Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339-010/KEYLYNK-010)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of the combination of the polyadenosine 5'-diphosphoribose poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and pembrolizumab in the treatment of participants with mCRPC who have failed to respond to either abiraterone acetate or enzalutamide (but not both) and to chemotherapy. The primary study hypotheses are that the combination of pembrolizumab plus olaparib is superior to abiraterone acetate or enzalutamide with respect to: Overall Survival (OS) and Radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 as assessed by blinded independent central review (BICR) As of Amendment 06, the Data Monitoring Committee (DMC) is no longer applicable. Participants still on treatment may have the option to continue receiving study intervention or SOC if they are deriving clinical benefit, until criteria for discontinuation are met. Participants who are still on study treatment and deriving clinical benefit will no longer have tumor response assessments by BICR. However, local tumor imaging assessments should continue per SOC schedule. In addition, ePRO assessments will no longer be performed and biomarker samples will no longer be collected.

Official Title
-----------------
A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Who Are Unselected for Homologous Recombination Repair Defects and Have Failed Prior Treatment With One Next-generation Hormonal Agent (NHA) and Chemotherapy (KEYLYNK-010)

Conditions
-----------------
Prostatic Neoplasms

Intervention / Treatment
-----------------
* Biological: Pembrolizumab
* Drug: Olaparib
* Drug: Abiraterone acetate
* Drug: Prednisone
* Drug: Enzalutamide
* Drug: Prednisolone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology Has prostate cancer progression while receiving androgen deprivation therapy (or post bilateral orchiectomy) within 6 months before screening Has current evidence of metastatic disease documented by bone lesions on bone scan and/or soft tissue disease shown by computed tomography/magnetic resonance imaging (CT/MRI) Has received prior treatment with abiraterone acetate OR enzalutamide, but not both Have disease that progressed during or after treatment with abiraterone acetate for either metastatic hormone-sensitive prostate cancer (mHSPC) or mCRP or enzalutamide for mCRPC for at least 8 weeks (at least 14 weeks for participants with bone progression) Participants that received abiraterone acetate for mHSPC may not have received abiraterone acetate or enzalutamide for mCRPC Have received docetaxel chemotherapy regimen for mCRPC and have had progressive disease during or after treatment with docetaxel Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM) If receiving bone resorptive therapy, including but not limited to bisphosphonates or denosumab, must have been receiving stable doses before randomization Must agree to refrain from donating sperm during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention PLUS be abstinent from heterosexual intercourse OR must agree to use contraception unless confirmed to be azoospermic Contraception use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirement above, the local label requirements are to be followed. Has provided tumor tissue from a fresh core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated. Samples from tumors progressing at a prior site of radiation are allowed. Participants with bone-only or bone-predominant disease may provide a bone biopsy sample Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization Exclusion Criteria: Has a known additional malignancy that is progressing or has required active treatment in the last 3 years Has an active autoimmune disease that has required systemic treatment in the past 2 years Has a history of (noninfectious) pneumonitis requiring steroids, or has current pneumonitis Has known active human immunodeficiency virus (HIV), hepatitis B virus (e.g., hepatitis B surface antigen reactive) or hepatitis C virus (HCV) infection (e.g., HCV RNA [qualitative] is detected) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has a history of seizure or any condition that may predispose to seizure Has a history of loss of consciousness within 12 months of screening Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features suggestive of MDS/AML Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy Has (≥Grade 3) hypersensitivity to pembrolizumab and/or any of its excipients Has known hypersensitivity to the components or excipients in olaparib, abiraterone acetate, prednisone or prednisolone, or enzalutamide Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease) Has received an anticancer monoclonal antibody (mAb) before randomization Has received prior treatment with olaparib or any other PARP inhibitor Has received prior treatment with apalutamide or darolutamide Has received prior treatment with enzalutamide or apalutamide for metastatic hormone-sensitive prostate cancer Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA (e.g., saw palmetto) before the date of randomization Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer Has received prior treatment with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, or CD137) Is currently receiving either strong or moderate inhibitors of cytochrome P450 [CYP] (CYP3A4) that cannot be discontinued for the duration of the study Has received a previous allogenic bone marrow transplant or double umbilical cord transplantation (dUCBT) or a solid organ transplant Has received a live vaccine within 30 days prior to the date of randomization Is currently participating in or has participated in a study of an investigational agent, or has used an investigational device, within 4 weeks before the date of randomization Has a bone superscan Is expecting to father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study intervention

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Olaparib<br>Participants will receive olaparib 600 mg as two 150 mg oral tablets twice daily (BID) continuously until progression PLUS on Day 1 of each 21-day cycle, pembrolizumab 200 mg by intravenous (IV) infusion for up to 35 cycles (approximately 2 years). | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: KEYTRUDA®;Drug: Olaparib<br>* Oral tablets<br>* Other names: LYNPARZA®;|
| Active Comparator: Next-generation Hormonal Agent Monotherapy (NHA)<br>Participants will receive a single NHA, which will be either abiraterone acetate (participants previously treated with enzalutamide) 1000 mg as two 500 mg or four 250 mg oral tablets once daily (QD) PLUS prednisone or prednisolone 10 mg as one 5 mg tablet BID until progression OR enzalutamide (participants previously treated with abiraterone acetate) 160 mg as four 40 mg oral tablets or capsules OR two 80 mg tablets QD until progression. | Drug: Abiraterone acetate<br>* Oral tablets<br>* Other names: JNJ-212082;Drug: Prednisone<br>* Oral tablets<br>Drug: Enzalutamide<br>* Oral tablets or oral capsules<br>* Other names: ASP-9785;Drug: Prednisolone<br>* Oral tablets<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival (OS) is defined as the time from randomization to death due to any cause. The nonparametric Kaplan-Meier method was used to estimate the survival curves. | Up to  31 months | 
| Radiographic Progression-Free Survival (rPFS) | rPFS is defined as the time from randomization to the first documented progressive disease (PD) per PCWG-modified RECIST 1.1 based on BICR or death due to any cause, whichever occurred first. Per PCWG-modified RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions or ≥2 new bone lesions was also considered PD. PCWG-modified RECIST is similar to RECIST 1.1 with the exception that a confirmation assessment of PD (>4 weeks after the initial PD) is required for participants who remain on treatment following a documented PD per RECIST 1.1 and PCWG rules include new bone lesions. The rPFS per PCWG-modified RECIST as assessed by BICR for all participants is presented. The nonparametric Kaplan-Meier method was used to estimate the survival curves. | Up to  31 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initiation of the First Subsequent Anticancer Therapy (TFST) | TFST is the time from randomization to initiation of the first subsequent anticancer therapy defined as the first anti-cancer treatment not part of the study arm for a given participant, or death, whichever occurs first. The nonparametric Kaplan-Meier method was used to estimate the survival curves. | Up to  31 months | 
| Objective Response Rate (ORR) | ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions per RECIST 1.1 and no evidence of disease (NED) bone scan) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1 and Non-PD, non-evaluable (NE), or NED bone scan or CR with non-PD or NE bone scan.) The percentage of participants who experienced CR or PR as assessed by BICR is presented. | Up to  31 months | 
| Duration of Response (DOR) | DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per PCWG-modified RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of ≥ 2 new bone lesions is also considered PD. DOR as assessed by BICR is presented. | Up to  24 months | 
| Time to Prostate-Specific Antigen (PSA) Progression | Time to PSA progression is defined as the time from randomization to PSA progression. PSA progression date is defined as the date of: 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, OR 2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline. The nonparametric Kaplan-Meier method was used to estimate the survival curves. | Up to  31 months | 
| Time to First Symptomatic Skeletal-Related Event (SSRE) | SSRE is defined as the time from randomization to the first symptomatic skeletal-related event, defined as whichever occurs first: First use of external-beam radiation therapy (EBRT) to prevent or relieve skeletal symptoms; Occurrence of new symptomatic pathologic bone fracture (vertebral or nonvertebral); Occurrence of spinal cord compression; or Tumor-related orthopedic surgical intervention | Up to  31 months | 
| Time to Radiographic Soft Tissue Progression | Time to radiographic soft tissue progression is defined as the time from randomization to radiographic soft tissue progression per soft tissue rule of PCWG-modified RECIST 1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Time to radiographic soft tissue progression as assessed by BICR is presented. | Up to  31 months | 
| Time to Pain Progression (TTPP) | TTPP is defined as the time from randomization to pain progression as determined by Item 3 of the Brief Pain Inventory Short Form (BPI-SF) and by the Analgesic Quantification Algorithm (AQA) score. Pain progression is defined as: For participants who are asymptomatic at baseline, a ≥2-point change from baseline in the average (4-7 days) BPI-SF item 3 score at 2 consecutive visits OR initiation of opioid use for pain For participants who are symptomatic at baseline (average BPI-SF Item 3 score >0 and/or currently taking opioids), a ≥2-point change from baseline in the average BPI-SF Item 3 score and an average worst pain score ≥4 and no decrease in average opioid use (≥1-point decrease in AQA score from a starting value of 2 or higher) OR any increase in opioid use at 2 consecutive follow-up visits. Participants who had more than 2 consecutive visits that were not evaluable for pain progression were censored at the last evaluable assessment. | Up to  31 months | 
| Number of Participants Who Experience an Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experienced an adverse event are presented. | Up to  31 months | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | The number of participants who discontinue study treatment due to an AE are presented. | Up to  880 Days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)