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ASCO 2020

ASCO 2020: Phase III Study of Pembrolizumab plus Enzalutamide and ADT for Patients with Metastatic Hormone-Sensitive Prostate Cancer: KEYNOTE-991

(UroToday.com) Pembrolizumab is an anti–PD-1 antibody that has shown antitumor activity as monotherapy and in combination with other agents in metastatic castration-resistant prostate cancer (mCRPC). As the antitumor effects of enzalutamide may be pro-immunogenic, it is hypothesized that combining pembrolizumab and enzalutamide could show additive or synergistic antitumor activity. Furthermore, pembrolizumab plus enzalutamide previously showed antitumor activity in patients with mCRPC for whom abiraterone failed (KEYNOTE-365, NCT02861573)1 and in patients with mCRPC for whom enzalutamide monotherapy failed (KEYNOTE 199, NCT02787005).2 As such, these data warrant further evaluation of the combination of pembrolizumab plus enzalutamide when given at the initiation of ADT. At the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Dr. Christian Gratzke and colleagues discussed the trial design for the important phase III KEYNOTE-991 study.

KEYNOTE-991 (NCT04191096) is a Phase III trial to evaluate the efficacy and safety of enzalutamide + ADT + either pembrolizumab or placebo in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Approximately 1,232 patients will be randomly assigned 1:1 to receive enzalutamide 160 mg orally once daily + ADT + pembrolizumab 200 mg IV every three weeks versus enzalutamide 160 mg orally once daily + ADT + placebo 200 mg IV every three weeks. The trial design for KEYNOTE-991 is as follows:

trial design for KEYNOTE 991

ADT is defined as the receipt of a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist during study treatment or bilateral orchiectomy. Treatment will be stratified by prior docetaxel therapy (yes or no) and the presence of high-volume disease (yes or no). High-volume disease is defined as the presence of visceral metastases or ≥ 4 bone lesions with ≥ 1 beyond the vertebral bodies or pelvis. Patients with mHSPC with ≥ 2 bone lesions and/or visceral disease who are naïve to next-generation hormone agents and who have ECOG performance status 0 or 1 are eligible. Additionally, patients 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 every 12 weeks starting from the date of randomization. Treatment will continue with pembrolizumab for 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 dual primary endpoints are radiographic progression-free survival (PFS) per PCWG3-modified RECIST v1.1 assessed by blinded independent central review and overall survival.

Secondary endpoints 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
  • Time to radiographic soft tissue progression.

Other endpoints are safety and patient-reported outcomes (ie. time to pain progression). KEYNOTE-991 is currently enrolling at 40 sites in Australia, Chile, Columbia, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States.

Clinical trial information: NCT04191096.

Presented by: Christian Gratzke, MD, University Medical Center Freiburg, Freiburg, Germany

Co-Authors: Joseph E Burgents, Cuizhen Niu, Christian Heinrich Poehlein, Charles G. Drake; Merck & Co., Inc., Kenilworth, NJ; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Augusta, Georgia, Twitter: @zklaassen_md, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020   

References:

  1. Fong JC, et al. J Clin Oncol 2019;37(supple 7): Abstract 171
  2. Graff, Julie Nicole, Emmanuel S. Antonarakis, Christopher J. Hoimes, Scott T. Tagawa, Clara Hwang, Deepak Kilari, A. J. Ten Tije et al. "Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4-5." (2020): 15-15.