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)

• 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: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: January 9, 2017
• First Posted Date: January 10, 2017
• Results First Submitted Date: April 5, 2021
• Results First Posted Date: April 30, 2021
• Last Update Posted Date: February 17, 2023
• Actual Study Start Date: January 10, 2017
• Actual Primary Completion Date: December 20, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 5, 2021)

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.

• Original Primary Outcome Measures (submitted: January 9, 2017): Overall surivival (OS) [ Time Frame: Baseline until death ( up to approximately 42 months) ]

Current Secondary Outcome Measures (submitted: April 5, 2021)

• 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
• 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.
• 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
• 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
• 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
• 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.
• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: January 9, 2017)

• Percentage of Participants who Survived at Month 12 and 24 [ Time Frame: Months 12, 24 ]
• Time to Cancer-Related Pain Progression, as Assessed Using Modified Brief Pain Inventory (BPI) [ Time Frame: Baseline until disease progression (up to approximately 42 months) ]
• Time to First Symptomatic Skeletal Event (SSE) [ Time Frame: Baseline up to 42 months ]
• Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria [ Time Frame: Baseline until disease progression or death (assessed at baseline then every 9 weeks for first 27 weeks thereafter every 12 weeks until confirmed radiographic disease progression, death, loss to follow-up, up to approximately 42 months) ]
• Percentage of Participants Who are Radiographic Progression-Free at Month 6 and 12 [ Time Frame: Months 6, 12 ]
• Immune-Modified rPFS, as Assessed by the Investigator [ Time Frame: Baseline until disease progression or death (assessed at baseline then every 9 weeks for first 27 weeks thereafter every 12 weeks until confirmed radiographic disease progression, death, loss to follow-up, up to approximately 42 months) ]
• Percentage of Participants With Greater Than (>) 50% Decrease in Prostate-Specific Antigen (PSA) From Baseline [ Time Frame: Baseline up to 42 months (assessed at Screening then prior to study treatment on Day 1 of every cycle [cycle length: 21 days], until confirmed radiographic disease progression, up to 42 months) ]
• Time to PSA Progression [ Time Frame: Baseline up to 42 months (assessed at Screening then prior to study treatment on Day 1 of every cycle (cycle length: 21 days), until confirmed radiographic disease progression, up to 42 months) ]
• Percentage of Participant With Objective Response, as Determined by the Investigator Through use of PCWG3 Criteria and Immune Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Criteria [ Time Frame: Baseline until disease progression or death (assessed at baseline then every 9 weeks for first 27 weeks thereafter every 12 weeks until confirmed radiographic disease progression, death, loss to follow-up, up to approximately 42 months) ]
• Percentage of Participants With Adverse Events [ Time Frame: Baseline up to 42 month ]
• Minimum Observed Serum Concentration (Cmin) of Atezolizumab [ Time Frame: predose (0 hours[h]) on Day 1 Cycle 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); at atezolizumab discontinuation visit (30 days after last dose); and 120 days after last dose of atezolizumab up to 42 months ]
• Maximum Observed Serum Concentration (Cmax) of Atezolizumab [ Time Frame: predose (0 h) on Day 1 Cycle 1, 2, 3, 4, 8, 12, 16 (Cycle length: 21 days); 0.5h postdose (infusion:60 minutes) on Day 1 of Cycle 1; at atezolizumab discontinuation visit (30 days after last dose); 120 days after last dose of Atezolizumab up to 42 months ]
• Plasma Concentration of Enzalutamide [ Time Frame: predose (0 h) and 1 h postdose on Day 1 Cycle 1 and 3 (Cycle length: 21 days); pre-dose (-1 h) on Day 1 Cycle 8; up to 42 months ]
• Plasma Concentration of N-desmethyl Enzalutamide [ Time Frame: predose (0 h) and 1 h postdose on Day 1 Cycle 1 and 3 (Cycle length: 21 days); pre-dose (-1 h) on Day 1 Cycle 8; up to 42 months ]
• Percentage of Participants With Anti-therapeutic Antibody (ATAs) to Atezolizumab [ Time Frame: predose (0 h) on Day 1 Cycle 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 ]
• Percentage of Participants who Required Initiation or Increase in Opiate Analgesic use for Cancer Pain [ Time Frame: Baseline up to 42 months ]
• Time to Initiation or Increased Opiate Analgesic Use [ Time Frame: Baseline up to 42 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: 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.
  Other Name: Tecentriq®
• Drug: Enzalutamide
  Enzalutamide capsules will be administered orally at a dose of 160 mg daily.
  Other Name: Xtandi®

Study Arms

• 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).
  Interventions:

  • Drug: Atezolizumab
  • Drug: Enzalutamide
• 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).
  Intervention: Drug: Enzalutamide

• Publications *: Powles T, Yuen KC, Gillessen S, Kadel EE 3rd, Rathkopf D, Matsubara N, Drake CG, Fizazi K, Piulats JM, Wysocki PJ, Buchschacher GL Jr, Alekseev B, Mellado B, Karaszewska B, Doss JF, Rasuo G, Datye A, Mariathasan S, Williams P, Sweeney CJ. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022 Jan;28(1):144-153. doi: 10.1038/s41591-021-01600-6. Epub 2022 Jan 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2023): 772
• Original Estimated Enrollment (submitted: January 9, 2017): 558
• Actual Study Completion Date: December 20, 2022
• Actual Primary Completion Date: December 20, 2022 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, China, Czechia, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Korea, Republic of, Poland, Russian Federation, Spain, Switzerland, Taiwan, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT03016312
• Other Study ID Numbers: CO39385; 2016-003092-22 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: January 2023