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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 (IMbassador250)

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ClinicalTrials.gov Identifier: NCT03016312
Recruitment Status : Completed
First Posted : January 10, 2017
Results First Posted : April 30, 2021
Last Update Posted : February 17, 2023
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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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.

Condition or disease Intervention/treatment Phase
Prostatic Neoplasms, Castration-Resistant Drug: Atezolizumab Drug: Enzalutamide Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 772 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 10, 2017
Actual Primary Completion Date : December 20, 2022
Actual Study Completion Date : December 20, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arms and Interventions
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Arm Intervention/treatment
Experimental: Atezolizumab + 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).
 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.
Other Name: Tecentriq®

Drug: Enzalutamide
Enzalutamide capsules will be administered orally at a dose of 160 mg daily.
Other Name: Xtandi®
Active Comparator: Enzalutamide
Participants will receive enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity (up to approximately 42 months).
 Drug: Enzalutamide
Enzalutamide capsules will be administered orally at a dose of 160 mg daily.
Other Name: Xtandi®


Outcome Measures
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Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: 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 :
  1. Percentage of Participants Who Survived at Month 12 and 24 [ Time Frame: Months 12, 24 ]
    OS (Overall Survival is defined as the time from randomization to death from any cause) probability at 12 and 24 months

  2. Time to First Symptomatic Skeletal Event (SSE) [ Time Frame: 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.

  3. Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria [ Time Frame: 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

  4. Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria [ Time Frame: 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

  5. Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline [ Time Frame: 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

  6. Time to PSA Progression, Assessed as Per PCWG3 Criteria [ Time Frame: 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.

  7. Percentage of Participant With Objective Response, as Determined by the Investigator Through Use of PCWG3 Criteria [ Time Frame: 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

  8. Percentage of Participants With Adverse Events [ Time Frame: 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.

  9. Minimum Observed Serum Concentration (Cmin) of Atezolizumab [ Time Frame: 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) ]
    Atezolizumab serum concentration data (minimum [Cmin]) will be reported and summarized for each cycle where collected as appropriate.

  10. Maximum Observed Serum Concentration (Cmax) of Atezolizumab [ Time Frame: 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) ]
    Atezolizumab serum concentration data (maximum [Cmax]) will be reported and summarized for each cycle where collected as appropriate.

  11. Plasma Concentration of Enzalutamide [ Time Frame: 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 ]
    Plasma concentrations of Enzalutamide will be reported and summarized using descriptive statistics for each cycle and treatment arm, as appropriate.

  12. Plasma Concentration of N-Desmethyl Enzalutamide [ Time Frame: 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 ]
    Plasma concentrations of N-desmethyl enzalutamide will be reported and summarized using descriptive statistics for each cycle and treatment arm, as appropriate.

  13. Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab [ Time Frame: 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 ATA-positive participants and ATA-negative participants at baseline (baseline prevalence) and after baseline (post-baseline incidence) will be summarized by treatment group.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03016312


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol and Statistical Analysis Plan  [PDF] February 14, 2020

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03016312    
Other Study ID Numbers: CO39385
2016-003092-22 ( EudraCT Number )
First Posted: January 10, 2017    Key Record Dates
Results First Posted: April 30, 2021
Last Update Posted: February 17, 2023
Last Verified: January 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Prostatic Neoplasms
Prostatic Neoplasms, Castration-Resistant
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Genital Diseases
 Urogenital Diseases
Prostatic Diseases
Male Urogenital Diseases
Atezolizumab
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Antineoplastic Agents