Background Antitumor activity with pembrolizumab + enzalutamide was observed in cohort C of the phase 1b/2 KEYNOTE-365 (NCT02861573) study of abiraterone acetate–pretreated patients with mCRPC and in a phase 2 study (NCT02312557) of patients with mCRPC who experienced progression with enzalutamide alone. In KEYNOTE-365 cohort C, prostate-specific antigen (PSA) response rate was 22%, objective response rate (ORR) was 20%, and 12-month PFS and OS rates were 24.6% and 72.8%, respectively. Safety and tolerability of the combination was consistent with individual profiles of each agent. In the phase 2 study of enzalutamide-pretreated patients, 5 of 28 patients (18%) had a PSA decline of ≥50%, and 3 of 12 patients (25%) with measurable disease achieved objective response. KEYNOTE-641 (NCT03834493) is a randomized, phase 3 trial to assess efficacy and safety of pembrolizumab + enzalutamide versus placebo + enzalutamide in patients with mCRPC.

Methods Enrolled patients have biochemical or radiographic progression with androgen deprivation therapy/after bilateral orchiectomy within 6 months of screening, ECOG PS 0/1, ongoing androgen deprivation with serum testosterone <50 ng/dL, and tumor tissue availability for biomarker analysis. The study continues to enroll those who previously had abiraterone acetate therapy; the abiraterone-naive cohort is filled. Exclusion criteria are prior chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor. Treatment stratification factors are prior abiraterone acetate treatment (yes or no), metastases location (bone only or liver or other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes or no). Response and progression will be determined by imaging (CT/MRI/bone) per PCWG3–modified RECIST v1.1 on visits Q9W during the first year and Q12W thereafter. Approximately 1200 adults will be randomly assigned 1:1 in a double-blind fashion to receive enzalutamide 160 mg orally once daily + pembrolizumab 200 mg IV Q3W or enzalutamide 160 mg orally once daily + placebo for a maximum of 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Coprimary end points are radiographic PFS per PCWG3-modified RECIST v1.1, as assessed by blinded independent central review, and OS. The key secondary end point is time to subsequent anticancer therapy or death. Other secondary end points are ORR, DOR, PSA response rate, PSA undetectable rate, time to PSA progression, time to pain progression, time to symptomatic skeletal-related event, time to soft tissue progression, and safety. KEYNOTE-641 is ongoing or planned in 21 countries across Asia, Australia, Europe, and North and South America.

Results N/A

Conclusions N/A

Trial Registration ClinicalTrials. gov, NCT03834493

Ethics Approval The study and the protocol were approved by the Institutional Review Board or ethics committee at each site.