A Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Enzalutamide in Participants With Metastatic Castration-Resistant Prostrate Cancer (mCRPC) After Failure of an Androgen Synthesis Inhibitor And Failure of, Ineligibility For, or Refusal of a Taxane Regimen

Prostatic Neoplasms, Castration-Resistant Clinical Trial

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Official title:

A Phase III, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Enzalutamide Versus Enzalutamide Alone in Patients With Metastatic Castration-Resistant Prostate Cancer After Failure of an Androgen Synthesis Inhibitor and Failure of, Ineligibility for, or Refusal of a Taxane Regimen

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03016312
• Other study ID #: CO39385
• Secondary ID: 2016-003092-22
• Status: Completed
• Phase: Phase 3
• Start date: January 10, 2017
• Est. completion date: December 20, 2022

Study information

• Verified date: January 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This Phase III, multicenter, randomized, open-label study will evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [anti-PD-L1] antibody) in combination with enzalutamide compared with enzalutamide alone in participants with mCRPC after failure of an androgen synthesis inhibitor (e.g., abiraterone) and failure of, ineligibility for, or refusal of a taxane regimen. Participants will be randomized to one of the two treatment arms (atezolizumab in combination with enzalutamide, and enzalutamide alone) in a 1:1 ratio (experimental to control arm) in global randomized phase. Participants will receive treatment until investigator-assessed confirmed radiographic disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria or unacceptable toxicity.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 772
• Est. completion date: December 20, 2022
• Est. primary completion date: December 20, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy greater than or equal to (>/=) 3 months
• Histologically confirmed adenocarcinoma of the prostate
• Known castrate-resistant disease with serum testosterone level less than or equal to (</=) 50 nanograms per deciliter (ng/dL) with prior surgical castration or ongoing androgen deprivation for the duration of the study
• Progressive disease prior to screening by PSA or imaging per PCWG3 criteria during or following the direct prior line of therapy in the setting of medical or surgical castration
• One prior regimen/line of a taxane-containing regimen for mCRPC or refusal or ineligibility of a taxane-containing regimen
• Progression on a prior regimen/line of an androgen synthesis inhibitor for prostate cancer
• Availability of a representative tumor specimen from a site not previously irradiated that is suitable for determination of programmed death-ligand 1 (PD-L1) status via central testing
• Adequate hematologic and end organ function

Exclusion Criteria:

• Prior treatment with enzalutamide or any other newer hormonal androgen receptor inhibitor (e.g., apalutamide, ODM-201)
• Treatment with any approved anti-cancer therapy, including chemotherapy, immunotherapy, radiopharmaceutical or hormonal therapy (with the exception of abiraterone), within 4 weeks prior to initiation of study treatment
• Treatment with abiraterone within 2 weeks prior to study treatment
• Structurally unstable bone lesions suggesting impending fracture
• Known or suspected brain metastasis or active leptomeningeal disease
• Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
• Active or history of autoimmune disease or immune deficiency
• Prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Positive human immunodeficiency virus (HIV) test, active tuberculosis, active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
• Prior treatment with cluster of differentiation (CD)137 agonists or immune checkpoint blockade therapies, including anti Cytotoxic T Lymphocyte-Associated 4 (CTLA4), anti-programmed death 1 (PD-1), and anti-PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug, whichever is shorter, prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study
• History of seizure or any condition that may predispose to seizure within 12 months prior to study treatment, including history of unexplained loss of consciousness or transient ischemic attack

Related Conditions & MeSH terms

• Prostatic Neoplasms
• Prostatic Neoplasms, Castration-Resistant

Intervention

Drug:
• Atezolizumab
Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg), intravenous (IV) infusion on Day 1 of each 21-day cycle.
• Enzalutamide
Enzalutamide capsules will be administered orally at a dose of 160 mg daily.

Locations

Country	Name	City	State
Australia	Eastern Health; Cancer Services	Box Hill	New South Wales
Australia	Monash Medical Centre; Oncology	Clayton	Victoria
Australia	Concord Repatriation General Hospital; Concord Cancer Centre	Concord	New South Wales
Australia	Royal Brisbane & Women's Hosp; Cancer Care Serv	Herston	Queensland
Australia	Adelaide Cancer Centre	Kurralta Park	South Australia
Australia	Macquarie University Hospital	Macquarie Park	New South Wales
Austria	LKH-UNIV. KLINIKUM GRAZ; Klinische Abteilung für Onkologie	Graz
Austria	Ordensklinikum Linz Elisabethinen; Abteilung für Urologie und Andrologie	Linz
Austria	Medizinische Universität Wien; Universitätsklinik für Urologie	Wien
Belgium	Onze Lieve Vrouwziekenhuis Aalst	Aalst
Belgium	UZ Gent	Gent
Belgium	CHU Sart-Tilman	Liège
Canada	Tom Baker Cancer Centre-Calgary	Calgary	Alberta
Canada	Hopital Charles Lemoyne; Centre Integre de Lutte Contre Le Cancer de La Monteregie	Greenfield Park	Quebec
Canada	Kingston General Hospital	Kingston	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Lakeridge Health Oshawa; Oncology	Oshawa	Ontario
Canada	CHU de Québec - Université Laval - Hôtel-Dieu de Québec	Quebec
Canada	Centre Hospitalier Universitaire de Sherbrooke - Hopital Fleurimont	Sherbrooke	Quebec
Canada	Princess Margaret Cancer Center	Toronto	Ontario
China	Friendship Hospital, Capital Medical University	Beijing
China	Jiangsu Cancer Hospital	Nanjing City
China	Zhongshan Hospital Fudan University	Shanghai
China	Fudan University Shanghai Cancer Center	Shanghai City
Czechia	Fakultni nemocnice u sv. Anny v Brne	Brno
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Thomayerova nemocnice	Praha 4 - Krc
Denmark	Aalborg Universitetshospital; Klinik Kirurgi-Kræft, Onkologisk afd.	Aalborg
Denmark	Herlev Hospital; Afdeling for Kræftbehandling	Herlev
Denmark	Odense Universitetshospital, Onkologisk Afdeling R	Odense C
France	Institut Sainte-Catherine; Oncologie	Avignon
France	Centre Francois Baclesse; Oncologie	Caen
France	Hopital Louis Pasteur; Medecine B	Colmar
France	Centre Oscar Lambret; Chir Cancerologie General	Lille
France	Clinique Chenieux; Oncology	Limoges
France	Hopital Saint Louis, Service D Oncologie Medicale	Paris
France	Hopital d'Instruction des Armees de Begin	Saint-Mande
France	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse
France	Institut Gustave Roussy	Villejuif
Germany	Universitätsklinikum Freiburg; Chirurgische Klinik; Abteilung Urologie	Freiburg
Germany	Medizinische Hochschule Hannover; Klinik für Urologie und Onkologische Urologie	Hannover
Germany	Universitätsklinikum Münster, Klinik für Urologie und Kinderurologie	Münster
Germany	Universitätsklinikum Tübingen; Klinik für Urologie	Tübingen
Germany	Urologisches Zentrum Euregio; Würselen, Urologische Praxis am Wasserturm	Würselen
Greece	Alexandras Hospital; Dept. of Clin. Therapeutics, Athens Uni School of Medicine	Athens
Greece	Anticancer Hospital Ag Savas; 1St Dept of Internal Medicine	Athens
Greece	Athens Medical Center; Dept. of Oncology	Athens
Greece	IASO General Hospital of Athens	Athens
Greece	Agioi Anargyroi Cancer Hospital; 2Nd Oncology Dept.	Kifisia
Greece	University Hospital of Patras Medical Oncology	Patras
Greece	Papageorgiou General Hospital; Medical Oncology	Thessaloniki
Hungary	Orszagos Onkologiai Intezet; "C" Belgyógyászati-Onkológiai és Klinikai Farmakológiai Osztály	Budapest
Hungary	Semmelwies University of Medicine; Urology Dept.	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont ; Department of Oncology	Debrecen
Italy	Ospedale Area Aretina Nord; U.O.C. Oncologia	Arezzo	Toscana
Italy	Irccs Ist. Tumori Giovanni Paolo Ii; Dipartimento Oncologia Medica	Bari	Puglia
Italy	A.O. Istituti Ospitalieri - Cremona; S.C. Oncologia	Cremona	Lombardia
Italy	IRCCS AOU San Martino - IST; Oncologia Medica 1	Genova	Liguria
Italy	Irccs Istituto Europeo Di Oncologia (IEO); Cure Mediche	Milano	Lombardia
Italy	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2	Milano	Lombardia
Italy	A.O. Universitaria Policlinico Di Modena; Oncologia	Modena	Emilia-Romagna
Italy	ISTITUTO NAZIONALE TUMORI IRCCS FONDAZIONE G. PASCALE; Dipartimento Uro-Ginecologico	Napoli	Campania
Italy	IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Prima	Padova	Veneto
Italy	Azienda Ospedaliera San Camillo Forlanini; Oncologia Medica	Roma	Lazio
Italy	IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia	San Giovanni Rotondo	Puglia
Japan	Nagoya City University Hospital	Aichi
Japan	National Cancer Center East	Chiba
Japan	Toho University Sakura Medical Center	Chiba
Japan	Kyushu University Hospital	Fukuoka
Japan	National Hospital Organization Hokkaido Cancer Center	Hokkaido
Japan	Kitasato University Hospital	Kanagawa
Japan	Yokohama City University Medical Center	Kanagawa
Japan	University Hospital Kyoto Prefectural University of Medicine	Kyoto
Japan	Nara Medical University Hospital	Nara
Japan	Niigata University Medical & Dental Hospital	Niigata
Japan	Kansai Medical University Hospital	Osaka
Japan	Nippon Medical School Hospital	Tokyo
Japan	The Jikei University Hospital	Tokyo
Japan	Toranomon Hospital	Tokyo
Korea, Republic of	National Cancer Center	Goyang-si
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Poland	Medical University of Bialystok; Oncology clinic	Bialystok
Poland	Przychodnia Lekarska KOMED, Roman Karaszewski	Konin
Poland	Szpital Uniwersytecki w Krakowie, Oddzial Kliniczny Kliniki Onkologii	Kraków
Poland	Woj. Wielospec. Centrum Onkologii i Traumatologii	Lódz
Poland	SPZOZ Opolskie Centrum Onkologii im. Prof. Tadeusza Koszarawskiego	Opole
Poland	Europejskie Centrum Zdrowia Otwock Szpital im. Fryderyka Chopina, Klinika Onkologii	Otwock
Poland	Szpital Sw. Elzbiety - Mokotowskie Centrum Medyczne Sp. z o.o.	Warszawa
Poland	Wojewodzki Szpital; Specjalistyczny ul.	Wroclaw
Russian Federation	P.A. Herzen Oncological Inst. ; Oncology	Moscow
Russian Federation	Russian Scientific Center of Roentgenoradiology	Moscow
Russian Federation	SBEI HPE "The First St.Petersburg State Medical University n.a. acad. I.P.Pavlova"of MoH of RF	Sankt-peterburg	Leningrad
Spain	Institut Catala d´Oncologia Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clínic i Provincial; Servicio de Oncología	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau; Servicio de Oncologia	Barcelona
Spain	Hospital Universitari Vall d'Hebron; Oncology	Barcelona
Spain	Hospital Universitario Reina Sofia; Servicio de Oncologia	Córdoba	Cordoba
Spain	Insititut Catala D'Oncologia	Hospitalet de Llobregat	Barcelona
Spain	Hospital Clinico San Carlos; Servicio de Oncologia	Madrid
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga
Spain	Clinica Universitaria de Navarra; Servicio de Oncologia	Pamplona	Navarra
Spain	Corporacio Sanitaria Parc Tauli; Servicio de Oncologia	Sabadell	Barcelona
Spain	Hospital Universitario Virgen del Rocio; Servicio de Oncologia	Sevilla
Switzerland	Inselspital Bern; Universitätsklinik für medizinische Onkologie	Bern
Switzerland	Kantonsspital St. Gallen; Onkologie/Hämatologie	St. Gallen
Taiwan	Taichung Veterans General Hospital; Division of Urology	Taichung
Taiwan	National Taiwan University Hospital, Department of Urology	Taipei
Taiwan	TAIPEI VETERANS GENERAL HOSPITAL, Urology	Taipei
Taiwan	Chang Gung Memorial Hospital-LinKou; Urology	Taoyuan
United Kingdom	Royal Blackburn Hospital	Blackburn
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Barts and the London NHS Trust.	London
United Kingdom	Sarah Cannon Research Institute	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Royal Marsden Hospital; Institute of Cancer Research	Sutton
United States	New York Oncology Hematology, P.C.	Albany	New York
United States	Virginia Cancer Specialists - Alexandria	Alexandria	Virginia
United States	University of Colorado; Division of Medical Oncology	Aurora	Colorado
United States	Texas Oncology Cancer Center	Austin	Texas
United States	MSKCC at Basking Ridge	Basking Ridge	New Jersey
United States	Lynn Cancer Institute/Boca Raton Regional Hospital	Boca Raton	Florida
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Charleston Oncology, P .A	Charleston	South Carolina
United States	SCRI Tennessee Oncology Chattanooga	Chattanooga	Tennessee
United States	Oncology Hematology Care, Inc.	Cincinnati	Ohio
United States	James Cancer Hospital;Solove Research Institute	Columbus	Ohio
United States	Texas Oncology - Methodist Dallas Cancer Center	Dallas	Texas
United States	Karmanos Cancer Institute..	Detroit	Michigan
United States	City of Hope Medical Grp Inc.	Duarte	California
United States	SCRI Florida Cancer Specialists South	Fort Myers	Florida
United States	Texas Oncology, P.A. - Fort Worth	Fort Worth	Texas
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Texas Oncology - Memorial City	Houston	Texas
United States	Investigative Clin Rsch of IN	Indianapolis	Indiana
United States	Texas Oncology-Tyler	Irving	Texas
United States	University of California San Diego	La Jolla	California
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Kaiser Permanente San Diego - Los Angeles	Los Angeles	California
United States	Miami Cancer Institute of Baptist Health, Inc.	Miami	Florida
United States	Carolina Urologic Research Center	Myrtle Beach	South Carolina
United States	Yale School of Medicine	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	Nebraska Cancer Specialists; Oncology Hematology West, PC	Omaha	Nebraska
United States	Urology Cancer Center & GU Research Network	Omaha	Nebraska
United States	UC Irvine Medical Center	Orange	California
United States	Allegheny Cancer Center	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Cancer Institute; Division of Medical Oncology	Pittsburgh	Pennsylvania
United States	Miriam Hospital	Providence	Rhode Island
United States	Associates in Oncology/Hematology P.C.	Rockville	Maryland
United States	Florida Cancer Specialist, North Region	Saint Petersburg	Florida
United States	Pacific Hematology Oncology Associates	San Francisco	California
United States	Stamford Hospital; BCC, MOHR	Stamford	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Greece,  Hungary,  Italy,  Japan,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	Overall Survival is defined as the time from randomization to death from any cause.	Baseline until death from any cause (up to approximately 42 months)
Secondary	Percentage of Participants Who Survived at Month 12 and 24	OS (Overall Survival is defined as the time from randomization to death from any cause) probability at 12 and 24 months	Months 12, 24
Secondary	Time to First Symptomatic Skeletal Event (SSE)	An SSE is defined as external beam radiation therapy to relieve skeletal symptoms (including initiation of radium-223 dichloride or other types of radionuclide therapy to treat symptoms of bone metastases), new symptomatic pathologic bone fracture, clinically apparent occurrence of spinal cord compression, or tumor related orthopedic surgical intervention.	Baseline up to end of study (up to approximately 42 months)
Secondary	Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria	rPFS is defined as the time from randomization to the earliest occurrence of one of the following: A participant is considered to have progressed by bone scan if: The first bone scan with =2 new lesions compared to baseline is observed < 12 weeks from randomization and is confirmed by a second bone scan taken =6 weeks later showing =2 additional new lesions (a total of =4 new lesions compared to baseline); the date of progression is the date of the first post-treatment scan, OR After the first post-treatment scan, =2 new lesions are observed relative to the first post-treatment scan, which is confirmed on a subsequent scan =6 weeks later; the date of progression is the date of the post-treatment scan when =2 new lesions were first documented.; Progression of soft tissue lesions, as defined per PCWG3 modified RECIST v1.1; Death from any cause	Baseline until disease progression or death from any cause (up to approximately 42 months)
Secondary	Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria	rPFS is defined as the time from randomization to the earliest occurrence of one of the following: A participant is considered to have progressed by bone scan if: The first bone scan with =2 new lesions compared to baseline is observed < 12 weeks from randomization and is confirmed by a second bone scan taken =6 weeks later showing =2 additional new lesions (a total of =4 new lesions compared to baseline); the date of progression is the date of the first post-treatment scan, OR After the first post-treatment scan, =2 new lesions are observed relative to the first post-treatment scan, which is confirmed on a subsequent scan =6 weeks later; the date of progression is the date of the post-treatment scan when =2 new lesions were first documented.; Progression of soft tissue lesions, as defined per PCWG3 modified RECIST v1.1; Death from any cause	Months 6, 12
Secondary	Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline	PSA response rate, defined as a > 50% decrease in PSA from baseline that is confirmed after = 3 weeks by a consecutive confirmatory PSA measurement	Baseline until disease progression (up to approximately 42 months)
Secondary	Time to PSA Progression, Assessed as Per PCWG3 Criteria	In participants with no PSA decline from baseline, PSA progression is defined as a =25% increase and an absolute increase of =2 ng/mL above the baseline value, =12 weeks after baseline. In participants with an initial PSA decline from baseline, PSA progression is defined as a =25% increase and an absolute increase of =2 ng/mL above the nadir value, which is confirmed by a consecutive second value obtained =3 weeks later.	Baseline until disease progression (up to approximately 42 months)
Secondary	Percentage of Participant With Objective Response, as Determined by the Investigator Through Use of PCWG3 Criteria	Objective response rate in soft tissue lesions, defined as the percentage of participants with either a CR or PR on two consecutive occasions = 6 weeks apart, as determined by the investigator through use of PCWG3 criteria	Baseline until disease progression or death from any cause (up to approximately 42 months)
Secondary	Percentage of Participants With Adverse Events	Verbatim description of adverse events will be coded to MedDRA preferred terms and graded according to NCI CTCAE v4.0.	Baseline up to end of study (up to approximately 42 month
Secondary	Minimum Observed Serum Concentration (Cmin) of Atezolizumab	Atezolizumab serum concentration data (minimum [Cmin]) will be reported and summarized for each cycle where collected as appropriate.	Pre-infusion (0 hour[hr]) on Day 1 Cycles 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); treatment discontinuation visit, 120 days after last dose (up to approximately 42 months)
Secondary	Maximum Observed Serum Concentration (Cmax) of Atezolizumab	Atezolizumab serum concentration data (maximum [Cmax]) will be reported and summarized for each cycle where collected as appropriate.	Pre-infusion (0 hr) on Day 1 Cycles 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); 0.5 hr post-infusion (infusion duration: 60 minutes [min]) on Day 1 Cycle 1; treatment discontinuation visit, 120 days after last dose (up to approximately 42 months)
Secondary	Plasma Concentration of Enzalutamide	Plasma concentrations of Enzalutamide will be reported and summarized using descriptive statistics for each cycle and treatment arm, as appropriate.	Predose (0 hr) and 1 hr postdose on Day 1 Cycle 1 and 3 (Cycle length: 21 days); pre-dose (within 1 hr) on Day 1 Cycle 8
Secondary	Plasma Concentration of N-Desmethyl Enzalutamide	Plasma concentrations of N-desmethyl enzalutamide will be reported and summarized using descriptive statistics for each cycle and treatment arm, as appropriate.	Predose (0 hr) and 1 hr postdose on Day 1 Cycle 1 and 3 (Cycle length: 21 days); pre-dose (within 1 hr) on Day 1 Cycle 8
Secondary	Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab	The numbers and proportions of ATA-positive participants and ATA-negative participants at baseline (baseline prevalence) and after baseline (post-baseline incidence) will be summarized by treatment group.	Predose (0 hr) on Day 1 Cycles 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); at atezolizumab discontinuation visit (30 days after last dose); 120 days after last dose of atezolizumab; up to 42 months