A Study of Nivolumab Plus Ipilimumab, Ipilimumab Alone, or Cabazitaxel in Men With Metastatic Castration-Resistant Prostate Cancer (CheckMate 650)

In Cohort D, ORR is defined as the percentage of participants who had confirmed complete or partial BOR by BICR among randomized subjects with measurable disease at baseline as entered in Interactive Response Technologies web-based system (IWRS). For participants without documented progression or subsequent therapy, all available response assessments will contribute to the BOR assessment. Partial Response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Tumor assessments were performed every 8 weeks (± 7 days) for 6 months since treatment initiation and thereafter every 12 weeks (± 7 days). Confidence-interval based on Clopper Pearson method.

Time frame: From randomization to the date of objectively documented progression or the date of subsequent systemic anti-cancer therapy, whichever occurred first (assessed up to approximately 61 months)

Population: All randomized Cohort D participants with measurable disease at baseline. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

Objective response rate (ORR) is defined as the percent of participants who had confirmed complete or partial best overall response (BOR) per retrospective Blinded Independent Central Review (BICR) among treated participants with measurable disease at baseline. For participants without documented progression by RECIST v1.1 or subsequent therapy, all available response assessments contributed to the BOR assessment. Partial Response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Tumor assessments were performed every 8 weeks (± 7 days) for 6 months since treatment initiation and thereafter every 12 weeks (± 7 days). Confidence-interval based on Clopper Pearson method.

Time frame: From first dose to the date of objectively documented progression or the date of subsequent systemic anti-cancer therapy, whichever occurred first (assessed up to approximately 61 months)

Population: All treated Cohort B and C participants with measurable disease at baseline; pre-specified only to be collected for Cohorts B and C.

Radiographic progression-free survival (rPFS) is defined as the time between the date of randomization and the first date of documented progression per BICR or death due to any cause, whichever occurs first. The following progressive diseases were collected, documented and assessed as below: Radiographic progression per BICR assessment 1. Bone disease progression by (Prostate Cancer Working Group) PCWG2 2. Non-bone soft tissue disease progression by RECIST v1.1 Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates.

Time frame: From randomization and the first date of documented progression or death due to any cause, whichever occurs first (assessed up to approximately 61 months)

Population: All randomized Cohort D participants (i) Participants who did not progress or die were censored on the date of their last evaluable tumor assessment (ie, bone scan, CT, MRI). (ii) Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

Radiographic progression-free survival (rPFS) is defined as the time between the date of first treatment and the first date of documented radiographic progression or death due to any cause, whichever occurs first. The following progressive diseases were collected, documented and assessed as below: Radiographic progression per retrospective Blinded Independent Central Review (BICR) assessment 1. Bone disease progression by Prostate Cancer Working Group (PCWG2) 2. Non-bone soft tissue disease progression by RECIST v1.1 Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates.

Time frame: From first dose to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months)

Population: All treated Cohort B and C participants. (i) Participants who did not progress or die were censored on the date of their last evaluable tumor assessment (ie, bone scan, CT, MRI). (ii) Participants who did not have any on study tumor assessments and did not die were censored on their date of first treatment. Pre-specified only to be collected for Cohorts B and C.

The European Quality of Life 5D-3L Scale (EQ-5D-3L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. Responses are: '1' = no problem, and '3' = the most serious problem. The responses are combined in a 5-digit number. These health states are converted to a single index value using the crosswalk method to the EQ-5D-3L value set from the United Kingdom (UK). The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility. Baseline evaluations or events are defined as occurring before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations.

Time frame: At baseline and 4 weeks after first dose.

Population: All randomized Cohort D participants with baseline and week 4 scores

The European Quality of Life 5D-3L Scale (EQ-5D-3L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. Responses are: '1' = no problem, and '3' = the most serious problem. The responses are combined in a 5-digit number. These health states are converted to a single index value using the crosswalk method to the EQ-5D-3L value set from the United Kingdom (UK). The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility. Baseline evaluations or events are defined as occurring before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations.

Time frame: At baseline and at Week 4 of Cycle 2.

Population: All treated Cohort B and C participants with baseline and week 4 (cycle 2) scores. Pre-specified only to be collected for Cohorts B and C.

The Functional Assessment of Cancer Therapy - Prostate (FACT-P) is a multidimensional, self-report Quality of Life (QoL) instrument designed for use with prostate cancer patients. It consists of 27 core items. The Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being. This is further supplemented by the Prostate Cancer Subscale (PCS), 12 disease-specific items to assess for prostate-related symptoms. Each item is rated from 0 (Not at all) to 4 (Very much) and combined to produce subscale scores for each domain, a Trial Outcome Index which is based on the Physical and Functional well-being scales and the PCS as well as a total score which ranges from 0 to 156. Higher scores represent better QoL. Baseline evaluations or events were defined as those that occur before or on the date and time of the first dose of study treatment.

Time frame: At baseline and 4 weeks after first dose.

Population: All randomized Cohort D participants with baseline and week 4 scores; pre-specified for data to be collected only from Cohort D participants.

Change between Mean BPI-SF scores at baseline and week 4 (cycle 2). The BPI-SF measures pain severity through the use of a numerical rating scale. Participants rate the severity of their pain at its ''worst,'' ''least,'' and ''average'' in the last 24 hours using an 11-point numerical rating scale with anchors of ''0 = no pain'' and ''10 = pain as bad as you can imagine.'' A higher score = a worse outcome. Pain Severity Score = Mean of items 3-6 (pain at its worst, pain at its least). Baseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations.

Time frame: At baseline and 4 weeks after first dose.

Population: All randomized Cohort D participants with baseline and week 4 scores

Change between Mean BPI-SF scores at baseline and week 4 (cycle 2). The BPI-SF measures pain severity through the use of a numerical rating scale. Participants rate the severity of their pain at its ''worst,'' ''least,'' and ''average'' in the last 24 hours using an 11-point numerical rating scale with anchors of ''0 = no pain'' and ''10 = pain as bad as you can imagine.'' A higher score = a worse outcome. Pain Severity Score = Mean of items 3-6 (pain at its worst, pain at its least). Baseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations.

Time frame: At baseline and Week 4 (Cycle 2)

Population: All treated Cohort B and C participants with baseline and week 4 (cycle 2) scores. Pre-specified only to be collected for Cohorts B and C.

Overall survival (OS) is defined as the time from randomization to the date of death from any cause. For participants who were alive, their survival time was censored at the last known alive date. Overall survival was censored for participants at the date of first treatment if they had no follow-up. Based on Kaplan-Meier estimates.

Time frame: From randomization to the date of death due to any cause (assessed up to approximately 93 months)

Population: All randomized participants in Cohort D.

Overall survival (OS) is defined as the time from first treatment to the date of death from any cause. For participants who were alive, their survival time was censored at the last known alive date. Overall survival was censored for participants at the date of first treatment if they had no follow-up. Based on Kaplan-Meier estimates.

Time frame: From first dose to the date of death due to any cause (assessed up to approximately 61 months)

Population: All treated participants in Cohorts B and C; pre-specified only to be collected for Cohorts B and C.

The percent of participants with a 50% or greater decrease in prostate-specific antigen (PSA) from baseline to the lowest post-baseline PSA result. Baseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. Confidence-interval based on Clopper Pearson method.

Time frame: From baseline to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 93 months)

Population: All randomized participants with PSA values at baseline and at least one post-baseline assessment in Cohort D. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported.

The percent of participants with a 50% or greater decrease in prostate-specific antigen (PSA) from baseline to the lowest post-baseline PSA result. BBaseline evaluations or events are defined as evaluations or events that occur before the date and time of the first dose of study treatment. Evaluations on the same date and time of the first dose of study treatment were considered as baseline evaluations. Confidence-interval based on Clopper Pearson method.

Time frame: From baseline to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months)

Population: All treated participants with PSA values at baseline and at least one postbaseline assessment in Cohorts B and C. Pre-specified only to be collected for Cohorts B and C.

Radiographic/clinical progression-free survival (rcPFS) is the time between first dose and first documented progression or death due to any cause, whichever occurred first. Radiographic progression per Investigator assessment: 1. Bone disease progression by Prostate Cancer Working Group (PCWG2) 2. Non-bone soft tissue disease progression by RECIST v1.1 Clinical progression per investigator assessment: 1. Need for palliative radiation therapy involving more than one site, OR 2. Surgery of kyphoplasty to any neoplastic lesion, OR 3. Cancer-associated clinical deterioration determined by treating physician. Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates.

Time frame: From randomization and the first date of documented progression or death due to any cause, whichever occurs first (assessed up to approximately 93 months)

Population: All randomized Cohort D participants (i) Participants who did not progress or die were censored on the date of their last evaluable tumor assessment (ie, bone scan, CT, MRI). (ii) Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

Radiographic/clinical progression-free survival (rcPFS) is the time between first dose and first documented progression or death due to any cause, whichever occurred first. Radiographic progression per Investigator assessment: 1. Bone disease progression by Prostate Cancer Working Group (PCWG2) 2. Non-bone soft tissue disease progression by RECIST v1.1 Clinical progression per investigator assessment: 1. Need for palliative radiation therapy involving more than one site, OR 2. Surgery of kyphoplasty to any neoplastic lesion, OR 3. Cancer-associated clinical deterioration determined by treating physician. Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates.

Time frame: From first dose to the date of objectively documented progression or death due to any cause, whichever occurred first (assessed up to approximately 61 months)

Population: All treated Cohort B, C participants. (i) Participants who did not progress or die were censored on the date of their last evaluable tumor assessment (ie, bone scan, CT, MRI). (ii) Participants who did not have any on study tumor assessments and did not die were censored on their date of first treatment. Pre-specified only to be collected for Cohorts B and C.

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation in a participant administered study treatment and that does not necessarily have a causal relationship with this treatment.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 6.19 months assessed up to approximately 26.8 months)

Population: All treated participants in Cohort D. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported.

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation in a participant administered study treatment and that does not necessarily have a causal relationship with this treatment.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months)

Population: All treated participants in Cohorts A, B and C

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 6.19 months assessed up to approximately 26.8 months)

Population: All treated participants in Cohort D. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported.

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months)

Population: All treated participants in Cohorts A, B and C

Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity.

Time frame: From first dose to 100 days after last dose of study therapy (an average of 8.48 months assessed up to approximately 29.09 months)

Population: All treated participants in Cohort D. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported.

Immune-mediated adverse events (IMAEs) are AEs consistent with an immune-mediated mechanism or immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor progression) have been ruled out. IMAEs can include events with an alternate etiology which were exacerbated by the induction of autoimmunity.

Time frame: From first dose to 100 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 20.7 months)

Population: All treated participants in Cohorts A, B and C.

A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 6.19 months assessed up to approximately 26.8 months)

Population: All treated participants in Cohort D. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported.

A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months)

Population: All treated participants in Cohorts A, B and C

Death due to any cause.

Time frame: From first dose to 100 days after last dose of study therapy (an average of 8.48 months assessed up to approximately 29.09 months)

Population: All treated participants in Cohort D. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported.

Death due to any cause.

Time frame: From first dose to 100 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 20.7 months).

Population: All treated participants in Cohorts A, B and C.

The number of participants with an change in laboratory values from baseline Grade in Cohort D.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 6.19 months assessed up to approximately 26.8 months)

Population: All treated participants in Cohort D with baseline laboratory measurements. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

The number of participants with a change in laboratory values from baseline Grade in Cohorts A, B and C.

Time frame: From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months)

Population: All treated participants in Cohorts A, B and C with baseline laboratory measurements.

The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal

Time frame: From first dose to 30 days after last dose of study therapy (an average of 6.19 months assessed up to approximately 26.8 months)

Population: All Treated Participants in Cohort D with at least one on-treatment liver function measurement. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

The number of participants with laboratory abnormalities in specific liver tests based on SI conventional units. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase ULN = Upper Limit of Normal

Time frame: From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months)

Population: All Treated Participants in Cohorts A, B and C with at least one on-treatment liver function measurement.

The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal

Time frame: From first dose to 30 days after last dose of study therapy (an average of 2.8 months assessed up to approximately 18.2 months)

Population: Treated participants in Cohorts A, B and C with at least one on-treatment TSH measurement. Treated subjects in Cohort B with adequate follow-up of at least 24 weeks are included.

The number of participants with laboratory abnormalities in specific thyroid tests based on SI conventional units. TSH = Thyroid Stimulating Hormone LLN = Lower Limit of Normal ULN = Upper Limit of Normal

Time frame: From first dose to 30 days after last dose of study therapy (an average of 6.19 months assessed up to approximately 26.8 months)

Population: Treated participants in Cohort D with at least one on-treatment TSH measurement. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

In Cohort D, ORR is defined as the percentage of participants who had confirmed complete or partial BOR by BICR among randomized subjects with measurable disease at baseline as entered in Interactive Response Technologies web-based system (IWRS). For participants without documented progression or subsequent therapy, all available response assessments will contribute to the BOR assessment. Partial Response is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Tumor assessments were performed every 8 weeks (± 7 days) for 6 months since treatment initiation and thereafter every 12 weeks (± 7 days). Confidence-interval based on Clopper Pearson method.

Time frame: From randomization to the date of objectively documented progression or the date of subsequent systemic anti-cancer therapy, whichever occurred first (assessed up to approximately 93 months)

Population: All randomized Cohort D participants with measurable disease at baseline. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.

Radiographic progression-free survival (rPFS) is defined as the time between the date of randomization and the first date of documented progression per BICR or death due to any cause, whichever occurs first. The following progressive diseases were collected, documented and assessed as below: Radiographic progression per BICR assessment 1. Bone disease progression by (Prostate Cancer Working Group) PCWG2 2. Non-bone soft tissue disease progression by RECIST v1.1 Progressive disease is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm (the appearance of one or more new lesions is also considered progression). Based on Kaplan-Meier estimates.

Time frame: From randomization and the first date of documented progression or death due to any cause, whichever occurs first (assessed up to approximately 93 months)

Population: All randomized Cohort D participants (i) Participants who did not progress or die were censored on the date of their last evaluable tumor assessment (ie, bone scan, CT, MRI). (ii) Participants who did not have any on study tumor assessments and did not die were censored on their date of randomization. For Arm D3 and D4 crossover participants, the data prior to the first dose date received in Arm D1 is being reported in their originally assigned Arm.