Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study

Julie N Graff¹, Christopher J Hoimes^{2

3}, Winald R Gerritsen⁴, Ulka N Vaishampayan⁵, Tony Elliott⁶, Clara Hwang⁷, Albert J Ten Tije⁸, Aurelius Omlin⁹, Raymond S McDermott¹⁰, Yves Fradet¹¹, Scott T Tagawa¹², Deepak Kilari¹³, Cristiano Ferrario¹⁴, Hiroji Uemura¹⁵, Robert J Jones¹⁶, Satoshi Fukasawa¹⁷, Avivit Peer¹⁸, Cuizhen Niu¹⁹, Christian H Poehlein²⁰, Ping Qiu²⁰, Leah Suttner²⁰, Ronald de Wit²¹, Charles Schloss²⁰, Johann S de Bono²², Emmanuel S Antonarakis^{23

24}

Affiliations

¹ Oregon Health and Science University, Portland, OR, USA. graffj@ohsu.edu.
² Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
³ Duke University School of Medicine, Durham, NC, USA.
⁴ Radboud University Medical Center, Nijmegen, Netherlands.
⁵ University of Michigan and Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
⁶ NHS Lothian, Edinburgh, UK.
⁷ Henry Ford Health System, Detroit, MI, USA.
⁸ Amphia Hospital, Breda, Netherlands.
⁹ Onkozentrum Zurich, University of Zurich and Tumorzentrum Hirslanden Zurich, Zurich, Switzerland.
¹⁰ Tallaght University Hospital, Dublin, Ireland.
¹¹ CHU de Québec-Université Laval, Québec City, QC, Canada.
¹² Weill Cornell Medical College, New York, NY, USA.
¹³ Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁴ Jewish General Hospital, Montreal, QC, Canada.
¹⁵ Yokohama City University Medical Center, Yokohama, Japan.
¹⁶ University of Glasgow, Glasgow, UK.
¹⁷ Chiba Cancer Center, Chiba, Japan.
¹⁸ Rambam Health Care Campus, Haifa, Israel.
¹⁹ MSD China, Beijing, China.
²⁰ Merck & Co., Inc., Rahway, NJ, USA.
²¹ Erasmus University Medical Center, Rotterdam, Netherlands.
²² The Royal Marsden Hospital NHS Foundation Trust and the Institute of Cancer Research, London, UK.
²³ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
²⁴ University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA.

PMID: 39134652
DOI: 10.1038/s41391-024-00865-5

Clinical Trial

Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study

Julie N Graff et al. Prostate Cancer Prostatic Dis. 2025 Jun.

. 2025 Jun;28(2):411-418.

doi: 10.1038/s41391-024-00865-5. Epub 2024 Aug 12.

Authors

Affiliations

¹ Oregon Health and Science University, Portland, OR, USA. graffj@ohsu.edu.
² Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
³ Duke University School of Medicine, Durham, NC, USA.
⁴ Radboud University Medical Center, Nijmegen, Netherlands.
⁵ University of Michigan and Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
⁶ NHS Lothian, Edinburgh, UK.
⁷ Henry Ford Health System, Detroit, MI, USA.
⁸ Amphia Hospital, Breda, Netherlands.
⁹ Onkozentrum Zurich, University of Zurich and Tumorzentrum Hirslanden Zurich, Zurich, Switzerland.
¹⁰ Tallaght University Hospital, Dublin, Ireland.
¹¹ CHU de Québec-Université Laval, Québec City, QC, Canada.
¹² Weill Cornell Medical College, New York, NY, USA.
¹³ Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁴ Jewish General Hospital, Montreal, QC, Canada.
¹⁵ Yokohama City University Medical Center, Yokohama, Japan.
¹⁶ University of Glasgow, Glasgow, UK.
¹⁷ Chiba Cancer Center, Chiba, Japan.
¹⁸ Rambam Health Care Campus, Haifa, Israel.
¹⁹ MSD China, Beijing, China.
²⁰ Merck & Co., Inc., Rahway, NJ, USA.
²¹ Erasmus University Medical Center, Rotterdam, Netherlands.
²² The Royal Marsden Hospital NHS Foundation Trust and the Institute of Cancer Research, London, UK.
²³ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
²⁴ University of Minnesota, Masonic Cancer Center, Minneapolis, MN, USA.

PMID: 39134652
DOI: 10.1038/s41391-024-00865-5

Abstract

Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented.

Methods: Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined.

Results: A total of 126 patients were treated (C4, n = 81; C5, n = 45). Median age was 72 years (range 43-92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1-21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7-64.3%) in C4 and 51.1% (95% CI 35.8-66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0-22.6) in C4 and 20.8 months (95% CI 14.1-28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome).

Conclusions: The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile.

Clinical trial registry and id: ClinicalTrials.gov, NCT02787005.

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Conflict of interest statement

Competing interests: The authors report the following competing interests. AO has received institutional funding for service as an advisor/consultant for AstraZeneca, Astellas, Bayer, Janssen, Molecular Partners, MSD, Myriad, Pfizer, Roche, and Sanofi Aventis; has received personal fees for service as an advisor/consultant for Astellas, AstraZeneca, Bayer, Janssen, Merck & Co., Inc., MSD, and Novartis; has received institutional funding for serving as a speaker for Astellas, AstraZeneca, Bayer, Janssen, and MSD; has received institutional research funding from Janssen and TEVA; and has received travel, accommodations, or expenses from Astellas, Bayer, Janssen, and Sanofi Aventis. AP has received honoraria from Bristol Myers Squibb, MSD, and Pfizer; has received personal fees for service as an advisor/consultant for Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Medison Pharma, MSD, Pfizer, and Roche; and has received travel, accommodations, or expenses from Astellas, AstraZeneca, Bristol Myers Squibb, and Pfizer. AJtT, SF, and TE declare no conflicts of interest. CJH has received personal fees for service as an advisor/consultant for Astellas, Bristol Myers Squibb, Dynavax, Foundation Medicine, Merck & Co., Inc., Seagen, and Tempus; has received personal fees for service as an invited speaker from Bristol Myers Squibb and Eisai; has served as a steering committee member for Merck & Co., Inc. and Seagen (no financial interest); and has received institutional research funding from AbbVie, Alkermes, Astellas, Bayer, Bellicum, BioNTech, Bristol Myers Squibb, Dynavax, Genentech, Janssen, Mirati, NeoImmune Tech, Pfizer, Phosplatin, and Prometheus. CF has received honoraria from Astellas Pharma, AstraZeneca, Bayer, Knights Therapeutics, Merck & Co., Inc., Novartis, Pfizer, and Roche Canada; has received personal fees for service as an advisor/consultant for AstraZeneca, Merck & Co., Inc., Novartis, and Roche; has received personal fees for service as a speaker for AstraZeneca, Knights Therapeutics, Merck & Co., Inc., and Novartis; has received personal fees for expert testimony from Seattle Genetics/Astellas; and has received institutional research funding from Astellas Pharma, AstraZeneca, Bayer, Immunomedics, Janssen Oncology, Lilly, Merck & Co., Inc., Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Sermonix Pharmaceuticals, and Zymeworks. CH has received personal fees for service as an advisor/consultant for EMD Serono, Genzyme, and Tempus; holds stock in Johnson and Johnson; has received research funding from AstraZeneca, Bausch Health, Bayer, Exelixis, Genentech, Merck & Co., Inc., and Seagen; and has received travel, accommodations, or expense from Bayer, Dendreon, Genentech, Janssen, and Merck & Co., Inc. CN is an employee of MSD China. CHP, CS, and PQ are employees of and own stock in Merck & Co., Inc. DK has received honoraria from Exelixis and Pfizer; has received personal fees for service as an advisor/consultant for Aveo, Eisai, Exelixis, Merck & Co., Inc., Myovant, and Sanofi; and has received personal fees for service as a speaker for Aveo, Janssen, MJH life science, Sanofi, and Seagen. ESA has received personal fees for service as an advisor/consultant for Aadi Bioscience, Aikido Pharma, Amgen, AstraZeneca, Bayer, Blue Earth Diagnostics, CM Propel, Corcept Therapeutics, EcoR1, Foundation Medicine, Hookipa Pharma, Ismar, Janssen, KeyQuest Health, MacroGenics, Menarini Silicon Biosystems, Merck & Co., Inc., Sanofi, Tempus, UroWebinar, and Z-Alpha; has received institutional research funding from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Constellation Pharma, Merck & Co., Inc., and Sanofi; has received travel, accommodations, or expense from Sanofi; and holds patents with Qiagen. HU has received honoraria from AstraZeneca, Astellas, Bayer, Janssen, Sanofi, and Takeda; has received personal fees for service as an advisor/consultant for Astellas, Bayer, Janssen, and Sanofi. JSdB has received personal fees for service as an advisor/consultant from Amgen, AstraZeneca, Astellas, Bayer, Bioxcel Therapeutics, Daiichi, Genentech/Roche, GSK, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Pfizer, and Sanofi Aventis; has received institutional research funding from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex; and was named as an inventor (without financial interest) for patent 8,822,438 submitted by Janssen that covers the use of abiraterone acetate with corticosteroids. The Institute of Cancer Research has a commercial interest in abiraterone and PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). JSdB is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. JNG has received institutional funding from Astellas, Clovis, Curium, Janssen, Merck & Co., Inc., Pfizer, and Sanofi; and has served as a non-remunerated consultant for Curium, Janssen, and Merck & Co., Inc. LS is an employee of and owns stock in Merck & Co., Inc., and has an immediate family member who is an employee of and owns stock in Bristol Myers Squibb. RdW has received personal fees for service as an advisor/consultant for Astellas, Bayer, Hengrui, Merck & Co., Inc., and Orion; and has received institutional research funding from Bayer. RJJ has received personal fees for service as an advisor/consultant and as a speaker for Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Janssen, Ipsen, Merck Serono, MSD, Novartis/AAA, and Pfizer; has received travel, accommodations, or expenses from Bayer, Bristol Myers Squibb, Ipsen, and MSD; and has received research funding from Astellas, AstraZeneca, Clovis, Exelixis, and Roche. RSM has received honoraria from Astellas, Bayer, Bristol Myers Squibb, Clovis, Ipsen, Janssen, MSD, Novartis, Pfizer, and Sanofi; has received personal fees for service as a speaker for MSD; has received institutional research funding from Bayer, Bristol Myers Squibb, and MSD; and has received travel, accommodations, or expenses from Ipsen, Janssen, Pfizer, and Roche. STT has received honoraria from AAA/Novartis, AbbVie, AIkido Pharma, Amgen, Astellas, Bayer, Blue Earth, Clarity, Clovis, Convergent Therapeutics, Daiichi Sankyo, Dendreon, EMD Serono, Endocyte, Eisai, Genentech, Genomic Health, Immunomedics, Janssen, Karyopharm, Medivation, Merck & Co., Inc., Myovant, Pfizer, POINT Biopharma, QED, Sanofi, Seattle Genetics, Tolmar, and Telix Pharma; has received institutional funding from AbbVie, Ambrx Amgen, Astellas, AstraZeneca, Atlab, Aveo, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Dendreon, Endocyte, Genentech, Gilead, Immunomedics, Inovio, Janssen, Karyopharm, Lilly, Medivation, Merck & Co., Inc., Millennium, Newlink, Novartis, POINT Biopharma, Progenics, Rexahn, Sanofi, and Seattle Genetics; and has patents, licensing, royalties, or other intellectual property with Gilead. UNV has received personal fees for service as an advisor/consultant from Aldermes, Bristol Myers Squibb, Exelixis, Gilead, Merck & Co., Inc., Novartis, Pfizer, and Seagen; has received personal fees for service as a speaker for Bayer, Exelixis, and Genzyme; has received research funding from Merck & Co., Inc., and Bristol Myers Squibb; and serves as a board member for the Michigan Society of Hematology/Oncology. WRG has received institutional funding for service as an advisor/consultant for Bayer, Bristol Myers Squibb, and MSD; and has received personal fees and institutional funding for service as a speaker for Bayer and MSD. YF has received honoraria from Astellas, Ferring, Janssen, TerSera, and Tolmar; has received personal fees for service as an advisor/consultant for Astellas, AstraZeneca, Ferring, Janssen, Merck & Co., Inc., TerSera, and Tolmar; has received travel, accommodations, or expenses from TerSera; and has received institutional funding from IMVinc, Merck & Co., Inc., and TerSera.

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Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study

Affiliations

Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Associated data

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