Phase III study of pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): KEYNOTE-991.

Abstract

TPS5595 Background: Pembro, an anti–PD-1 antibody, has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enza may be pro-immunogenic, we hypothesized that combining pembro and enza could show additive or synergistic antitumor activity. Furthermore, pembro + enza previously showed antitumor activity in pts with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573) and in pts with mCRPC for whom enza monotherapy failed (KEYNOTE 199, NCT02787005). These data warrant further evaluation of the combination of pembro + enza when given at the initiation of ADT. Methods: KEYNOTE-991 (NCT04191096) is a phase III trial to evaluate the efficacy and safety of enza + ADT + either pembro or placebo in patients with mHSPC. Approximately 1232 pts will be randomly assigned 1:1 to receive enza 160 mg orally once daily + ADT + pembro 200 mg IV every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. ADT is receipt of an LHRH agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Pts with mHSPC, with ≥2 bone lesions and/or visceral disease, who are naive to next-generation hormone agents, and who have ECOG PS 0 or 1 are eligible. Pts must provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Treatment will continue with pembro for up to 35 cycles, and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. Dual primary end points are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by BICR and overall survival. Secondary end points are time to first subsequent anticancer therapy, time to symptomatic skeletal-related event, PFS2 (progression after next line of therapy or death), prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, and time to radiographic soft tissue progression. Other end points are safety and patient-reported outcomes (eg, time to pain progression). Clinical trial information: NCT04191096 .