Metastatic Hormone-Sensitive Prostate CancerPhase 3NCT04191096
Efficacy and Safety of Pembrolizumab (MK-3475) Plus Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (MK-3475-991/KEYNOTE-991)
A Phase 3 study testing Pembrolizumab, Enzalutamide and Androgen Deprivation Therapy (ADT) in people with Metastatic Hormone-Sensitive Prostate Cancer, run by Merck Sharp & Dohme LLC at 234 sites in 29 countries.
Trial summary
This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus Androgen Deprivation Therapy (ADT) versus placebo plus enzalutamide plus ADT in participants with mHSPC. Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Metastatic Hormone-Sensitive Prostate Cancer
- What is being tested?
- Pembrolizumab, Enzalutamide and Androgen Deprivation Therapy (ADT)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,251 participants
- Where
- 234 sitesin 29 countries
- Study dates
- 12 Feb 2020to 8 Apr 2026
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male participants with histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
- Has metastatic disease assessed by investigator and verified by BICR by either ≥2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI)
- Willing to maintain continuous Androgen Deprivation Therapy (ADT) with a luteinizing-hormone releasing hormone (LHRH) agonists or antagonists during study treatment or have a history of bilateral orchiectomy
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization
- Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
- Has adequate organ function
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- Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed). Participants with bone only or bone predominant disease may provide a bone biopsy sample
- Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic
- Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex
Who cannot join
- Has a known additional malignancy that is progressing or has required active treatment in the last 3 years
- Has an active autoimmune disease that has required systemic treatment in past 2 years
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
- Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications
- Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules
- Has an active infection (including tuberculosis) requiring systemic therapy
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- Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
- Has known or suspected central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has a history of seizure or any condition that may predispose to seizure
- Has a history of loss of consciousness within 12 months of screening
- Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure
- Has hypotension (systolic blood pressure <86 millimeters of mercury [mmHg]) or uncontrolled hypertension (systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg) at the screening visit
- Has a history of clinically significant ventricular arrhythmias
- Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
- Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for >39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT
- Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide)
- Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
- Has received a live vaccine within 30 days prior to randomization
- Has a "superscan" bone scan
- Has had an allogenic tissue/solid organ transplant
- Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
- Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions:
- Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel
- May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization
- For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization
- Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted
Trial locations and contacts
234 sites in 29 countries.
234 sites in 29 countries
United States27 sites
Alaska Clinical Research Center ( Site 0274)
Anchorage, Alaska, 99503
Providence Alaska Medical Center ( Site 0276)
Anchorage, Alaska, 99508
Winship Cancer Institute of Emory University ( Site 0209)
Atlanta, Georgia, 30322-1013
University of Colorado, Anschutz Cancer Pavilion ( Site 0236)
Aurora, Colorado, 80045
MidLantic Urology ( Site 0273)
Bala-Cynwyd, Pennsylvania, 19004
The Sidney Kimmel Comprehensive Cancer Center ( Site 0204)
Baltimore, Maryland, 21287
St. Vincent Frontier Cancer Center-Research ( Site 0213)
Billings, Montana, 59102
Ralph H. Johnson VA Center ( Site 0256)
Charleston, South Carolina, 29401
The University of Chicago ( Site 0264)
Chicago, Illinois, 60637
TriState Urologic Services PSC Inc. dba The Urology Group ( Site 0253)
Cincinnati, Ohio, 45212
City of Hope Medical Center ( Site 0217)
Duarte, California, 91010
Duke University ( Site 0206)
Durham, North Carolina, 27710
Inova Health System ( Site 0205)
Fairfax, Virginia, 22031
Comprehensive Cancer Centers of Nevada ( Site 0269)
Las Vegas, Nevada, 89169
UCLA Hematology/Oncology - Santa Monica ( Site 0241)
Los Angeles, California, 90404
Hartford HealthCare Medical Group ( Site 0212)
Manchester, Connecticut, 06042
Carolina Urologic Research Center ( Site 0259)
Myrtle Beach, South Carolina, 29572
Urology Associates [Nashville, TN] ( Site 0233)
Nashville, Tennessee, 37209
Smilow Cancer Center at Yale-New Haven ( Site 0250)
New Haven, Connecticut, 06510
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health ( Site 0270)
New York, New York, 10016
Weill Cornell Medical College ( Site 0263)
New York, New York, 10065
Fred Hutchinson Cancer Center ( Site 0258)
Seattle, Washington, 98109
Springfield Clinic [Springfield, IL] ( Site 0240)
Springfield, Illinois, 62702
Associated Medical Professionals of NY ( Site 0251)
Syracuse, New York, 13210
Cotton-O'Neil Cancer Center ( Site 0228)
Topeka, Kansas, 66606
Urology of Virginia ( Site 0224)
Virginia Beach, Virginia, 23462
Sibley Memorial Hospital ( Site 0275)
Washington D.C., District of Columbia, 20016
China24 sites
Peking University First Hospital ( Site 0800)
Beijing, Beijing Municipality, 100034
Beijing Cancer Hospital ( Site 0802)
Beijing, Beijing Municipality, 100142
Hunan Cancer Hospital ( Site 0817)
Changsha, Hunan, 410013
Chongqing Cancer Hospital ( Site 0815)
Chongqing, Chongqing Municipality, 400030
The First Affiliated Hospital of Guangzhou Medical University-Urology ( Site 0837)
Guangdong, Guangdong, 510080
Sun Yat-Sen University Cancer Center ( Site 0825)
Guangzhou, Guangdong, 510060
Sun Yat Sen Memorial Hospital ( Site 0819)
Guangzhou, Guangdong, 510220
Southern Medical University Nanfang Hospital ( Site 0838)
Guangzhou, Guangdong, 510515
2nd Affil Hosp of Zhejiang University College of Medicine ( Site 0808)
Hangzhou, Zhejiang, 310009
The 1st Affil Hosp of College of Medicine, Zhejiang Univ ( Site 0830)
Hangzhou, Zhejiang, 310009
Zhejiang Provincial People's Hospital ( Site 0809)
Hangzhou, Zhejiang, 310014
Harbin Medical University Cancer Hospital ( Site 0822)
Harbin, Heilongjiang, 150081
The First Affiliated Hospital of Nanchang University ( Site 0821)
Nanchang, Jiangxi, 330006
Nanjing Drum Tower Hospital ( Site 0811)
Nanjing, Jiangsu, 210008
Ningbo First Hospital-Urology ( Site 0835)
Ningbo, Zhejiang, 315010
Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0807)
Shanghai, Shanghai Municipality, 200127
Tianjin Medical University Cancer Institute & Hospital ( Site 0804)
Tianjin, Tianjin Municipality, 300000
The First Affiliated Hospital of Wenzhou Medical University ( Site 0834)
Wenzhou, Zhejiang, 325000
Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site 0829)
Wuhan, Hubei, 430000
Hubei Cancer Hospital ( Site 0833)
Wuhan, Hubei, 430079
The Second Affiliated Hosp of Xi'an Jiaotong Univ College of Medicine ( Site 0831)
Xi'an, Shaanxi, 710004
The first affiliated Hospital of Xi an Jiaotong University ( Site 0812)
Xi’an, Shanxi, 710061
The First Affiliated Hospital of Xiamen University ( Site 0816)
Xiamen, Fujian, 361003
Henan Cancer Hospital ( Site 0818)
Zhengzhou, Henan, 450008
Japan19 sites
Chiba Cancer Center ( Site 0733)
Chiba, 260-8717
Harasanshin Hospital ( Site 0747)
Fukuoka, 812-0033
Hamamatsu University Hospital ( Site 0748)
Hamamatsu, Shizuoka, 431-3192
Saitama Medical University International Medical Center ( Site 0737)
Hidaka, Saitama, 350-1298
Nara Medical University Hospital ( Site 0744)
Kashihara, Nara, 634-8522
Dokkyo Medical University Saitama Medical Center ( Site 0736)
Koshigaya, Saitama, 343-8555
Nagano Municipal Hospital ( Site 0731)
Nagano, 381-8551
Osaka Metropolitan University Hospital ( Site 0741)
Osaka, 545-8586
Kitasato University Hospital ( Site 0734)
Sagamihara, Kanagawa, 252-0375
Toho University Sakura Medical Center ( Site 0732)
Sakura, Chiba, 285-8741
Sapporo Medical University Hospital ( Site 0730)
Sapporo, Hokkaido, 060-8543
Kindai University Hospital ( Site 0743)
Sayama, Osaka, 589-8511
The University of Osaka Hospital ( Site 0742)
Suita, Osaka, 565-0871
Toranomon Hospital ( Site 0740)
Tokyo, 105-8470
Nippon Medical School Hospital ( Site 0738)
Tokyo, 113-8603
Tokyo Women's Medical University ( Site 0739)
Tokyo, 162-8666
Ehime University Hospital ( Site 0745)
Tōon, Ehime, 791-0295
Yamaguchi University Hospital ( Site 0746)
Ube, Yamaguchi, 755-8505
Yokohama City University Medical Center ( Site 0735)
Yokohama, Kanagawa, 232-0024
France13 sites
CHU-Jean Minjoz ( Site 1101)
Besançon, Doubs, 25000
Institut Bergonie ( Site 1104)
Bordeaux, Gironde, 33076
CHU de Brest -Site Hopital Morvan ( Site 1103)
Brest, Finistere, 29200
Hopital Henri Mondor ( Site 1116)
Créteil, Val-de-Marne, 94010
Centre Georges Francois Leclerc ( Site 1112)
Dijon, Cote-d Or, 21079
Centre Bourgogne ( Site 1119)
Lille, Hauts-de-France, 59000
Centre Leon-Berard ( Site 1110)
Lyon, Rhone, 69373
Centre D Oncologie de Gentilly ( Site 1107)
Nancy, Meurthe-et-Moselle, 54000
Hospices Civils de Lyon Centre Hospitalier Lyon Sud ( Site 1102)
Pierre-Bénite, Rhone, 69310
Institut Jean Godinot-Clinical Research Unit ( Site 1118)
Reims, Marne, 51100
C.H.R.U. de Rennes. Hopital de Pontchaillou ( Site 1117)
Rennes, Ille-et-Vilaine, 35033
Institut de cancérologie Strasbourg Europe (ICANS) ( Site 1114)
Strasbourg, Alsace, 67200
Hopital Foch ( Site 1105)
Suresnes, Hauts-de-Seine, 92151
Italy10 sites
Centro Di Riferimento Oncologico ( Site 1511)
Aviano, Pordenone, 33081
IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 1509)
Bari, 70124
Azienda Ospedaliera Cannizzaro ( Site 1501)
Catania, 95126
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori ( Site 1503)
Meldola, Forli-Cesena, 47014
Istituto Nazionale dei Tumori ( Site 1510)
Milan, 20133
Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1508)
Naples, 80131
Fondazione Policlinico Universitario A. Gemelli ( Site 1512)
Rome, Lazio, 00168
Istituto Clinico Humanitas Research Hospital ( Site 1500)
Rozzano, Lombardy, 20089
Azienda Ospedaliera Santa Maria ( Site 1502)
Terni, 05100
A.O. Verona-Ospedale Civile Maggiore Borgo-Trento ( Site 1504)
Verona, 37126
Poland10 sites
Szpital Uniwersytecki nr 1 im. Dr. Antoniego Jurasza w Bydgoszczy ( Site 1720)
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-094
Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 1716)
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-796
Wojewodzki Szpital Specjalistyczny nr 4 w Bytomiu ( Site 1717)
Bytom, Silesian Voivodeship, 41-900
Szpital Wojewodzki im. Mikolaja Kopernika ( Site 1709)
Koszalin, West Pomeranian Voivodeship, 75-581
Szpital Uniwersytecki w Krakowie ( Site 1707)
Krakow, Lesser Poland Voivodeship, 30-688
Uniwersytecki Szpital Kliniczny w Poznaniu ( Site 1710)
Poznan, Greater Poland Voivodeship, 61-848
Wojewodzki Szpital im. Sw. Ojca Pio w Przemyslu ( Site 1700)
Przemyśl, Podkarpackie Voivodeship, 37-700
Radomskie Centrum Onkologii ( Site 1701)
Radom, Masovian Voivodeship, 26-600
Twoja Przychodnia - Szczeciskie Centrum Medyczne ( Site 1721)
Szczecin, West Pomeranian Voivodeship, 71-434
MICS Centrum Medyczne Torun ( Site 1718)
Torun, Kuyavian-Pomeranian Voivodeship, 87-100
Australia9 sites
Box Hill Hospital ( Site 0304)
Box Hill, Victoria, 3128
Chris OBrien Lifehouse ( Site 0300)
Camperdown, New South Wales, 2050
Monash Health ( Site 0305)
Clayton, Victoria, 3168
Gallipoli Medical Research Ltd ( Site 0309)
Greenslopes, Queensland, 4120
Peter MacCallum Cancer Centre-Parkville Cancer Clinical Trials Unit (PCCTU) ( Site 0306)
Melbourne, Victoria, 3000
Fiona Stanley Hospital ( Site 0311)
Perth, Western Australia, 6150
Port Macquarie Base Hospital ( Site 0301)
Port Macquarie, New South Wales, 2444
John Flynn Hospital & Medical Centre ( Site 0308)
Tugun, Queensland, 4224
Riverina Cancer Care Center ( Site 0302)
Wagga Wagga, New South Wales, 2650
Germany9 sites
Charite Universitaetsmedizin Berlin ( Site 1201)
Berlin, 10117
Staedtisches Klinikum Braunschweig gGmbH ( Site 1217)
Braunschweig, Lower Saxony, 38126
Universitaetsklinikum der Technischen Universitaet Dresden ( Site 1204)
Dresden, Saxony, 01307
Universitaetsklinikum Freiburg ( Site 1200)
Freiburg im Breisgau, Baden-Wurttemberg, 79106
Universitaetsklinikum Hamburg-Eppendorf ( Site 1212)
Hamburg, 20246
Universitaetsklinikum Magdeburg A.o.R. ( Site 1211)
Magdeburg, Saxony-Anhalt, 39120
Klinikum Rechts der Isar ( Site 1206)
München, Bavaria, 81675
Klinikum der Universitaet Muenchen - Grosshadern ( Site 1210)
Munich, Bavaria, 81377
Klinikum Nuernberg Nord ( Site 1213)
Nuremberg, Bavaria, 90419
Brazil7 sites
Clinica de Oncologia Reichow ( Site 2308)
Blumenau, Santa Catarina, 89010-340
Instituto de Cancer e Transplante de Curitiba ICTR ( Site 2306)
Curitiba, Paraná, 80510-130
Oncocentro Ceara ( Site 2309)
Fortaleza, Ceará, 60135-237
Fundacao Dr Amaral Carvalho ( Site 2302)
Jaú, São Paulo, 17210-120
Hospital Sao Vicente de Paulo ( Site 2303)
Passo Fundo, Rio Grande do Sul, 99010-080
Hospital de Clinicas de Porto Alegre ( Site 2304)
Porto Alegre, Rio Grande do Sul, 90035-903
Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 2305)
São Paulo, 12460-000
Chile7 sites
IC La Serena Research ( Site 2406)
La Serena, Coquimbo Region, 1720430
Clinica Alemana ( Site 2408)
Santiago, Region M. de Santiago, 7650568
Pontificia Universidad Catolica de Chile ( Site 2402)
Santiago, Region M. de Santiago, 8330024
Bradfordhill ( Site 2403)
Santiago, Region M. de Santiago, 8420383
Clinica Universidad Catolica del Maule ( Site 2407)
Talca, Maule Region, 3465584
Centro Investigación del Cáncer James Lind ( Site 2401)
Temuco, Araucania, 4800827
Oncocentro ( Site 2400)
Viña del Mar, Valparaiso, 2520598
Netherlands7 sites
Meander Medisch Centrum ( Site 1602)
Amersfoort, Utrecht, 3813TZ
Antoni van Leeuwenhoek Ziekenhuis ( Site 1603)
Amsterdam, North Holland, 1066 CX
Vrije Universiteit Medisch Centrum ( Site 1601)
Amsterdam, North Holland, 1081 HV
Radboud University Medical Center ( Site 1606)
Nijmegen, Gelderland, 6500 HB
Franciscus Gasthuis en Vlietland ( Site 1605)
Schiedam, South Holland, 3118 JH
St. Antonius Ziekenhuis ( Site 1600)
Utrecht, 3543 AZ
Isala Klinieken, Locatie Sophia ( Site 1604)
Zwolle, Overijssel, 8025 AB
South Korea7 sites
Kyungpook National University Chilgok Hospital ( Site 0404)
Daegu, Kyongsangbuk-do, 41404
National Cancer Center ( Site 0400)
Gyeonggi-do, Kyonggi-do, 10408
Chonnam National University Hwasun Hospital ( Site 0406)
Jeollanam-do, Jeonranamdo, 58128
Seoul National University Bundang Hospital ( Site 0401)
Seongnam-si, Kyonggi-do, 13620
Seoul National University Hospital ( Site 0405)
Seoul, 03080
Severance Hospital Yonsei University Health System ( Site 0402)
Seoul, 03722
Asan Medical Center ( Site 0403)
Seoul, 05505
Spain7 sites
Institut Català d'Oncologia (ICO) - Girona ( Site 1900)
Girona, Gerona, 17007
Instituto Catalan de Oncologia - ICO ( Site 1901)
L'Hospitalet de Llobregat, Barcelona, 08908
Hospital Universitario Lucus Augusti ( Site 1905)
Lugo, 27003
Hospital Universitario Ramon y Cajal ( Site 1902)
Madrid, 28034
Hospital Clinico San Carlos ( Site 1906)
Madrid, 28040
Hospital 12 de Octubre de Madrid ( Site 1903)
Madrid, 28041
Hospital Virgen de la Macarena ( Site 1904)
Seville, 41009
Turkey (Türkiye)7 sites
Acibadem Adana Hastanesi ( Site 2106)
Adana, 01130
Ankara Bilkent Sehir Hastanesi ( Site 2103)
Ankara, Adana, 06800
Ankara Universitesi Tip Fakultesi. ( Site 2101)
Ankara, 06100
Hacettepe Universitesi Tıp Fakultesi ( Site 2105)
Ankara, 06230
Istanbul Uni. Cerrahpasa Tip Fakultesi ( Site 2100)
Istanbul, 34098
Ege University Medical Faculty Tulay Aktas Oncology Hospital ( Site 2102)
Izmir, 35100
Konya Necmettin Erbakan University Medical Faculty ( Site 2104)
Konya, 42080
Canada6 sites
CISSS de la Monteregie-Centre ( Site 0105)
Greenfield Park, Quebec, J4V 2H1
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0109)
Montreal, Quebec, H2X 3E4
CIUSSS Ouest de l Ile - St-Mary s Hospital ( Site 0106)
Montreal, Quebec, H3T 1M5
The Ottawa Hospital ( Site 0100)
Ottawa, Ontario, K1H 8L6
Centre intégré de cancérologie du CHU de Québec Université Laval, Hôpital de l'Enfant-Jésus ( Site 0101)
Québec, Quebec, G1J 1Z4
Niagara Health System - St. Catharines ( Site 0107)
St. Catharines, Ontario, L2S 0A9
Ireland6 sites
Cork University Hospital ( Site 1304)
Cork, T12 DC4A
St Vincents University Hospital ( Site 1300)
Dublin, Dublin, D04 T6F4
Tallaght University Hospital ( Site 1301)
Dublin, D24 NR0A
Beaumont Hospital ( Site 1302)
Dublin, Dublin 9
University Hospital Limerick ( Site 1305)
Limerick, V94 F858
University Hospital Waterford ( Site 1303)
Waterford, X91 ER8E
Israel6 sites
Rambam Health Care Campus-Oncology Division ( Site 1400)
Haifa, 3109601
Hadassah Ein Kerem Medical Center ( Site 1404)
Jerusalem, 9112001
Meir Medical Center ( Site 1401)
Kfar Saba, 4428164
Rabin Medical Center ( Site 1402)
Petah Tikva, 4941492
Sourasky Medical Center ( Site 1403)
Tel Aviv, 6423906
Yitzhak Shamir Medical Center. ( Site 1405)
Ẕerifin, 70300
Mexico6 sites
Centro Estatal de Cancerologia de Chihuahua ( Site 2608)
Chihuahua City, 31000
Hospital Civil de Guadalajara Fray Antonio Alcalde ( Site 2607)
Guadalajara, Jalisco, 44280
Grupo Medico Camino SC ( Site 2613)
Mexico City, 03310
Centro Oncologico Internacional. SEDNA ( Site 2609)
Mexico City, 04700
Boca Raton Clinical Research QTO ( Site 2611)
Querétaro, 76070
Hospital San Lucas Cardiologica del Sureste ( Site 2606)
Tuxtla Gutiérrez, Chiapas, 29090
Colombia5 sites
Clinica de la Costa S.A.S. ( Site 2504)
Barranquilla, Atlántico, 080020
Administradora Country SA - Clinica del Country ( Site 2507)
Bogotá, Bogota D.C., 110221
Instituto Nacional de Cancerologia E.S.E ( Site 2506)
Bogotá, Bogota D.C., 111511
Hemato Oncologos ( Site 2503)
Cali, Valle del Cauca Department, 760042
Sociedad de Oncología Y Hematología del Cesar S.A.S. ( Site 2509)
Valledupar, Cesar Department, 200001
Denmark5 sites
Aalborg Universitetshospital ( Site 1000)
Aalborg, North Denmark, 9000
Rigshospitalet ( Site 1005)
Copenhagen, Capital Region, 2100
Herlev og Gentofte Hospital. ( Site 1004)
Herlev, Capital Region, 2730
Odense Universitetshospital ( Site 1003)
Odense, Region Syddanmark, 5000
Vejle Sygehus ( Site 1002)
Vejle, Region Syddanmark, 7100
Peru5 sites
Hospital Nacional Carlos Alberto Seguin Escobedo ESSALUD ( Site 2700)
Arequipa, Ariqipa, 04001
Hospital Nacional Guillermo Almenara Irigoyen ( Site 2708)
Lima, 15033
IPOR Instituto Peruano de Oncología & Radioterapia-Centro de Investigación ( Site 2706)
Lima, 15036
Hospital Militar Central [Lima, Peru] ( Site 2704)
Lima, 15076
Clinica Peruano Americana S.A. ( Site 2702)
Trujillo, La Libertad, 13011
Russia5 sites
Krasnoyarsk Regional Clinical Oncological Dispensary ( Site 1810)
Krasnoyarsk, Krasnoyarsk Krai, 660133
SBIH City clinical hospital named after D.D. Pletniov ( Site 1813)
Moscow, Moscow, 105077
Russian Scientific Center of Roentgenoradiology ( Site 1800)
Moscow, Moscow, 117997
Volga District Medical Center Federal Medical and Biological Agency ( Site 1805)
Nizhny Novgorod, Nizhny Novgorod Oblast, 603074
Omsk Clinical Oncology Dispensary ( Site 1809)
Omsk, Omsk Oblast, 644013
Taiwan5 sites
Kaohsiung Chang Gung Memorial Hospital ( Site 0504)
Kaohsiung City, 83301
National Cheng Kung University Hospital ( Site 0503)
Tainan, 70457
National Taiwan University Hospital ( Site 0500)
Taipei, 100
Taipei Veterans General Hospital ( Site 0501)
Taipei, 11217
Chang Gung Medical Foundation. Linkou ( Site 0502)
Taoyuan, 33305
United Kingdom5 sites
Aberdeen Royal Infirmary ( Site 1315)
Aberdeen, Aberdeen City, AB25 2ZN
Velindre Cancer Centre Hospital ( Site 1322)
Cardiff, Wales, CF14 2TL
University College London Hospitals NHS Foundation Trust ( Site 1320)
London, London, City of, NW1 2BU
ROYAL MARSDEN HOSPITAL (CHELSEA) ( Site 1318)
London, London, City of, SW3 6JJ
Royal Cornwall Hospitals NHS Trust ( Site 1317)
Truro, Cornwall, TR1 3LJ
Austria4 sites
Ordensklinikum Linz GmbH Elisabethinen ( Site 0901)
Linz, Upper Austria, 4020
Landeskrankenhaus Salzburg - Universitatklinikum der PMU ( Site 0900)
Salzburg, 5020
Krankenhaus der Barmherzigen Brüder Wien ( Site 0904)
Vienna, 1020
Medizinische Universität Wien ( Site 0903)
Vienna, 1090
Finland4 sites
HYKS ( Site 1020)
Helsinki, Southwest Finland, 00290
Keski-Suomen keskussairaala ( Site 1017)
Jyväskylä, Central Finland, 40620
Tampereen yliopistollinen sairaala ( Site 1022)
Tampere, Pirkanmaa, 33520
TYKS T-sairaala Syopatautien pkl ( Site 1019)
Turku, Southwest Finland, 20520
Switzerland4 sites
Kantonsspital Graubuenden ( Site 2003)
Chur, Kanton Graubünden, 7000
CHUV (centre hospitalier universitaire vaudois) ( Site 2002)
Lausanne, Canton of Vaud, 1011
Kantonsspital St. Gallen ( Site 2000)
Sankt Gallen, Canton of St. Gallen, 9007
Universitaetsspital Zuerich ( Site 2001)
Zurich, Canton of Zurich, 8091
Thailand4 sites
Chulalongkorn Hospital, Medical Oncology Unit ( Site 0600)
Bangkok, Bangkok, 10330
Ramathibodi Hospital. ( Site 0601)
Bangkok, Bangkok, 10400
Faculty of Medicine Siriraj Hospital ( Site 0602)
Bangkok, Bangkok, 10700
Srinagarind Hospital ( Site 0604)
Khon Kaen, 40002
About this study
Official title: A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (KEYNOTE-991)
This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus Androgen Deprivation Therapy (ADT) versus placebo plus enzalutamide plus ADT in participants with mHSPC. The primary hypothesis is that in participants with mHSPC, the combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to 1) radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) and 2) overall survival (OS). As of 19-JAN-2023, the study was unblinded and all study participants stopped ongoing treatment with pembrolizumab/placebo and will continue to receive Standard of Care treatment until meeting protocol-specified discontinuation criteria if deriving clinical benefit. Safety analysis will be performed at the end of the study; there will be no further analyses for efficacy and electronic patient-reported outcome (ePRO) endpoints collected from participants beyond the IA1 cutoff date. All study participants will stop ongoing treatment with pembrolizumab/placebo. Exceptions may be requested for study participants who, in the assessment of their study physician, are benefitting from the combination of enzalutamide and pembrolizumab, after consulting with the Sponsor. All other study participants should be discontinued from study and be offered standard of care (SOC) treatment as deemed necessary by the Investigator. If enzalutamide as SOC is not accessible off study to the participant, central sourcing may continue. As of Amendment 04, disease progression will no longer be centrally verified, participants will only be assessed locally. As of Amendment 4, Second Course treatment is not an option for participants. There are currently no participants in the Second Course Phase.
- Being tested
- Pembrolizumab, Enzalutamide, Androgen Deprivation Therapy (ADT), Placebo
- Keywords
- Programmed Cell Death-1 (PD1, PD-1),, Programmed Death-Ligand 1 (PDL1, PD-L1)
- Medical subject headings
- Parkinson Disease 4, Autosomal Dominant Lewy Body
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabBiological
Also called KEYTRUDA®, MK-3475
Pembrolizumab is administered as an IV infusion at 200 mg on Day 1 of each 21-day cycle for up to 35 cycles.
EnzalutamideDrug
Also called XTANDI®
Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.
Androgen Deprivation Therapy (ADT)Drug
Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.
PlaceboOther
Placebo infusion solution is administered as an IV infusion on Day 1 of each 21-day cycle for up to 35 cycles.
| Study group | Role | What they receive |
|---|---|---|
| Pembrolizumab + Enzalutamide + ADT | Experimental | Starting on Day 1 of each 21-day cycle, participants receive 200 mg pembrolizumab IV every 3 weeks (Q3W) for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a luteinizing-hormone releasing hormone (LHRH) agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met. Receives: Biological: Pembrolizumab; Drug: Enzalutamide; Drug: Androgen Deprivation Therapy (ADT) |
| Placebo + Enzalutamide + ADT | Placebo comparator | Starting on Day 1 of each 21-day cycle, participants receive placebo IV Q3W for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a LHRH agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met. Receives: Drug: Enzalutamide; Drug: Androgen Deprivation Therapy (ADT); Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Radiographic Progression-free Survival (rPFS) Per Prostate Cancer Working Group (PCWG)-Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
rPFS was defined as the time from randomization to occurrence of: radiological tumor progression using RECIST 1.1 as assessed by BICR; progression of bone lesions using PCWG criteria; or death due to any cause. Progression as per modified RECIST 1.1 was ≥20% increase in sum of diameters of target lesions and progression of existing non-target lesions. Progression of bone lesions by PCWG criteria was the appearance of ≥2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and was persistent for ≥6 weeks. The rPFS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without a rPFS event were censored at the date of last disease assessment.
Measured: Up to approximately 32 months
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.
Measured: Up to approximately 32 months
Secondary outcomes (12)
Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)
TFST was defined as the time from randomization to initiation of the first subsequent anti-cancer therapy or death; whichever occurred first. The TFST was calculated using the product limit (Kaplan-Meier) method for censored data. Participants without documented event at time of analysis will be censored at the date of last known time to have not received subsequent new anti-cancer therapy.
Measured: Up to Approximately 32 months
Time to First Symptomatic Skeletal-related Event (TTSSRE)
TTSSRE was the time from randomization to the first symptomatic skeletal-related event defined as: use of external-beam radiation therapy (EBRT) to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathologic bone fracture (vertebral or nonvertebral), occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention, whichever occurs first. The TTSSRE was calculated using the Kaplan-Meier method for censored data. Participants without symptomatic skeletal-related events were censored at the last evaluable assessment.
Measured: Up to Approximately 32 months
Time to Prostate-specific Antigen (PSA) Progression
Time to PSA progression was the time from randomization to PSA progression. The PSA progression date was defined as the date of 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, or 2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline. Time to PSA was calculated using Kaplan-Meier method for censored data. Participants without PSA progression were censored at the last PSA date.
Measured: Up to Approximately 32 months
Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of PCWG-Modified RECIST 1.1 as Assessed by BICR
The time to radiographic soft tissue progression was defined as the time from randomization to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1 as assessed by BICR. Progression was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered progression. Time to radiographic soft tissue progression was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without radiographic soft tissue progression were censored at the last evaluable assessment.
Measured: Up to Approximately 32 months
Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item #3 ("Worst Pain in 24 Hours") and Opiate Use
TTPP was defined as the time from randomization to pain progression as determined by Item 3 of the BPI-SF. Pain progression was defined as: 1) For participants asymptomatic at baseline: a >2-point change from baseline in the average BPI-SF item 3 score at 2 consecutive visits or initiation of opioid use for pain 2) For participants symptomatic at baseline (average BPI-SF Item 3 score >0 and/or currently taking opioids; a >2-point change from baseline in the average BPI-SF Item 3 score and the average worst pain score >4 and no decrease in average opioid use. TTPP was calculated using the Kaplan-Meier method for censored data. Participants who had > 2 consecutive visits that were not evaluable for pain progression were censored at the last evaluable assessment.
Measured: Up to Approximately 32 months
Time From Randomization to Disease Progression as Determined by Investigator Assessment After Next-line of Therapy or Death From Any Cause, Whichever Occurs First (PFS2)
PFS2 was defined as the time from randomization to disease progression as determined by investigator assessment of radiological or clinical progression after next-line of therapy or death from any cause, whichever occurs first.
Measured: Up to Approximately 32 months
Prostate-specific Antigen (PSA) Response Rate
PSA response rate was the percentage of participants who had PSA response defined as a reduction in the PSA level from baseline by >50%. The reduction in PSA level was confirmed by an additional PSA evaluation performed >3 weeks from the original response.
Measured: Up to Approximately 32 Months
Prostate-specific Antigen (PSA) Undetectable
PSA undetectable rate was defined as the percentage of participants with detectable PSA (> 0.2 ng/mL) at baseline, which becomes undetectable (< 0.2 ng/mL) during study treatment.
Measured: Up to Approximately 32 Months
Objective Response Rate (ORR) Per PCWG-Modified RECIST 1.1 as Assessed by BICR
ORR was defined as the percentage of participants with complete response (CR: disappearance of all target lesions per RECIST 1.1; and no evidence of disease (NED) on base scan per PCWG) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1; and non-progressive disease, non-evaluable [NE], or NED on bone scan or CR with non-progressive disease or NE bone scan per PCWG).
Measured: Up to Approximately 32 Months
Duration of Response (DOR) Per PCWG- Modified RECIST 1.1 as Assessed by BICR
DOR was defined as the time from first documented evidence of complete response (CR) or partial response (PR) per PCWG and RECIST 1.1 criteria until progressive disease (PD) or death. PD per RECIST 1.1 was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of a least 5 mm. PD per PCWG was the appearance of >2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and were persistent for >6 weeks. The DOR was calculated using the product-limit (Kaplan-Meier) method for censored data.
Measured: Up to Approximately 32 Months
Number of Participants Who Experience an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE could therefore have been any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. Participants who experienced an AE will be reported for each arm.
Measured: Up to Approximately 59 Months
Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
An AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinue study treatment due to an AE will be reported for each arm.
Measured: Up to Approximately 59 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Dec 2019
- Study start12 Feb 2020
- Primary completion31 Oct 2022
- Study completion8 Apr 2026
Why it stopped: The study stopped due to futility
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic Hormone-Sensitive Prostate CancerStudies of the same condition, open and under way.
- More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 1,251 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck Sharp & Dohme LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04191096
- Sponsor's protocol ID
- 3475-991
- Other IDs
- MK-3475-991, KEYNOTE-991, jRCT2080225171, 2023-507024-24-00, U1111-1294-9592, 2019-003633-41, 2019, 2023
- Status last verified
- Aug 2026
- First submitted
- 5 Dec 2019
- Last updated
- 28 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf
Publications
Gratzke C, Kwiatkowski M, De Giorgi U, Martins da Trindade K, De Santis M, Armstrong AJ, Niu C, Liu Y, Poehlein CH. KEYNOTE-991: pembrolizumab plus enzalutamide and androgen deprivation for metastatic hormone-sensitive prostate cancer. Future Oncol. 2023 Jan 27. doi: 10.2217/fon-2022-0776. Online ahead of print.
PubMed 36705526