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

Phase 3

Completed

Conditions: Prostatic Neoplasms, Castration-Resistant

Interventions: Drug: Atezolizumab
Drug: Enzalutamide

Registration Number: NCT03016312

Lead Sponsor: Hoffmann-La Roche

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 759

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Atezolizumab + Enzalutamide	Enzalutamide	Participants will receive atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity (up to approximately 42 months).
Atezolizumab + Enzalutamide	Atezolizumab	Participants will receive atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity (up to approximately 42 months).
Enzalutamide	Enzalutamide	Participants will receive enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity (up to approximately 42 months).

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	Baseline until death from any cause (up to approximately 42 months)	Overall Survival is defined as the time from randomization to death from any cause.

Secondary Outcome Measures

Name	Time	Method
Time to PSA Progression, Assessed as Per PCWG3 Criteria	Baseline until disease progression (up to approximately 42 months)	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.
Percentage of Participant With Objective Response, as Determined by the Investigator Through Use of PCWG3 Criteria	Baseline until disease progression or death from any cause (up to approximately 42 months)	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
Percentage of Participants With Adverse Events	Baseline up to end of study (up to approximately 42 month)	Verbatim description of adverse events will be coded to MedDRA preferred terms and graded according to NCI CTCAE v4.0.
Plasma Concentration of Enzalutamide	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	Safety visit-Discontinued participants had these visits within approximately 120 days after the last dosing; Study Completion Pre-dose visit-Participants had these visits at the last treatment dosing, samples were taken before the last dosing; Early Discontinuation Pre-dose visit-Participants who discontinued the study had these visits within the 30 days after their last dosing but samples were takes before their last dosing; Study Completion visit-Participants had these visits at their last treatment dosing but samples were taken after their last dosing; Early Discontinuation visit-Participants who discontinued the study had the visits within the 30 days after their last dosing but samples were taken after their last dosing; Unscheduled and Unscheduled Pre-dose Visits- At these visits, participants' samples were collected without dosing event and before dosing dosing at a visit unscheduled per protocol respectively. Enzalutamide Arm had no Atezolizumab dosing.
Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria	Baseline until disease progression or death from any cause (up to approximately 42 months)	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
Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria	Months 6, 12	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
Minimum Observed Serum Concentration (Cmin) of Atezolizumab	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)	Safety visit-Discontinued participants had these visits within approximately 120 days after the last dosing; Study Completion Pre-dose visit-Participants had these visits at the last treatment dosing, samples were taken before the last dosing; Early Discontinuation Pre-dose visit-Participants who discontinued the study had these visits within the 30 days after their last dosing but samples were takes before their last dosing; Study Completion visit-Participants had these visits at their last treatment dosing but samples were taken after their last dosing; Early Discontinuation visit-Participants who discontinued the study had the visits within the 30 days after their last dosing but samples were taken after their last dosing; Unscheduled and Unscheduled Pre-dose Visits- At these visits, participants' samples were collected without dosing event and before dosing dosing at a visit unscheduled per protocol respectively. Enzalutamide Arm had no Atezolizumab dosing.
Plasma Concentration of N-Desmethyl Enzalutamide	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	Safety visit-Discontinued participants had these visits within approximately 120 days after the last dosing; Study Completion Pre-dose visit-Participants had these visits at the last treatment dosing, samples were taken before the last dosing; Early Discontinuation Pre-dose visit-Participants who discontinued the study had these visits within the 30 days after their last dosing but samples were takes before their last dosing; Study Completion visit-Participants had these visits at their last treatment dosing but samples were taken after their last dosing; Early Discontinuation visit-Participants who discontinued the study had the visits within the 30 days after their last dosing but samples were taken after their last dosing; Unscheduled and Unscheduled Pre-dose Visits- At these visits, participants' samples were collected without dosing event and before dosing dosing at a visit unscheduled per protocol respectively. Enzalutamide Arm had no Atezolizumab dosing.
Percentage of Participants Who Survived at Month 6 and 12	Months 6, 12	OS (Overall Survival is defined as the time from randomization to death from any cause) probability at 6 and 12 months
Time to First Symptomatic Skeletal Event (SSE)	Baseline up to end of study (up to approximately 42 months)	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.
Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline	Baseline until disease progression (up to approximately 42 months)	PSA response rate, defined as a \> 50% decrease in PSA from baseline that is confirmed after ≥ 3 weeks by a consecutive confirmatory PSA measurement
Maximum Observed Serum Concentration (Cmax) of Atezolizumab	Day Cycle 1 Day 1 0.5 hr post-infusion (infusion duration: 60 minutes [min])	Safety visit-Discontinued participants had these visits within approximately 120 days after the last dosing; Study Completion Pre-dose visit-Participants had these visits at the last treatment dosing, samples were taken before the last dosing; Early Discontinuation Pre-dose visit-Participants who discontinued the study had these visits within the 30 days after their last dosing but samples were takes before their last dosing; Study Completion visit-Participants had these visits at their last treatment dosing but samples were taken after their last dosing; Early Discontinuation visit-Participants who discontinued the study had the visits within the 30 days after their last dosing but samples were taken after their last dosing; Unscheduled and Unscheduled Pre-dose Visits- At these visits, participants' samples were collected without dosing event and before dosing dosing at a visit unscheduled per protocol respectively. Enzalutamide Arm had no Atezolizumab dosing.
Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab	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	The numbers and proportions of ADA-positive participants and ADA-negative participants at baseline (baseline prevalence) and after baseline (post-baseline incidence) will be summarized by treatment group. Enzalutamide Arm has no Atezolizumab dosing therefore no participants to include here for Atezolizumab ADA.

Trial Locations

Locations (158): City of Hope Medical Grp Inc.
🇺🇸
Duarte, California, United States
University of California San Diego
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La Jolla, California, United States
Kaiser Permanente San Diego - Los Angeles
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Los Angeles, California, United States
UC Irvine Medical Center
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Orange, California, United States
Pacific Hematology Oncology Associates
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San Francisco, California, United States
University of Colorado; Division of Medical Oncology
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Aurora, Colorado, United States
Yale School of Medicine
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New Haven, Connecticut, United States
Stamford Hospital; BCC, MOHR
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Stamford, Connecticut, United States
Lynn Cancer Institute/Boca Raton Regional Hospital
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Boca Raton, Florida, United States
SCRI Florida Cancer Specialists South
🇺🇸
Fort Myers, Florida, United States
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City of Hope Medical Grp Inc.
🇺🇸Duarte, California, United States