KEYNOTE-641: Phase III study of pembrolizumab (pembro) plus enzalutamide for metastatic castration-resistant prostate cancer (mCRPC)

Abstract

Background: Treatment options for patients (pts) withmCRPC are noncurative, and life expectancy is only about 3 y. Enzalutamide plus the programmed death 1 (PD-1) inhibitor pembro showed activity in abiraterone-pretreated pts withmCRPC in the phase 1b/2 KEYNOTE-365 (NCT02861573) study. In another study (NCT02312557) some pts had profound anticancer response to pembro plus enzalutamide that lasted years. KEYNOTE-641 (NCT03834493) is a randomized phase 3 trial to evaluate efficacy and safety of pembro plus enzalutamide vs placebo plus enzalutamide for pts withmCRPC. Trial design: Adults (a[per mille sign][yen]18 y) with histologically or cytologically confirmed prostate cancer and mCRPC with biochemical or radiographic progression are eligible. Pts who received chemotherapy for mCRPC, checkpoint inhibition, or any treatment with a second-generation androgen receptor inhibitor (eg, enzalutamide, apalutamide, or darolutamide) are excluded. Pts intolerant to or progressed on prior abiraterone therapy were included. Pts must have ECOG PS 0/1, adequate organ function, and tissue for biomarker analysis. Approximately 1200 pts will be randomly assigned 1:1 to receive enzalutamide 160 mg/d plus pembro 200 mg Q3W or enzalutamide 160 mg/d plus placebo. Treatment will be stratified per prior abiraterone treatment (yes/no), metastases (bone only/liver/other), and prior docetaxel treatment for metastatic hormone-sensitive prostate cancer (yes/no). Responses will be assessed by CT/MRI and radionuclide bone imaging per PCWG-modified RECIST v1.1 every 9 wk during the first year and every 12 wk thereafter. Treatment will continue with enzalutamide plus pembro/placebo until radiographic disease progression, unacceptable toxicity, or consent withdrawal, with a maximum of 2 yr of treatment for the pembro/placebo component of the combination. Primary end points: overall survival and radiographic progressionfree survival by blinded independent central review. Key secondary efficacy end point is time to subsequent anticancer therapy or death; safety and tolerability will also be reported.