Study of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-641/KEYNOTE-641)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. There are two primary study hypotheses. Hypothesis 1: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Overall Survival (OS). Hypothesis 2: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Radiographic Progression-free Survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review.

Official Title
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A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-641)

Conditions
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Prostatic Neoplasms

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Enzalutamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to randomization Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI) Has met one of the following criteria with regard to abiraterone acetate exposure: (1) is abiraterone-naïve; (2) received prior abiraterone acetate for the treatment of mHSPC or mCRPC, for a minimum of 4 weeks and not progressed while on treatment; or (3) received prior abiraterone acetate for the treatment of mHSPC or mCRPC and progressed on treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression) Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM) Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization Participants must agree to the following during the study treatment period and for at least 90 days after the last dose of enzalutamide: Refrain from donating sperm, plus EITHER be abstinent OR must agree to use male condom Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in 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 past 2 years Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules Has an active infection (including tuberculosis) requiring systemic therapy Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease Has known active human immunodeficiency virus (HIV), concurrent active hepatitis B virus (HBV) or known active hepatitis C virus (HCV) infection Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients 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 hypotension (systolic blood pressure <86 millimeters of mercury [mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg) at the screening visit Has bradycardia (heart rate of <50 beats per minute) on the screening electrocardiogram (ECG) Has history of prostate cancer progression on ketoconazole Has had prior treatment with enzalutamide, apalutamide, darolutamide or cytochrome P450 (CYP) 17 inhibitor other than abiraterone acetate Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto) prior to randomization Has received a live or live attenuated vaccine within 30 days prior to randomization Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment Has a superscan bone scan Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of enzalutamide Has had an allogenic tissue/solid organ transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Enzalutamide<br>Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered orally (PO) once a day (QD) continuously until progression. | Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;Drug: Enzalutamide<br>* Capsules/Tablets<br>* Other names: XTANDI®;|
| Placebo Comparator: Placebo + Enzalutamide<br>Participants receive placebo by IV infusion administered on Day 1 Q3W for up to 35 cycles (approximately 2 years) PLUS enzalutamide 160 mg administered PO QD continuously until progression. | Drug: Enzalutamide<br>* Capsules/Tablets<br>* Other names: XTANDI®;Drug: Placebo<br>* IV infusion<br>* Other names: Normal saline or dextrose infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from randomization to death due to any cause. The OS for all participants is presented. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review | rPFS was defined as the time from randomization to the first documented progressive disease (PD) per PCWG-modified RECIST 1.1 based on blinded independent central review or death due to any cause, whichever occurred first. The rPFS per PCWG-modified RECIST for all participants is presented. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST) | TFST was defined as time from randomization to initiation of the first subsequent anti-cancer therapy or death, whichever occurs first. The TFST for all participants is presented. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Prostate-specific Antigen (PSA) Response Rate | PSA response rate was defined as percentage of participants in the analysis population who have a negative change (decrease) in PSA level of ≥50% measured twice ≥3 weeks apart. The analysis was performed on participants who had baseline PSA measurements. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Prostate-specific Antigen (PSA) Undetectable Rate | PSA undetectable rate was defined as percentage of participants in the analysis population with PSA <0.2 ng/mL during study treatment. The analysis was performed on participants who had baseline PSA measurements. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Objective Response (OR) Per Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by as Assessed by Blinded Independent Central Review | OR was 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) on bone scan per PCWG) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1; and non-progressive disease, non-evaluable [NE], or NED on bone scan or CR with non-progressive disease or NE bone scan per PCWG). | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Duration of Response (DOR) Per Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by as Assessed by Blinded Independent Central Review | DOR was defined as the time from first documented evidence of complete response (CR) or partial response (PR) per PCWG and RECIST 1.1 criteria until progressive disease (PD) or death. PD per RECIST 1.1 was 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. PD per PCWG was the appearance of ≥2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and were persistent for ≥6 weeks. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data. If a participant had not progressed, the participant was censored at the date of last disease assessment. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Time to Prostate-specific Antigen (PSA) Progression | 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. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by as Assessed by Blinded Independent Central Review | Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1 | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 (Worst Pain in 24 Hours) and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] Score) | Time from randomization to pain progression. In this study, pain progression was assessed by participant responses to Item 3 of the BPI-SF and participant AQA Scores which are both assessed by participants daily for 7 consecutive days. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Time to First Symptomatic Skeletal-related Event (SSRE) | Time from randomization to the first SSRE. SSRE is defined as radiation to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathological fracture, spinal cord compression, or surgery to bone. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Number of Participants Who Experience an Adverse Event (AE) | An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants who experienced an AE is presented. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is defined as any untoward medical occurrence associated with the use of a drug in a participant, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product and does not imply any judgment about causality. The number of participants who discontinued study treatment due to an AE is presented. | Up to 40 months (through database cut-off date of 12-Dec-2022) | 

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