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)

The primary objective of this Phase 3, randomized, double-blind trial is to compare **pembrolizumab** plus **enzalutamide** versus placebo plus enzalutamide in participants with **metastatic castration-resistant prostate cancer** (mCRPC) with respect to overall survival (OS) and radiographic progression-free survival (rPFS) as assessed by blinded independent central review (BICR) using Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). These endpoints are clinically relevant as they provide critical insights into the efficacy of the treatment regimen in prolonging life and delaying disease progression in a challenging patient population.

Secondary objectives include:

• Comparing the time to initiation of the first subsequent anti-cancer therapy or death (TFST).
• Evaluating prostate-specific antigen (PSA) response rate, PSA undetectable rate, and objective response rate (ORR) and duration of response (DOR) per PCWG-modified RECIST 1.1 as assessed by BICR.
• Assessing time to PSA progression, time to first symptomatic skeletal-related event (SSRE), time to radiographic soft tissue progression, and time to pain progression (TTPP) based on Brief Pain Inventory-Short Form (BPI-SF) and opiate analgesic use.
• Evaluating the safety and tolerability of pembrolizumab plus enzalutamide versus placebo plus enzalutamide.

The clinical trial involves a total of **744 participants** diagnosed with **metastatic castration-resistant prostate cancer**. The study population is exclusively male, as the condition is specific to males, with an age range that includes both middle-aged and older adults. Participants were selected based on specific criteria, including histologically- or cytologically-confirmed adenocarcinoma of the prostate, evidence of prostate cancer progression while on androgen deprivation therapy, and current evidence of metastatic disease. The trial does not include a vulnerable population, and participants are required to have ongoing androgen deprivation with serum testosterone levels below 50 ng/dL. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to compare the efficacy of pembrolizumab plus enzalutamide versus placebo plus enzalutamide in terms of overall survival and radiographic progression-free survival.

The clinical trial is a **Phase 3, randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of **pembrolizumab** plus **enzalutamide** versus placebo plus enzalutamide in participants with **metastatic castration-resistant prostate cancer**. The trial aims to compare the two treatment regimens with respect to overall survival and radiographic progression-free survival, as assessed by blinded independent central review. The study is expected to run from July 2019 to February 2025, with a maximum treatment period of 36 months for pembrolizumab and 24 months for enzalutamide.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically-confirmed adenocarcinoma of the prostate and evidence of metastatic disease. Following randomization, participants will receive either the investigational treatment or placebo, administered via **intravenous infusion** for pembrolizumab and **oral** administration for enzalutamide. Regular follow-up visits will be conducted to monitor safety, efficacy, and disease progression, with assessments including imaging studies and laboratory tests. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

Participant involvement is expected to last up to 36 months, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Primary endpoints include overall survival and radiographic progression-free survival, while secondary endpoints encompass various measures of treatment response and safety, such as time to initiation of subsequent therapy, prostate-specific antigen response rate, and incidence of adverse events.

The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. Pembrolizumab is an active substance classified as a protein of other origin. It is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 10.4 g over a treatment period of up to 36 months. Pembrolizumab is provided by Merck Sharp & Dohme BV and is identified by the product code MK-3475. The trial aims to evaluate the efficacy of pembrolizumab in combination with enzalutamide compared to a placebo plus enzalutamide in participants with metastatic castration-resistant prostate cancer (mCRPC).

**Enzalutamide** is another experimental medication used in this trial. It is provided in **capsule** form and is administered **orally**. The maximum daily dose of enzalutamide is 160 mg, with a total maximum dose of 116.8 g over a treatment period of up to 24 months. Enzalutamide is classified as a chemical substance and is used in combination with pembrolizumab to assess its impact on overall survival and radiographic progression-free survival in the study participants.

The trial also includes the use of a **placebo** in combination with enzalutamide to serve as a comparator treatment. The placebo is administered in a manner consistent with the active treatments to maintain the double-blind nature of the study. The placebo is used to evaluate the efficacy of the pembrolizumab and enzalutamide combination by providing a baseline for comparison in terms of overall survival and radiographic progression-free survival.

Additionally, **Normal Saline or Dextrose** may be used as a non-experimental treatment in the trial. These solutions are typically used as diluents for intravenous infusions and are administered via **intravenous infusion**. They do not contain active substances and serve as a vehicle for the administration of the experimental medications. The use of these solutions ensures the proper delivery and absorption of the active treatments during the trial.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include **Overall Survival (OS)** and **Radiographic Progression-free Survival (rPFS)**, evaluated according to the 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 (BICR). Secondary endpoints encompass a range of measures, including Time to Initiation of the First Subsequent Anti-Cancer Therapy or Death (TFST), Prostate-specific Antigen (PSA) Response Rate, PSA Undetectable Rate, Objective Response Rate (ORR) per PCWG-modified RECIST 1.1, Duration of Response (DOR) per PCWG-modified RECIST 1.1, Time to PSA Progression, Time to Radiographic Soft Tissue Progression per Soft Tissue Rules of PCWG-modified RECIST 1.1, Time to Pain Progression (TTPP), Time to First Symptomatic Skeletal-Related Event (SSRE), and the number of participants experiencing at least one adverse event (AE) or discontinuing study treatment due to an AE.