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)

• ClinicalTrials.gov Identifier: NCT03834493
• Recruitment Status: Active, not recruiting
• First Posted: February 8, 2019
• Last Update Posted: May 31, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: February 6, 2019
• First Posted Date: February 8, 2019
• Last Update Posted Date: May 31, 2023
• Actual Study Start Date: July 28, 2019
• Actual Primary Completion Date: December 12, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2023)

• Overall Survival (OS) [ Time Frame: Up to ~ 41 months ]
  Time from randomization to death due to any cause
• 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 [ Time Frame: Up to ~ 41 months ]
  Time from randomization to radiographic progression, or death due to any cause, whichever occurs first

Original Primary Outcome Measures (submitted: February 6, 2019)

• Overall Survival (OS) [ Time Frame: Up to approximately 52 months ]
  Time from randomization to death due to any cause
• 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 [ Time Frame: Up to approximately 52 months ]
  Time from randomization to radiographic progression, or death due to any cause, whichever occurs first

Current Secondary Outcome Measures (submitted: May 29, 2023)

• Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST) [ Time Frame: Up to ~ 46 months ]
  Time from randomization to initiation of the first subsequent anti-cancer therapy or death, whichever occurs first
• Prostate-specific Antigen (PSA) Response Rate [ Time Frame: Up to ~ 46 months ]
  Percentage of participants in the analysis population who have a negative change (decrease) in PSA level of ≥50% measured twice ≥3 weeks apart
• Prostate-specific Antigen (PSA) Undetectable Rate [ Time Frame: Up to ~ 46 months ]
  Percentage of participants in the analysis population with PSA <0.2 ng/mL during study treatment
• Objective Response Rate (ORR) 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 [ Time Frame: Up to ~ 46 months ]
  Percentage of participants in the analysis population who have a best overall response of either confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified RECIST 1.1
• Duration of Response (DOR) 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 [ Time Frame: Up to ~ 46 months ]
  Time from first documented evidence of confirmed Complete Response (CR) or Partial Response (PR) per PCWG-modified RECIST 1.1 until disease progression or death from any cause, whichever occurs first
• Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: Up to ~ 46 months ]
  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
• 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) as Assessed by Blinded Independent Central Review [ Time Frame: Up to ~ 46 months ]
  Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1
• 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 Frame: Up to ~ 46 months ]
  Time from randomization to pain progression. In this study, pain progression will be 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
• Time to First Symptomatic Skeletal-related Event (SSRE) [ Time Frame: Up to ~ 46 months ]
  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
• Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to ~ 53 months ]
  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
• Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to ~ 53 months ]
  The number of participants who discontinue study treatment due to an AE will be presented

Original Secondary Outcome Measures (submitted: February 6, 2019)

• Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST) [ Time Frame: Up to approximately 52 months ]
  Time from randomization to initiation of the first subsequent anti-cancer therapy or death, whichever occurs first
• Prostate-specific Antigen (PSA) Response Rate [ Time Frame: Up to approximately 52 months ]
  Percentage of participants in the analysis population who have a negative change (decrease) in PSA level of ≥50% measured twice ≥3 weeks apart
• Prostate-specific Antigen (PSA) Undetectable Rate [ Time Frame: Up to approximately 52 months ]
  Percentage of participants in the analysis population with PSA <0.2 ng/mL during study treatment
• Objective Response Rate (ORR) 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 [ Time Frame: Up to approximately 52 months ]
  Percentage of participants in the analysis population who have a best overall response of either confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified RECIST 1.1
• Duration of Response (DOR) 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 [ Time Frame: Up to approximately 52 months ]
  Time from first documented evidence of confirmed Complete Response (CR) or Partial Response (PR) per PCWG-modified RECIST 1.1 until disease progression or death from any cause, whichever occurs first
• Time to Prostate-specific Antigen (PSA) Progression [ Time Frame: Up to approximately 52 months ]
  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
• 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) as Assessed by Blinded Independent Central Review [ Time Frame: Up to approximately 52 months ]
  Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1
• 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 Frame: Up to approximately 52 months ]
  Time from randomization to pain progression. In this study, pain progression will be 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
• Time to First Symptomatic Skeletal-related Event (SSRE) [ Time Frame: Up to approximately 52 months ]
  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
• Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 52 months ]
  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
• Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 52 months ]
  The number of participants who discontinue study treatment due to an AE will be presented

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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)

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

Study became unblinded in February 2023.

Primary Purpose: Treatment

• Condition: Prostatic Neoplasms

Intervention

• Biological: Pembrolizumab
  IV infusion
  Other Names:

  • KEYTRUDA®
  • MK-3475
• Drug: Enzalutamide
  Capsules/Tablets
  Other Name: XTANDI®
• Drug: Placebo
  IV infusion
  Other Name: Normal saline or dextrose infusion

Study Arms

• Experimental: Pembrolizumab + Enzalutamide
  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.
  Interventions:

  • Biological: Pembrolizumab
  • Drug: Enzalutamide
• Placebo Comparator: Placebo + Enzalutamide
  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.
  Interventions:

  • Drug: Enzalutamide
  • Drug: Placebo

• Publications *: Graff JN, Liang LW, Kim J, Stenzl A. KEYNOTE-641: a Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer. Future Oncol. 2021 Aug;17(23):3017-3026. doi: 10.2217/fon-2020-1008. Epub 2021 May 28.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 26, 2023): 1244
• Original Estimated Enrollment (submitted: February 6, 2019): 1200
• Estimated Study Completion Date: December 28, 2023
• Actual Primary Completion Date: December 12, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Chile, Colombia, Czechia, France, Germany, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, New Zealand, Poland, Puerto Rico, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03834493
• Other Study ID Numbers: 3475-641; MK-3475-641 ( Other Identifier: Merck Protocol Number ); KEYNOTE-641 ( Other Identifier: Merck ); 195005 ( Registry Identifier: JAPIC-CTI ); 2022-500785-10-00 ( Registry Identifier: EU CT ); 2018-004117-40 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: May 2023