Study of Pembrolizumab (MK-3475) Plus Docetaxel Versus Placebo Plus Docetaxel in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-921/KEYNOTE-921)

Prostatic Neoplasms Clinical Trial

Official title:

A Phase 3, Randomized, Double-blind Study of Pembrolizumab (MK-3475) Plus Docetaxel Plus Prednisone Versus Placebo Plus Docetaxel Plus Prednisone in Participants With Chemotherapy-naïve Metastatic Castration-Resistant Prostate Cancer (mCRPC) Who Have Progressed on a Next Generation Hormonal Agent (NHA) (KEYNOTE-921)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03834506
• Other study ID #: 3475-921
• Secondary ID: MK-3475-921KEYNO
• Status: Completed
• Phase: Phase 3
• Start date: May 2, 2019
• Est. completion date: July 18, 2023

Study information

• Verified date: August 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and docetaxel in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC but have progressed on or are intolerant to Next Generation Hormonal Agent (NHA).

There are two primary study hypotheses.

Hypothesis 1: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone with respect to Overall Survival (OS).

Hypothesis 2: The combination of pembrolizumab plus docetaxel plus prednisone is superior to placebo plus docetaxel plus prednisone with respect to 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.

Description:

With Amendment 6 (effective date: 29-Sep-2022), all participants will be unblinded and placebo treatment will be stopping. Participants who are deemed to be deriving clinical benefit from treatment may continue at the discretion of the investigator.

The global study for MK-3475-921 enrolled 1030 participants. Of the 1030 total participants enrolled in the global study, 21 were also enrolled in the China extension study for MK-3475-921 (NCT04907227).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1030
• Est. completion date: July 18, 2023
• Est. primary completion date: June 20, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology

• Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to screening

• Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI)

• Has received prior treatment with one (but not more than one) NHA (eg, abiraterone acetate, enzalutamide, apalutamide, or darolutamide) for metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC) and either a) progressed through treatment OR b) has become intolerant of the drug

• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)

• Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization

• Participants must agree to the following during the study treatment period and for at least 120 days after the last dose of pembrolizumab or for at least 180 days after the last dose of docetaxel (whichever is longer): Refrain from donating sperm PLUS Use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)

• Participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex

• 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

• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization

Exclusion Criteria:

• 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

• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

• Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis

• Has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its excipients

• Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)

• Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization or who has not recovered (i.e., Grade =1 or at baseline) from AEs due to mAbs

• Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g. saw palmetto) prior to randomization

• Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer

• 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 PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX-40, CD137)

• Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC

• Has hypersensitivity to docetaxel or polysorbate 80

• Is currently receiving either strong or moderate inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study

• Has received prior targeted small molecule therapy or abiraterone acetate, enzalutamide, apalutamide, or darolutamide within 4 weeks prior to the first dose of study treatment, or has not recovered (i.e., Grade =1 or at baseline) from AEs due to a previously administered agent

• Has received prior radiotherapy to within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis

• Has received a live vaccine within 30 days prior to randomization

• Has received treatment with 5a reductase inhibitors (eg, finasteride or dutasteride), estrogens, and/or cyproterone within 4 weeks prior to randomization

• Has received prior treatment with ketoconazole for prostate cancer

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment

• Has a "superscan" bone scan

• 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 had an allogenic tissue/solid organ transplant

Related Conditions & MeSH terms

• Prostatic Neoplasms

Intervention

Biological:
• Pembrolizumab
IV infusion

Drug:
• Docetaxel
IV infusion
• Prednisone
Oral tablets
• Placebo
IV infusion
• Dexamethasone
Oral tablets

Locations

Country	Name	City	State
Argentina	Centro de Oncologia e Investigacion Buenos Aires COIBA ( Site 1013)	Berazategui	Buenos Aires
Argentina	Centro de Diagnostico Urologico ( Site 1008)	Buenos Aires	Caba
Argentina	Hospital Aleman ( Site 1004)	Buenos Aires
Argentina	Hospital Britanico de Buenos Aires ( Site 1006)	Buenos Aires	Caba
Argentina	Instituto de Investigaciones Metabolicas [Buenos Aires, Argentina] ( Site 1011)	Buenos Aires
Argentina	Instituto Medico Alexander Fleming ( Site 1010)	Buenos Aires
Argentina	CEMAIC ( Site 1014)	Cordoba
Argentina	Instituto de Investigaciones Clinicas ( Site 1000)	Mar del Plata	Buenos Aires
Argentina	Sanatorio Parque ( Site 1002)	Rosario	Santa Fe
Australia	St George Hospital ( Site 0157)	Kogarah	New South Wales
Australia	Macquarie University ( Site 0151)	Macquarie University	New South Wales
Australia	Hollywood Private Hospital ( Site 0163)	Nedlands	Western Australia
Australia	Port Macquarie Base Hospital ( Site 0153)	Port Macquarie	New South Wales
Australia	Redcliffe Hospital ( Site 0161)	Redcliffe	Queensland
Australia	John Flynn Hospital & Medical Centre ( Site 0164)	Tugun	Queensland
Australia	Calvary Mater Newcastle ( Site 0148)	Waratah	New South Wales
Austria	Medizinische Universitat Graz ( Site 0374)	Graz	Steiermark
Austria	Ordensklinikum Linz GmbH Elisabethinen ( Site 0373)	Linz	Oberosterreich
Austria	SCRI-CCCIT GesmbH ( Site 0371)	Salzburg
Austria	Medizinische Universitaet Wien ( Site 0375)	Wien
Brazil	Hospital de Caridade de Ijui ( Site 1038)	Ijui	Rio Grande Do Sul
Brazil	Centro de Novos Tratamentos Itajai - Clinica de Neoplasias Litoral ( Site 1035)	Itajai	Santa Catarina
Brazil	Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs ( Site 1021)	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital de Base de Sao Jose de Rio Preto ( Site 1022)	Sao Jose do Rio Preto	Sao Paulo
Brazil	A.C. Camargo Cancer Center ( Site 1026)	Sao Paulo
Canada	Nova Scotia Health Authority QEII-HSC ( Site 0114)	Halifax	Nova Scotia
Canada	Hamilton Health Sciences-Juravinski Cancer Centre ( Site 0116)	Hamilton	Ontario
Canada	Grand River Hospital ( Site 0120)	Kitchener	Ontario
Canada	Lakeridge Health ( Site 0117)	Oshawa	Ontario
Canada	CHU de Quebec-Universite Laval-Hotel Dieu de Quebec ( Site 0103)	Quebec
Canada	CIUSSS du Bas Saint Laurent - Hopital Regional de Rimouski ( Site 0102)	Rimouski	Quebec
Canada	CIUSSS de l Estrie - CHUS - Centre Hosp. Univ. Sherbrooke ( Site 0105)	Sherbrooke	Quebec
Canada	Princess Margaret Cancer Centre ( Site 0107)	Toronto	Ontario
Canada	Sunnybrook Research Institute ( Site 0108)	Toronto	Ontario
Chile	Bradford Hill Centro de Investigaciones Clinicas ( Site 1044)	Santiago	Region M. De Santiago
Chile	Fundacion Arturo Lopez Perez ( Site 1049)	Santiago	Region M. De Santiago
Chile	Pontificia Universidad Catolica de Chile ( Site 1047)	Santiago	Region M. De Santiago
Chile	Centro Investigación del Cáncer James Lind ( Site 1041)	Temuco	Araucania
Chile	Rey y Oreilly Limitada ( Site 1048)	Temuco	Araucania
Chile	Centro de Investigaciones Clinicas Vina del Mar ( Site 1042)	Vina del Mar	Valparaiso
China	Beijing Cancer Hospital ( Site 1305)	Beijing	Beijing
China	Peking University First Hospital ( Site 1303)	Beijing	Beijing
China	The Fifth Medical Center of PLA General Hospital ( Site 1307)	Beijing	Beijing
China	Hunan Cancer Hospital ( Site 1320)	Changsha	Hunan
China	Sun Yat Sen Memorial Hospital ( Site 1323)	Guangzhou	Guangdong
China	The First Affiliated Hospital of Guangzhou Medical University ( Site 1330)	Guangzhou	Guangdong
China	The Second Affiliated Hospital of Zhejiang University School of Medicine ( Site 1309)	Hangzhou	Zhejiang
China	Zhejiang Provincial People's Hospital ( Site 1310)	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital ( Site 1326)	Harbin	Heilongjiang
China	Nanjing Drum Tower Hospital ( Site 1312)	Nanjing	Jiangsu
China	Fudan University Shanghai Cancer Center ( Site 1300)	Shanghai	Shanghai
China	Zhongshan Hospital Fudan University ( Site 1301)	Shanghai	Shanghai
China	Hubei Cancer Hospital ( Site 1329)	Wuhan	Hubei
China	The First Affiliated Hospital of Xiamen University ( Site 1319)	Xiamen	Fujian
China	Henan Cancer Hospital ( Site 1321)	Zhengzhou	Henan
Colombia	Biomelab S A S ( Site 1067)	Barranquilla	Atlantico
Colombia	Clinica de la Costa Ltda. ( Site 1073)	Barranquilla	Atlantico
Colombia	Clinica Colsanitas S.A. Sede Clinica Universitaria Colombia ( Site 1062)	Bogota	Distrito Capital De Bogota
Colombia	Instituto Nacional de Cancerologia E.S.E ( Site 1061)	Bogota	Distrito Capital De Bogota
Colombia	Centro Medico Imbanaco de Cali S.A ( Site 1064)	Cali	Valle Del Cauca
Colombia	Hemato Oncologos S.A. ( Site 1065)	Cali	Valle Del Cauca
Colombia	Hospital Pablo Tobon Uribe ( Site 1066)	Medellin	Antioquia
Colombia	Oncomedica S.A. ( Site 1057)	Monteria	Cordoba
Colombia	Oncologos del Occidente S.A. ( Site 1072)	Pereira	Risaralda
Colombia	Sociedad de Oncología Y Hematología del Cesar S.A.S. ( Site 1068)	Valledupar	Cesar
France	CHU Amiens Picardie Site Sud Amiens ( Site 0438)	Amiens	Somme
France	Institut Sainte Catherine ( Site 0447)	Avignon	Vaucluse
France	CHU Jean Minjoz ( Site 0423)	Besancon	Doubs
France	Institut Bergonie ( Site 0421)	Bordeaux	Gironde
France	CHU de Brest -Site Hopital Morvan ( Site 0441)	Brest	Finistere
France	Centre Jean Perrin ( Site 0434)	Clermont-Ferrand	Auvergne
France	Centre Leon Berard ( Site 0422)	Lyon	Auvergne
France	Institut Paoli Calmettes. ( Site 0419)	Marseille	Bouches-du-Rhone
France	Centre D Oncologie de Gentilly ( Site 0432)	Nancy	Meurthe-et-Moselle
France	Centre Hospitalier Regional du Orleans ( Site 0430)	Orleans	Loiret
France	Institut Mutualiste Montsouris ( Site 0446)	Paris
France	C.H.U. Lyon Sud ( Site 0436)	Pierre Benite	Rhone
France	Institut De Cancerologie De L Ouest ( Site 0448)	Saint Herblain	Loire-Atlantique
France	C.H. de Saint Quentin ( Site 0481)	Saint Quentin	Aisne
France	Clinique Sainte Anne ( Site 0431)	Strasbourg	Alsace
France	Hopital Foch ( Site 0428)	Suresnes	Hauts-de-Seine
France	Institut Claudius Regaud IUCT Oncopole ( Site 0418)	Toulouse	Haute-Garonne
France	Institut Gustave Roussy ( Site 0416)	Villejuif	Val-de-Marne
Germany	Uniklinik RWTH Aachen ( Site 0308)	Aachen	Nordrhein-Westfalen
Germany	Charite Universitaetsmedizin Berlin ( Site 0301)	Berlin
Germany	Universitaetsklinikum Freiburg - Medizinische Klinik ( Site 0304)	Freiburg	Baden-Wurttemberg
Germany	Universitaetsklinikum Goettingen ( Site 0345)	Goettingen	Niedersachsen
Germany	Universitaetsklinikum des Saarlandes ( Site 0348)	Homburg	Saarland
Germany	Universitaetsklinikum Jena ( Site 0305)	Jena	Thuringen
Germany	Universitaetsklinikum in Mannheim ( Site 0314)	Mannheim	Baden-Wurttemberg
Germany	Klinikum Rechts der Isar ( Site 0300)	Muenchen	Bayern
Germany	Universitaetsklinik der Paracelsus Medizinischen Privatuniversitaet ( Site 0318)	Nuernberg	Bayern
Germany	Studienpraxis Urologie ( Site 0309)	Nuertingen	Baden-Wurttemberg
Germany	Universitaetsklinik fuer Urologie ( Site 0307)	Tuebingen	Baden-Wurttemberg
Germany	Universitaetsklinikum Wuerzburg ( Site 0302)	Wuerzburg	Bayern
Ireland	Cork University Hospital ( Site 0727)	Cork
Ireland	Tallaght University Hospital ( Site 0730)	Dublin
Ireland	Mid Western Cancer Centre ( Site 0728)	Limerick
Israel	Soroka Medical Center ( Site 0548)	Beer Sheva
Israel	Assaf Harofeh MC ( Site 0547)	Beer Yaakov-Zerifin
Israel	Rambam Medical Center ( Site 0543)	Haifa
Israel	Hadassah Ein Kerem Medical Center ( Site 0546)	Jerusalem
Israel	Meir Medical Center ( Site 0544)	Kfar Saba
Israel	Rabin Medical Center ( Site 0545)	Petach-Tikwa
Israel	Chaim Sheba Medical Center ( Site 0541)	Ramat Gan
Israel	Sourasky Medical Center ( Site 0542)	Tel Aviv
Italy	Azienda Ospedaliera Cannizzaro ( Site 0458)	Catania
Italy	A.O. Universitaria di Modena ( Site 0454)	Modena
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0457)	Napoli
Italy	Azienda Ospedaliera San Camillo Forlanini ( Site 0455)	Roma
Italy	Istituto Clinico Humanitas Research Hospital ( Site 0452)	Rozzano	Milano
Italy	Azienda Ospedaliera Santa Maria Terni ( Site 0456)	Terni
Italy	Presidio Ospedaliero Santa Chiara ( Site 0451)	Trento
Japan	Chiba Cancer Center ( Site 0704)	Chiba
Japan	Kyushu University Hospital ( Site 0718)	Fukuoka
Japan	Hamamatsu University Hospital ( Site 0720)	Hamamatsu	Shizuoka
Japan	Saitama Medical University International Medical Center ( Site 0708)	Hidaka	Saitama
Japan	Kanazawa University Hospital ( Site 0701)	Kanazawa	Ishikawa
Japan	Nara Medical University Hospital ( Site 0715)	Kashihara	Nara
Japan	National Cancer Center Hospital East ( Site 0702)	Kashiwa	Chiba
Japan	Dokkyo Medical University Saitama Medical Center ( Site 0707)	Koshigaya	Saitama
Japan	National Hospital Organization Shikoku Cancer Center ( Site 0716)	Matsuyama	Ehime
Japan	University of Miyazaki Hospital ( Site 0721)	Miyazaki
Japan	Nagasaki University Hospital ( Site 0719)	Nagasaki
Japan	Kindai University Hospital ( Site 0714)	Osakasayama	Osaka
Japan	Kitasato University Hospital ( Site 0705)	Sagamihara	Kanagawa
Japan	Toho University Sakura Medical Center ( Site 0703)	Sakura	Chiba
Japan	Osaka University Hospital ( Site 0713)	Suita	Osaka
Japan	Keio University Hospital ( Site 0710)	Tokyo
Japan	Nippon Medical School Hospital ( Site 0709)	Tokyo
Japan	Toranomon Hospital ( Site 0711)	Tokyo
Japan	Yamaguchi University Hospital ( Site 0717)	Ube	Yamaguchi
Japan	Yokohama City University Medical Center ( Site 0706)	Yokohama	Kanagawa
Korea, Republic of	National Cancer Center ( Site 0174)	Goyang-si	Kyonggi-do
Korea, Republic of	Seoul National University Bundang Hospital ( Site 0175)	Seongnam-si	Kyonggi-do
Korea, Republic of	Asan Medical Center ( Site 0176)	Seoul
Korea, Republic of	Samsung Medical Center ( Site 0172)	Seoul
Korea, Republic of	Seoul National University Hospital ( Site 0171)	Seoul
Netherlands	Antoni van Leeuwenhoek Ziekenhuis ( Site 0480)	Amsterdam	Noord-Holland
Netherlands	Reinier de Graaf Groep ( Site 0484)	Delft	Zuid-Holland
Netherlands	Jeroen Bosch Ziekenhuis ( Site 1200)	Den Bosch	Noord-Brabant
Netherlands	Hagaziekenhuis ( Site 1201)	Den Haag	Zuid-Holland
Netherlands	Ziekenhuis Gelderse Vallei ( Site 0485)	Ede	Gelderland
Netherlands	Catharina Ziekenhuis ( Site 0472)	Eindhoven	Noord-Brabant
Netherlands	Ziekenhuisgroep Twente ( Site 0469)	Hengelo	Overijssel
Netherlands	Ziekenhuis Hilversum ( Site 0466)	Hilversum	Noord-Holland
Netherlands	Medisch Centrum Leeuwarden ( Site 0477)	Leeuwarden	Fryslan
Netherlands	Radboud University Medical Center ( Site 0470)	Nijmegen	Gelderland
Netherlands	VieCuri Medisch Centrum ( Site 0487)	Venlo	Limburg
Russian Federation	Chelyabinsk Regional Clinical Oncological Dispensary ( Site 0565)	Chelyabinsk	Chelyabinskaya Oblast
Russian Federation	Krasnoyarsk Regional Clinical Oncological Dispensary ( Site 0585)	Krasnoyarsk	Krasnoyarskiy Kray
Russian Federation	Central Clinical Hospital with Polyclinic ( Site 0562)	Moscow	Moskva
Russian Federation	National Medical Research Radiological Center ( Site 0556)	Moscow	Moskva
Russian Federation	Russian Scientific Center of Radiology ( Site 0559)	Moscow	Moskva
Russian Federation	SBIH City clinical hospital named after D.D. Pletniov ( Site 0575)	Moscow	Moskva
Russian Federation	Volga District Medical Center Federal Medical and Biological Agency ( Site 0572)	Nizhny Novgorod	Nizhegorodskaya Oblast
Russian Federation	Omsk Clinical Oncology Dispensary ( Site 0568)	Omsk	Omskaya Oblast
Russian Federation	Clinical Research Center of specialized types medical care-Oncology ( Site 0570)	Saint Petersburg	Sankt-Peterburg
Russian Federation	Russian Scientific Center of Radiology and Surgical Technologies ( Site 0567)	Saint Petersburg	Sankt-Peterburg
Russian Federation	SPb SBHI City Clinical Oncological Dispensary ( Site 0571)	Saint Petersburg	Sankt-Peterburg
Russian Federation	Leningrad Regional Oncology Center ( Site 0588)	Saint-Petersburg	Sankt-Peterburg
Russian Federation	SBHI Samara Regional Clinical Oncology Dispensary ( Site 0576)	Samara	Samarskaya Oblast
Russian Federation	Tomsk National Research Medical Center of Russian Academy of Sciences ( Site 0579)	Tomsk	Tomskaya Oblast
Spain	Hospital Clinic ( Site 0323)	Barcelona
Spain	Hospital del Mar ( Site 0333)	Barcelona
Spain	Hospital Josep Trueta ( Site 0321)	Girona	Gerona
Spain	Instituto Catalan de Oncologia - ICO ( Site 0330)	L Hospitalet De Llobregat	Barcelona
Spain	Hospital Clinico San Carlos ( Site 0324)	Madrid
Spain	Hospital Universitario HM Sanchinarro ( Site 0322)	Madrid
Spain	Hospital Universitario Ramon y Cajal ( Site 0328)	Madrid
Spain	Hospital Universitario Virgen de la Victoria ( Site 0337)	Malaga
Spain	Hospital Consorci Sanitari Parc Tauli ( Site 0335)	Sabadell	Barcelona
Spain	Hospital Universitario Marques de Valdecilla ( Site 0336)	Santander	Cantabria
Spain	Hospital Virgen del Rocio ( Site 0329)	Sevilla
Taiwan	China Medical University Hospital ( Site 0132)	Taichung
Taiwan	Taichung Veterans General Hospital ( Site 0133)	Taichung
Taiwan	National Cheng Kung University Hospital ( Site 0134)	Tainen	Tainan
Taiwan	National Taiwan University Hospital ( Site 0131)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 0135)	Taipei
United Kingdom	University Hospitals Bristol NHS Foundation Trust ( Site 0530)	Bristol	Bristol, City Of
United Kingdom	Cambridge University Hospitals NHS Trust ( Site 0540)	Cambridge	Cambridgeshire
United Kingdom	Barts Cancer Institute ( Site 0483)	London	London, City Of
United Kingdom	Mount Vernon Cancer Centre ( Site 0536)	Northwood	Hertfordshire
United Kingdom	Weston Park Hospital ( Site 0539)	Sheffield	England
United Kingdom	University of North Midlands NHS Foundation Trust ( Site 0527)	Stoke-on-Trent	Staffordshire
United Kingdom	Royal Marsden Hospital ( Site 0526)	Sutton	England
United Kingdom	Torbay Hospital ( Site 0532)	Torquay	Devon
United States	Georgia Cancer Center at Augusta University ( Site 0026)	Augusta	Georgia
United States	University of Colorado Cancer Center ( Site 0022)	Aurora	Colorado
United States	St. Vincent Frontier Cancer Center ( Site 0016)	Billings	Montana
United States	Mount Sinai Hospital Medical Center ( Site 0042)	Chicago	Illinois
United States	University Hospitals Cleveland Medical Center ( Site 0036)	Cleveland	Ohio
United States	Henry Ford Health System ( Site 0039)	Detroit	Michigan
United States	Karmanos Cancer Institute ( Site 0077)	Detroit	Michigan
United States	Duke Cancer Center ( Site 0010)	Durham	North Carolina
United States	Inova Schar Cancer Institute ( Site 0006)	Fairfax	Virginia
United States	St. Joseph Heritage Healthcare ( Site 0069)	Fullerton	California
United States	Cancer & Hematology Centers of Western Michigan ( Site 0013)	Grand Rapids	Michigan
United States	John Theurer Cancer Center at Hackensack University Medical Center ( Site 0004)	Hackensack	New Jersey
United States	Comprehensive Cancer Centers of Nevada ( Site 0092)	Las Vegas	Nevada
United States	University of Southern California Norris Comprehensive Cancer Center ( Site 0061)	Los Angeles	California
United States	Methodist Hospital- Merriillville ( Site 0008)	Merrillville	Indiana
United States	University of South Alabama, Mitchell Cancer Institute ( Site 0065)	Mobile	Alabama
United States	Carolina Urologic Research Center ( Site 0070)	Myrtle Beach	South Carolina
United States	Yale Cancer Center ( Site 0038)	New Haven	Connecticut
United States	USC Norris Oncology Hematology Newport Beach ( Site 0093)	Newport Beach	California
United States	Nebraska Cancer Specialists ( Site 0034)	Omaha	Nebraska
United States	Oregon Health Sciences University ( Site 0031)	Portland	Oregon
United States	Virginia Cancer Institute ( Site 0052)	Richmond	Virginia
United States	Blue Ridge Cancer Care ( Site 0086)	Roanoke	Virginia
United States	Washington University School of Medicine ( Site 0057)	Saint Louis	Missouri
United States	W. G. Bill Hefner VA Medical Center ( Site 0029)	Salisbury	North Carolina
United States	University of California San Francisco ( Site 0023)	San Francisco	California
United States	Associated Medical Professionals of NY ( Site 0060)	Syracuse	New York
United States	Moffitt Cancer Center ( Site 0080)	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Brazil,  Canada,  Chile,  China,  Colombia,  France,  Germany,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Russian Federation,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Up to 36.5 months
Primary	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 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.	Up to approximately 28 months
Secondary	Time to Initiation of the First Subsequent Anti-cancer Therapy (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. Any participant not known to have further subsequent therapy or death was censored at the last known time that no subsequent new anti-cancer therapy was received.	Up to approximately 28 months
Secondary	Prostate-specific Antigen (PSA) Response Rate	The Prostate-specific Antigen (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. The analysis was performed on participants who had baseline PSA measurements.	Up to 36.5 months
Secondary	Objective Response Rate (ORR) 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	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 bone 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).	Up to 36.5 months
Secondary	Duration of Response (DOR) 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	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 at 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. If a participant had not progressed, the participant was censored at the date of last disease assessment.	Up to 36.5 months
Secondary	Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Analgesic Use Assessed by the Analgesic Quantification Algorithm [AQA] Score	TTPP was defined as the time from randomization to pain progression as determined by Item 3 of the BPI-SF and by the AQA score. Pain progression was defined as: For participants asymptomatic at baseline: a =2-point change from baseline in the average (4-7 days) BPI-SF item 3 score at 2 consecutive visits OR initiation of opioid use for pain; 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 an average worst pain score =4 and no decrease in average opioid use (=1-point decrease in AQA score from a starting value of 2 or higher) OR any increase in opioid use at 2 consecutive follow-up visits.; TTPP was calculated using the product-limit (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.	Up to 36.5 months
Secondary	Time to First Symptomatic Skeletal-related Event (SSRE)	SSRE 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 non-vertebral); Occurrence of spinal cord compression; Tumor-related orthopedic surgical intervention, whichever occurs first.; The SSRE was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without symptomatic skeletal-related events were censored at the last evaluable assessment.	Up to 36.5 months
Secondary	Time to Prostate-specific Antigen (PSA) Progression	The time to PSA progression was the time from randomization to PSA progression. The PSA progression date was defined as the date of: =25% increase and =2 ng/mL above the nadir, confirmed by a second value =3 weeks later if there was PSA decline from baseline; OR; =25% increase and =2 ng/mL increase from baseline beyond 12 weeks if there was no PSA decline from baseline; Time to PSA progression was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without PSA progression were censored at the last evaluable assessment.	Up to 36.5 months
Secondary	Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of 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)	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.	Up to 36.5 months
Secondary	Number of Participants Who Experienced 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 could therefore have been any unfavorable 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 experienced an AE is presented.	Up to approximately 30 months
Secondary	Number of Participants Who Discontinued 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 could therefore have been any unfavorable 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 discontinued study treatment due to an AE is presented.	Up to approximately 27 months

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