;Drug: Olaparib<br>* 200mg Olaparib will be given twice daily for a total of 3 cycles. Cycle 1 begins 21-days prior to radiation therapy.<br>* Other names: Lynparza;Drug: Androgen Deprivation Therapy<br>* 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.<br>Radiation: Radiation Therapy<br>* 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.<br>|
| Experimental: Arm 2 - Pembrolizumab<br>Patients with high-risk prostate cancer receiving combination therapy with Pembrolizumab. | Biological: Pembrolizumab<br>* 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.<br>* Other names: Keytruda;Drug: Androgen Deprivation Therapy<br>* 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.<br>Radiation: Radiation Therapy<br>* 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.<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
immunotherapy, PARP, radiation, androgen deprivation therapy, ADT, PD-1