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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)
Phase 3 trial testing Pembrolizumab in Prostatic Neoplasms in 1,244 participants. Participants enrolled and being followed up; not accepting new ones.
| Lead sponsor | Merck Sharp & Dohme LLC |
|---|---|
| Phase | Phase 3 |
| Status | Active, enrolled |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | triple |
| Primary purpose | treatment |
| Enrollment | 1,244 |
| Start date | 28 July 2019 |
| Primary completion | 12 December 2022 |
| Estimated completion | 29 May 2026 |
| Sites | 259 locations across Italy, Colombia, Japan, Taiwan, Ireland, Poland, South Korea, New Zealand |
Merck Sharp & Dohme LLC — full company profile →
18 and older, male only, with Prostatic Neoplasms. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
OS was defined as the time from randomization to death due to any cause. The OS for all participants is presented.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 24.7 | 22.0 – 26.8 |
| Placebo + Enzalutamide | 27.3 | 24.5 – 30.1 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 10.4 | 8.4 – 12.5 |
| Placebo + Enzalutamide | 9.0 | 8.3 – 11.5 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 13.2 | 11.7 – 15.7 |
| Placebo + Enzalutamide | 12.6 | 11.3 – 14.2 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 49.0 | 44.9 – 53.1 |
| Placebo + Enzalutamide | 45.1 | 41.1 – 49.2 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 13.1 | 10.5 – 16.1 |
| Placebo + Enzalutamide | 12.6 | 10.0 – 15.5 |
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).
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 12.2 | 9.8 – 15.1 |
| Placebo + Enzalutamide | 9.3 | 7.1 – 11.9 |
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-limi
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 16.1 | 1.4 – 35.3 |
| Placebo + Enzalutamide | 21.5 | 0.0 – 35.3 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 6.4 | 5.5 – 7.1 |
| Placebo + Enzalutamide | 5.6 | 4.9 – 6.9 |
Time from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 20.7 | 18.0 – 30.1 |
| Placebo + Enzalutamide | 26.3 | 17.8 – NA |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | NA | 23.3 – NA |
| Placebo + Enzalutamide | NA | NA – NA |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | NA | NA – NA |
| Placebo + Enzalutamide | NA | NA – NA |
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.
| Group | Value | 95% CI |
|---|---|---|
| Pembrolizumab + Enzalutamide | 594 | |
| Placebo + Enzalutamide | 596 |
Time frame: Up to 40 months (through database cut-off date of 12-Dec-2022). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Pembrolizumab + Enzalutamide | Placebo + Enzalutamide | Pembrolizumab + Enzalutami… |
|---|---|---|---|---|
| Pneumonia | Infections and infestations | — | — | — |
| Urinary tract infection | Infections and infestations | — | — | — |
| Spinal cord compression | Nervous system disorders | — | — | — |
| Haematuria | Renal and urinary disorders | — | — | — |
| Pyrexia | General disorders | — | — | — |
| Urosepsis | Infections and infestations | — | — | — |
| Anaemia | Blood and lymphatic system disorders | — | — | — |
| COVID-19 pneumonia | Infections and infestations | — | — | — |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Cardiac failure | Cardiac disorders | — | — | — |
| COVID-19 | Infections and infestations | — | — | — |
| Subdural haematoma | Injury, poisoning and procedural complications | — | — | — |
| Rash maculo-papular | Skin and subcutaneous tissue disorders | — | — | — |
| Spinal compression fracture | Injury, poisoning and procedural complications | — | — | — |
| Pathological fracture | Musculoskeletal and connective tissue disorders | — | — | — |
| Acute kidney injury | Renal and urinary disorders | — | — | — |
| Urinary retention | Renal and urinary disorders | — | — | — |
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Adrenal insufficiency | Endocrine disorders | — | — | — |
| Colitis | Gastrointestinal disorders | — | — | — |
| Alanine aminotransferase increased | Investigations | — | — | — |
| Hyponatraemia | Metabolism and nutrition disorders | — | — | — |
| Back pain | Musculoskeletal and connective tissue disorders | — | — | — |
| Cerebrovascular accident | Nervous system disorders | — | — | — |
| Reaction | System | Pembrolizumab + Enzalutamide | Placebo + Enzalutamide | Pembrolizumab + Enzalutami… |
|---|---|---|---|---|
| Fatigue | General disorders | — | — | — |
| Arthralgia | Musculoskeletal and connective tissue disorders | — | — | — |
| Decreased appetite | Metabolism and nutrition disorders | — | — | — |
| Anaemia | Blood and lymphatic system disorders | — | — | — |
| Rash | Skin and subcutaneous tissue disorders | — | — | — |
| Nausea | Gastrointestinal disorders | — | — | — |
| Back pain | Musculoskeletal and connective tissue disorders | — | — | — |
| Diarrhoea | Gastrointestinal disorders | — | — | — |
| Constipation | Gastrointestinal disorders | — | — | — |
| Asthenia | General disorders | — | — | — |
| Pruritus | Skin and subcutaneous tissue disorders | — | — | — |
| Weight decreased | Investigations | — | — | — |
| Hypothyroidism | Endocrine disorders | — | — | — |
| Hypertension | Vascular disorders | — | — | — |
| Pain in extremity | Musculoskeletal and connective tissue disorders | — | — | — |
| Headache | Nervous system disorders | — | — | — |
| Vomiting | Gastrointestinal disorders | — | — | — |
| COVID-19 | Infections and infestations | — | — | — |
| Bone pain | Musculoskeletal and connective tissue disorders | — | — | — |
| Insomnia | Psychiatric disorders | — | — | — |
| Hot flush | Vascular disorders | — | — | — |
| Oedema peripheral | General disorders | — | — | — |
| Pyrexia | General disorders | — | — | — |
| Urinary tract infection | Infections and infestations | — | — | — |
| Dizziness | Nervous system disorders | — | — | — |
| Haematuria | Renal and urinary disorders | — | — | — |
| Rash maculo-papular | Skin and subcutaneous tissue disorders | — | — | — |
| Aspartate aminotransferase increased | Investigations | — | — | — |
| Cough | Respiratory, thoracic and mediastinal disorders | — | — | — |
| Abdominal pain | Gastrointestinal disorders | — | — | — |
| Alanine aminotransferase increased | Investigations | — | — | — |
| Myalgia | Musculoskeletal and connective tissue disorders | — | — | — |
| Fall | Injury, poisoning and procedural complications | — | — | — |
| Blood alkaline phosphatase increased | Investigations | — | — | — |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | — | — | — |
| Dry skin | Skin and subcutaneous tissue disorders | — | — | — |
| Blood creatinine increased | Investigations | — | — | — |
| Hyponatraemia | Metabolism and nutrition disorders | — | — | — |
Most-reported serious reactions: Pneumonia, Urinary tract infection, Spinal cord compression, Haematuria, Pyrexia, Urosepsis, Anaemia, COVID-19 pneumonia.
Data from ClinicalTrials.gov NCT03834493 adverse events section.
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.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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