Prostatic Neoplasms, Castration-Resistant
Conditions
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.
Interventions
Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg), intravenous (IV) infusion on Day 1 of each 21-day cycle.
Enzalutamide capsules will be administered orally at a dose of 160 mg daily.
Sponsors
Study design
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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 |
| 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 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 |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Australia, Austria, Belgium, Canada, China, Czechia, Denmark, France, Germany, Greece, Hungary, Italy, Japan, Poland, Russia, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 155 centres in 21 countries.
Pre-assignment details
Total 759 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Atezolizumab + Enzalutamide Participants received atezolizumab along with enzalutamide until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity. | 379 |
| Enzalutamide Participants received enzalutamide alone until investigator-assessed confirmed radiographic disease progression per PCWG3 criteria or unacceptable toxicity. | 380 |
| Total | 759 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 210 | 184 |
| Overall Study | discontinued before the treatment started | 0 | 1 |
| Overall Study | loss to contact | 1 | 0 |
| Overall Study | Lost to Follow-up | 12 | 12 |
| Overall Study | Physician Decision | 1 | 3 |
| Overall Study | started a new cancer therapy | 1 | 0 |
| Overall Study | Terminated by the Sponsor's decision | 100 | 126 |
| Overall Study | Withdrawal by Subject | 37 | 44 |
Baseline characteristics
| Characteristic | Atezolizumab + Enzalutamide | Enzalutamide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 282 Participants | 290 Participants | 572 Participants |
| Age, Categorical Between 18 and 65 years | 97 Participants | 90 Participants | 187 Participants |
| Age, Continuous | 70.5 Years STANDARD_DEVIATION 8.3 | 70.6 Years STANDARD_DEVIATION 8.5 | 70.5 Years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 11 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 337 Participants | 345 Participants | 682 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 24 Participants | 24 Participants | 48 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 71 Participants | 65 Participants | 136 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 7 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 20 Participants | 39 Participants |
| Race (NIH/OMB) White | 279 Participants | 287 Participants | 566 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 379 Participants | 380 Participants | 759 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 219 / 379 | 191 / 380 |
| other Total, other adverse events | 339 / 374 | 309 / 376 |
| serious Total, serious adverse events | 139 / 374 | 87 / 376 |
Outcome results
Overall Survival (OS)
Overall Survival is defined as the time from randomization to death from any cause.
Time frame: Baseline until death from any cause (up to approximately 42 months)
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Enzalutamide | Overall Survival (OS) | 15.2 Months |
| Enzalutamide | Overall Survival (OS) | 16.6 Months |
Maximum Observed Serum Concentration (Cmax) of Atezolizumab
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.
Time frame: Day Cycle 1 Day 1 0.5 hr post-infusion (infusion duration: 60 minutes [min])
Population: PK evaluable population. This population is defined as all randomized participants regardless of whether the assigned study treatment was received. For PK analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Atezolizumab + Enzalutamide | Maximum Observed Serum Concentration (Cmax) of Atezolizumab | 365 Microgram/mL | Geometric Coefficient of Variation 26.5 |
Minimum Observed Serum Concentration (Cmin) of Atezolizumab
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.
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)
Population: PK evaluable population. This population is defined as all randomized participants regardless of whether the assigned study treatment was received. For PK analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Unscheduled Predose | 32.9 microgram/mL | Geometric Coefficient of Variation 326.5 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 2, Day 1, pre-dose | 76.4 microgram/mL | Geometric Coefficient of Variation 69.4 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 3, Day 1, pre-dose | 124 microgram/mL | Geometric Coefficient of Variation 79.5 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 4, Day 1, pre-dose | 147 microgram/mL | Geometric Coefficient of Variation 65.1 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 8, Day 1, pre-dose | 157 microgram/mL | Geometric Coefficient of Variation 305.9 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 12, Day 1, pre-dose | 155 microgram/mL | Geometric Coefficient of Variation 497.4 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 16, Day 1, pre-dose | 137 microgram/mL | Geometric Coefficient of Variation 144.9 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Safety visit | 2.69 microgram/mL | Geometric Coefficient of Variation 1759.3 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Study Completion/Early Discontinuation | 82.3 microgram/mL | Geometric Coefficient of Variation 1008.1 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Study Completion/Early Discontinuation pre-dose | 65.3 microgram/mL | Geometric Coefficient of Variation 106.9 |
| Atezolizumab + Enzalutamide | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Unscheduled | 50.5 microgram/mL | — |
| Unknown | Minimum Observed Serum Concentration (Cmin) of Atezolizumab | Cycle 1, Day 1, pre-dose | — microgram/mL | — |
Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
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.
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
Population: The safety population is defined as participants who received any amount of any component of the study treatments (atezolizumab, or enzalutamide). Participants will be allocated to treatment arms according to the treatment they actually received (i.e., participants randomized to enzalutamide alone who received at least one full or partial dose of atezolizumab will be included in the atezolizumab arm for safety).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Atezolizumab + Enzalutamide | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | With Positive Sample at Baseline | 2 Participants |
| Atezolizumab + Enzalutamide | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Without Positive Sample at Baseline | 368 Participants |
| Atezolizumab + Enzalutamide | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Participants positive for Treatment Emergent ADA: treatment induced | 52 Participants |
| Atezolizumab + Enzalutamide | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Participants positive for Treatment Emergent ADA: treatment enhanced | 0 Participants |
| Atezolizumab + Enzalutamide | Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab | Participants negative for Treatment Emergent ADA | 320 Participants |
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
Time frame: Months 6, 12
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atezolizumab + Enzalutamide | Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria | 6 months | 41.84 Percentage of Participants |
| Atezolizumab + Enzalutamide | Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria | 12 months | 14.89 Percentage of Participants |
| Enzalutamide | Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria | 6 months | 39.64 Percentage of Participants |
| Enzalutamide | Percentage of Participants Who Are Radiographic Progression-Free, as Assessed by the Investigator and Adapted From the PCWG3 Criteria | 12 months | 13.45 Percentage of Participants |
Percentage of Participants Who Survived at Month 6 and 12
OS (Overall Survival is defined as the time from randomization to death from any cause) probability at 6 and 12 months
Time frame: Months 6, 12
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atezolizumab + Enzalutamide | Percentage of Participants Who Survived at Month 6 and 12 | 6 Months | 85.12 Percentage of Participants |
| Atezolizumab + Enzalutamide | Percentage of Participants Who Survived at Month 6 and 12 | 12 Months | 60.61 Percentage of Participants |
| Enzalutamide | Percentage of Participants Who Survived at Month 6 and 12 | 6 Months | 85.32 Percentage of Participants |
| Enzalutamide | Percentage of Participants Who Survived at Month 6 and 12 | 12 Months | 64.65 Percentage of Participants |
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.
Time frame: Baseline up to end of study (up to approximately 42 month)
Population: The safety population is defined as participants who received any amount of any component of the study treatments (atezolizumab, or enzalutamide). Participants will be allocated to treatment arms according to the treatment they actually received (i.e., participants randomized to enzalutamide alone who received at least one full or partial dose of atezolizumab will be included in the atezolizumab arm for safety)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atezolizumab + Enzalutamide | Percentage of Participants With Adverse Events | Total number of participants with at least one adverse event | 96.8 Percentage of Participants |
| Atezolizumab + Enzalutamide | Percentage of Participants With Adverse Events | Total number of participants with at least one treatment related AE | 78.1 Percentage of Participants |
| Enzalutamide | Percentage of Participants With Adverse Events | Total number of participants with at least one adverse event | 92.3 Percentage of Participants |
| Enzalutamide | Percentage of Participants With Adverse Events | Total number of participants with at least one treatment related AE | 51.6 Percentage of Participants |
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
Time frame: Baseline until disease progression (up to approximately 42 months)
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Enzalutamide | Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline | 25.9 Percentage of Participants |
| Enzalutamide | Percentage of Participants With Greater Than (>) 50 Percent (%) Decrease in Prostate-Specific Antigen (PSA) From Baseline | 24.2 Percentage of Participants |
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
Time frame: Baseline until disease progression or death from any cause (up to approximately 42 months)
Population: * Participants were classified as missing or unevaluable if no post-baseline response assessments were available or all post-baseline response baseline assessments were unevaluable.~* Responders had to have a CR or PR on two consecutive occasions at least 6 weeks apart.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Enzalutamide | Percentage of Participant With Objective Response, as Determined by the Investigator Through Use of PCWG3 Criteria | 13.7 Percentage of Participants |
| Enzalutamide | Percentage of Participant With Objective Response, as Determined by the Investigator Through Use of PCWG3 Criteria | 7.4 Percentage of Participants |
Plasma Concentration of Enzalutamide
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.
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
Population: PK evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atezolizumab + Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 1 Day 1 1 Hr Post | 1.51 Microgram/mL | Geometric Coefficient of Variation 406.4 |
| Atezolizumab + Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 3 Day 1 1 Hr Post | 14.2 Microgram/mL | Geometric Coefficient of Variation 27.3 |
| Atezolizumab + Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 8 Day 1 Predose | 11.3 Microgram/mL | Geometric Coefficient of Variation 103.7 |
| Atezolizumab + Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 3 Day 1 Predose | 13.1 Microgram/mL | Geometric Coefficient of Variation 29 |
| Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 8 Day 1 Predose | 12.6 Microgram/mL | Geometric Coefficient of Variation 30.5 |
| Enzalutamide | Plasma Concentration of Enzalutamide | Unscheduled Predose | 10.5 Microgram/mL | — |
| Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 1 Day 1 1 Hr Post | 2.42 Microgram/mL | Geometric Coefficient of Variation 270.6 |
| Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 3 Day 1 Predose | 13.8 Microgram/mL | Geometric Coefficient of Variation 20.7 |
| Enzalutamide | Plasma Concentration of Enzalutamide | Cycle 3 Day 1 1 Hr Post | 16.0 Microgram/mL | Geometric Coefficient of Variation 19.8 |
| Unknown | Plasma Concentration of Enzalutamide | Cycle 1 Day 1 Predose | — Microgram/mL | — |
Plasma Concentration of N-Desmethyl Enzalutamide
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.
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
Population: PK evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Atezolizumab + Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 3 Day 1 1 Hr Post | 10.6 Microgram/mL | Geometric Coefficient of Variation 34.2 |
| Atezolizumab + Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 3 Day 1 Predose | 11.9 Microgram/mL | Geometric Coefficient of Variation 33.1 |
| Atezolizumab + Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 8 Day 1 Predose | 12.8 Microgram/mL | Geometric Coefficient of Variation 36.8 |
| Atezolizumab + Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 1 Day 1 1 Hr Post | 0.02 Microgram/mL | — |
| Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 8 Day 1 Predose | 13.1 Microgram/mL | Geometric Coefficient of Variation 32.6 |
| Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Unscheduled Predose | 13.3 Microgram/mL | — |
| Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 1 Day 1 1 Hr Post | 0.03 Microgram/mL | — |
| Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 3 Day 1 Predose | 11.9 Microgram/mL | Geometric Coefficient of Variation 28.8 |
| Enzalutamide | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 3 Day 1 1 Hr Post | 10.9 Microgram/mL | Geometric Coefficient of Variation 29.8 |
| Unknown | Plasma Concentration of N-Desmethyl Enzalutamide | Cycle 1 Day 1 Predose | — Microgram/mL | — |
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
Time frame: Baseline until disease progression or death from any cause (up to approximately 42 months)
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Enzalutamide | Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria | 4.2 Months |
| Enzalutamide | Radiographic Progression-Free Survival (rPFS), as Assessed by the Investigator and Adapted From the PCWG3 Criteria | 4.1 Months |
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.
Time frame: Baseline up to end of study (up to approximately 42 months)
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants from whom data was collected and analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Enzalutamide | Time to First Symptomatic Skeletal Event (SSE) | 24.1 Months |
| Enzalutamide | Time to First Symptomatic Skeletal Event (SSE) | 24.9 Months |
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.
Time frame: Baseline until disease progression (up to approximately 42 months)
Population: The intent-to-treat (ITT) population is defined as all randomized participants regardless of whether the assigned study treatment was received. For efficacy analyses, participants were analyzed according to their randomized treatment assignment. Here, Number Analyzed refers to number of participants in the ITT population with measurable soft tissue lesions at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Enzalutamide | Time to PSA Progression, Assessed as Per PCWG3 Criteria | 2.8 Months |
| Enzalutamide | Time to PSA Progression, Assessed as Per PCWG3 Criteria | 2.8 Months |