Phase 3 Randomized Double-Blind Trial of Pembrolizumab and Enzalutamide with ADT Versus Placebo and Enzalutamide with ADT in Metastatic Hormone-Sensitive Prostate Cancer
- Trial ID
- 2023-507024-24-00
- Protocol
- MK-3475-991
- Sponsor
- Merck Sharp & Dohme LLC
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind trial is to compare the efficacy of **pembrolizumab** (MK-3475) plus **enzalutamide** plus androgen deprivation therapy (ADT) versus placebo plus enzalutamide plus ADT in participants with metastatic hormone-sensitive prostate cancer (mHSPC). The primary endpoints are radiographic progression-free survival (rPFS) as assessed by blinded independent central review (BICR) using PCWG-modified RECIST 1.1 criteria, and overall survival (OS). These endpoints are clinically relevant as they provide insights into the potential of pembrolizumab in delaying disease progression and improving survival outcomes in mHSPC patients.
Secondary objectives include:
- Comparing the treatment regimens with respect to time to first subsequent therapy (TFST) and time to symptomatic skeletal-related event (TTSSRE).
- Assessing the regimens concerning time to prostate-specific antigen (PSA) progression, time to radiographic soft tissue progression, time to pain progression (TTPP), and second progression-free survival (PFS2).
- Evaluating PSA response rate, PSA undetectable rate, overall response rate (ORR), and duration of response (DOR) per PCWG-modified RECIST 1.1.
- Assessing the safety and tolerability of the treatment regimens.
Participants
The clinical trial involves a total of **965 male participants** diagnosed with **metastatic hormone-sensitive prostate cancer**. The study population is exclusively male, with an age range corresponding to categories 3 and 4, indicating adult and elderly participants. Participants were selected based on specific inclusion criteria, including histologically- or cytologically-confirmed adenocarcinoma of the prostate, metastatic disease verified by imaging, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All participants are required to maintain continuous androgen deprivation therapy (ADT) or have a history of bilateral orchiectomy. The trial does not include female subjects or vulnerable populations. Participants' general health status is assessed to ensure adequate organ function, and those receiving bone resorptive therapy must be on stable doses prior to randomization. Lifestyle considerations include the requirement for male participants to agree to specific reproductive precautions during and after the study intervention period.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of **pembrolizumab** plus **enzalutamide** plus androgen deprivation therapy (ADT) compared to placebo plus enzalutamide plus ADT in participants with metastatic hormone-sensitive prostate cancer (mHSPC). The trial aims to assess radiographic progression-free survival (rPFS) and overall survival (OS) as primary endpoints, with secondary endpoints including time to initiation of subsequent anti-cancer therapy, time to symptomatic skeletal-related events, and prostate-specific antigen (PSA) progression, among others. The study is expected to run from March 2020 to July 2026, with participant involvement lasting up to 104 weeks for enzalutamide and 24 weeks for pembrolizumab.
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, metastatic disease verification, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent.
The trial employs a double-blind design to ensure unbiased results, with neither participants nor investigators aware of the treatment allocation. The study involves oral administration of enzalutamide and intravenous infusion of pembrolizumab, with a placebo group receiving a matching regimen. The trial's methodology is structured to provide robust data on the comparative effectiveness of the investigational treatment versus standard care, contributing valuable insights into the management of mHSPC.
Treatment
The clinical trial involves the administration of **enzalutamide**, a chemical compound with the active substance name **ENZALUTAMIDE**. It is provided in a pharmaceutical form identified as PHF00007MIG and is administered orally. The maximum daily dose of enzalutamide is 160 mg, with a total maximum dose of 116,800 mg over a treatment period of up to 104 weeks. The medication is not a pediatric formulation and is classified under the ATC code L02BB04. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Pembrolizumab**, a biological agent with the active substance name **PEMBROLIZUMAB**, is also utilized in this study. It is administered as a solution for infusion via intravenous infusion. The maximum daily dose is 200 mg, with a total maximum dose of 7,000 mg over a treatment period of up to 24 weeks. Pembrolizumab is not a pediatric formulation and is identified by the sponsor product code MK-3475. The administration schedule and participant adherence will be closely monitored during the trial.
A placebo for pembrolizumab is included as a comparator treatment in the study. The placebo is designed to match the pembrolizumab in appearance and administration route but contains no active substance. It serves as a control to evaluate the efficacy and safety of the experimental treatments. The placebo is not a pediatric formulation, and its administration will be monitored to ensure compliance with the study protocol.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Radiographic Progression-free Survival (rPFS)** as per the Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), assessed by Blinded Independent Central Review (BICR), and **Overall Survival (OS)**. These endpoints will provide a comprehensive evaluation of the treatment's impact on disease progression and survival.
Secondary endpoints encompass a range of measures to further assess efficacy. These include Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST), Time to Symptomatic Skeletal-Related Event (TTSSRE), Time to Prostate-specific Antigen (PSA) Progression, and Time to Radiographic Soft Tissue Progression as per PCWG-modified RECIST 1.1, also assessed by BICR. Additional secondary endpoints include Time to Pain Progression (TTPP) as assessed by the Brief Pain Inventory-Short Form (BPI-SF) Item 3, 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, and the number of participants experiencing an Adverse Event (AE) or discontinuing study treatment due to an AE.
The efficacy parameters will be measured and collected at specified timepoints throughout the trial, with assessments conducted by BICR to ensure objectivity and consistency. The use of validated scales and criteria, such as RECIST 1.1 and BPI-SF, will facilitate standardized evaluation of treatment outcomes. The trial is designed to rigorously compare the efficacy of pembrolizumab plus enzalutamide plus ADT against placebo plus enzalutamide plus ADT in participants with metastatic hormone-sensitive prostate cancer (mHSPC).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male Participants with histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
- Has metastatic disease assessed by investigator and verified by BICR by either ≥2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI)
- Willing to maintain continuous ADT with a LHRH agonists or antagonists during study treatment or have a history of bilateral orchiectomy
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization
- Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
- Has adequate organ function
- 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
- Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic
- Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex
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 (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- Has known or suspected 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 had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure
- 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 a history of clinically significant ventricular arrhythmias
- Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
- Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for >39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT
- Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide)
- 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 a live vaccine within 30 days prior to randomization
- Has a "superscan" bone scan
- Has had an allogenic tissue/solid organ transplant
- Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
- Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions: a) Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel b) May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization c) For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization d) Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 10 Mar 2020 | 38 |
 Ireland | Not Recruiting | 10 Mar 2020 | 15 |
 Poland | Not Recruiting | 10 Mar 2020 | 69 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo for pembrolizumab | Placebo | N/A | — | — | — | N/A |
ENZALUTAMIDE | Test | PHF00007MIG | ORAL USE | 160 | 104 | SCP271579 |
PEMBROLIZUMAB | Test | — | INTRAVENOUS INFUSION | 200 | 24 | SUB167136 |