Article Text

Download PDFPDF

346 KEYNOTE-991: phase 3 study of pembrolizumab plus enzalutamide and androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC)
  1. Christian Gratzke1,
  2. Christian Gratzke1,
  3. Christian Gratzke1,
  4. Cuizhen Niu2,
  5. Christian Poehlein3 and
  6. Joseph Burgents3
  1. 1University Medical Center Freiburg, Freiburg, Germany
  2. 2MSD China, Beijing, China
  3. 3Merck and Co., Inc., Rahway, NJ, USA


Background Combination of pembrolizumab, an anti–PD-1 antibody, added to enzalutamide, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant mCRPC (KEYNOTE-365, NCT02861573) and in patients with mCRPC for whom enzalutamide was ineffective (KEYNOTE-199, NCT02787005). These data indicate that the combination of pembrolizumab + enzalutamide with ADT warrants phase 3 evaluation. Also, efficacy in enzalutamide may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembrolizumab.

Methods The KEYNOTE-991 (NCT04191096) phase 3 trial will evaluate the efficacy and safety of enzalutamide + ADT (LHRH agonist/antagonist during study treatment or bilateral orchiectomy) + pembrolizumab or placebo in patients with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Patients must provide tissue for biomarker analysis. Approximately 1232 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg orally once daily + ADT + pembrolizumab 200 mg IV every 3 weeks (Q3W) or enzalutamide 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembrolizumab up to 35 cycles and treatment with enzalutamide will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). CT or MRI and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q12W from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The co-primary end points are BICR-assessed radiographic PFS (according to PCWG3-modified RECIST v1.1) and OS. Key secondary end points are time to first subsequent anticancer therapy and time to symptomatic skeletal-related event. Other end points are PFS2 (progression after next line of therapy or death), PSA response rate, time to PSA progression, PSA undetectable rate, ORR, duration of response, time to soft tissue and radiographic bone progression per PCWG3-modified RECIST v1.1, safety, and patient-reported outcomes (eg, time to pain progression). Safety and tolerability will be evaluated using a tiered approach. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States.

Results N/A

Conclusions N/A

Trial Registration ClinicalTrials. gov: NCT04191096

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

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.