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)

Merck Sharp & Dohme (MSD)

Status and phase: Active, not recruiting; Phase 3

Conditions: Prostatic Neoplasms

Treatments: Drug: Placebo; Biological: Pembrolizumab; Drug: Enzalutamide

Study type: Interventional

Funder types: Industry

Identifiers

NCT03834493

2022-500785-10-00 (Registry Identifier)

MK-3475-641 (Other Identifier)

3475-641

KEYNOTE-641 (Other Identifier)

2018-004117-40 (EudraCT Number)

195005 (Registry Identifier)

Details and patient eligibility

About

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.

Enrollment: 1,244 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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1,244 participants in 2 patient groups, including a placebo group

Pembrolizumab + Enzalutamide

Experimental group

Description:

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.

Treatment:

Drug: Enzalutamide

Biological: Pembrolizumab

Placebo + Enzalutamide

Placebo Comparator group

Description:

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.

Treatment:

Drug: Enzalutamide

Drug: Placebo