An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily had a causal relationship with this study drug. An SAE was an AE which occurred during any study phase and at any dose of study drug, that fulfilled 1 or more of following: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability or incapacity, was a congenital abnormality or birth defect, or was an important medical event that might jeopardize the participant or might require medical intervention to prevent one of the outcomes listed above. TEAEs were AEs that started or worsened in severity on or after the date of the first dose of study drug through 30 after the end of study drug, or prior to initiation of another investigational agent or cytotoxic chemotherapy. The treatment-emergent non-serious AEs are presented with a frequency threshold of 5%.

The safety population included all participants who received any dose of the study drugs.

RP2D was based on pharmacokinetics (PK) parameters, pharmacodynamics (PD) parameters as well as efficacy and the overall tolerability of each combination (tazemetost with enzalutamide or tazemetostat with abiraterone/prednisone).

The safety population included all participants who received any dose of the study drugs.

rPFS was defined as the time from date of randomization (phase 2)/date of first dose of study drug (phase 1b) to the first objective evidence of radiographic progression using response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) (soft tissue) and prostate cancer clinical trials working group 3 (PCWG3) (bone), or death from any cause, whichever occurred first. The radiographic PD for soft tissue lesion was determined based on computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria and no confirmatory scan was required for soft tissue PD; for bone lesion was determined by 2 or more new bone lesions on bone scan per PCWG3 criteria (i.e., the appearance of 2 or more new bone lesions on bone scan) and the 2 scans (i.e., the confirmatory scan is required for bone disease progression) should be at least 6 weeks apart from each other.

The ITT population included all participants who were randomized into the study.

Blood samples were collected for evaluation of PSA. Confirmed PSA50 response was defined as >=50% decline of PSA from baseline at any time on study for participants with a baseline PSA >=1.0 microgram per liter (mcg/L) (nanogram/milliliter [ng/mL]) per PCWG3 criteria. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization.

Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. As pre-specified in statistical analysis plan (SAP), efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target lesions, any pathological lymph nodes (LN) must be <10 millimeter (mm) in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.

Phase 1b: Safety population included all participants who received any dose of study drugs. Phase 2: ITT population included all participants who were randomized into study. Only those participants with response are reported. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

BOR was defined as percentage of participants with CR, PR, stable disease (SD), PD, or not evaluable (NE). CR was defined as disappearance of all target lesions, any pathological LN must be <10 mm in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the drug started. In addition, the sum had an absolute increase from nadir of 5 mm. NE was defined as which cannot be classified by 1 of the above preceding definitions. Percentages are rounded off to the tenth decimal place.

Phase 1b: Safety population included all participants who received any dose of study drugs. Phase 2: ITT population included all participants who were randomized into study. Only those participants with response are reported. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

DCR at 6 months (24 weeks) was defined as percentage of participants with measurable soft tissue disease at baseline who had BOR of CR or PR and remaining on study without progression at 23 weeks or with a duration of SD for at least 23 weeks after of randomization (phase 2)/first dose (phase 1b) using overall imaging-based response assessed by RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone). BOR: percentage of participants with CR, PR, SD, PD, or NE. CR: disappearance of all target lesions, any pathological LN must be <10 mm in the short axis. PR: at least a 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: at least a 20% increase in sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the drug started. In addition, sum had an absolute increase from nadir of 5 mm.

Phase 1b:Safety population:all participants who received any dose of study drugs.Phase 2:ITT population:all participants who were randomized into study.Only those participants with data collected at specified timepoints are reported. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

Time to first SRE per PCWG3 criteria was defined as the time from the date of randomization (phase II)/date of the first dose of study drug (phase Ib) to the date of first SRE. An SRE was defined as radiation therapy or surgery to bone, pathologic bone fracture, or spinal cord compression.

Phase 1b:Safety population included all participants who received any dose of study drugs.Phase 2:ITT population included all participants who were randomized into study.Only those participants with confirmed SRE event are reported. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

TTNT was defined as the time from the date of randomization (phase II)/date of the first dose of the study drug (phase Ib) to the date of the first documented administration of systemic treatment for prostate cancer.

Phase 1b:Safety population: all participants who received any dose of study drugs. Phase 2:ITT population: all participants who were randomized into study. Only those participants who initiated next systemic treatment are reported. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

TTPP was defined as the duration from the date of randomization (phase II)/date of first dose of study drug (phase Ib) to the date of first PSA progression per PCWG3 criteria. PSA progression was defined as a >=25% increase and an absolute increase of >=2 mcg/L (2 ng/mL) above the nadir (or baseline value for participants who did not have a decline in PSA value beyond 12 weeks). Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization.

Phase 1b: Safety population: all participants who received any dose of study drugs. Phase 2: ITT population: all participants who were randomized into study. Only those participants with confirmed PSA progression are reported. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

Blood samples were collected for evaluation of CTC. Reduction in CTC was defined as participants from a state of having a detectable number of CTCs to having an undetectable number of CTCs. Percentage of participants with detectable CTC at baseline and non-detectable CTC are presented. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization. Percentage of participants with detectable CTC at baseline and non-detectable CTC at any post-baseline time point up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively are presented.

Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

Blood samples were collected for evaluation of CTC. CTC response was defined as a >=30% reduction in CTC number from baseline in participants who entered the study. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization.

Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. As pre-specified in SAP, efficacy results for phase 1b were performed by "treatment group" for Phase 1b which refers to 1) Tazemetostat + Enzalutamide and 2) Tazemetostat + Abiraterone/Prednisone regardless of dose level, hence pooled data for Phase 1b is presented.

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily had a causal relationship with this study drug. An SAE was an AE which occurred during any study phase and at any dose of the study drug, that fulfilled 1 or more of following: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability or incapacity, was a congenital abnormality or birth defect, or was an important medical event that might jeopardize the participant or might require medical intervention to prevent one of the outcomes listed above. TEAEs were AEs that started or worsened in severity on or after the date of the first dose of study drug through 30 after end of study drug, or prior to initiation of another investigational agent or cytotoxic chemotherapy. The treatment-emergent non-serious AEs are presented with a frequency threshold of 5%.

The safety population included all participants who received any dose of the study drugs.

Blood samples were collected at specified timepoints for the assessment of AUC0-last of tazemetostat.

The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. During the study, participants missed few scheduled site visits for sample collection, and only participants with data collected at specific timepoints are reported.

Blood samples were collected at specified timepoints for the assessment of Cmax of tazemetostat.

The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. During the study, participants missed few scheduled site visits for sample collection, and only participants with data collected at specific timepoints are reported.

Blood samples were collected at specified timepoints for the assessment of AUC0-8 of tazemetostat.

The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. During the study, participants missed few scheduled site visits for sample collection, and only participants with data collected at specific timepoints are reported.

Blood samples were collected at specified timepoints for the assessment of AUC0-12 of tazemetostat.

The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. During the study, participants missed few scheduled site visits for sample collection, and only participants with data collected at specific timepoints are reported.

Blood samples were collected at specified timepoints for the assessment of AUC0-24 of enzalutamide.

The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. During the study, participants missed few scheduled site visits for sample collection, and only participants with data collected at specific timepoints are reported.

For Phase 2, PK blood samples for assessment of Cmax of enzalutamide were pre-specified to be collected at different time points by treatment arm. In the Phase 2: Tazemetostat 1200 mg + Enzalutamide arm, samples were collected at Cycle 1 Days 2 and 21 only. In the Phase 2: Enzalutamide arm, samples were collected at Cycle 1 Day 1 only. No PK samples were collected at other time points for these arms.

The PK population included only participants with enzalutamide PK data collected at the protocol-specified time points. During the study, participants missed few scheduled site visits for sample collection, which contributed to differences in the number of participants analyzed across time points.

For Phase 2, PK blood samples for assessment of AUC0-last of enzalutamide were pre-specified to be collected at different time points by treatment arm. In the Phase 2: Tazemetostat 1200 mg + Enzalutamide arm, samples were collected at Cycle 1 Days 2 and 21 only. In the Phase 2: Enzalutamide arm, samples were collected at Cycle 1 Day 1 only. No PK samples were collected at other time points for these arms.

The PK population included only participants with enzalutamide PK data collected at the protocol-specified time points. During the study, participants missed few scheduled site visits for sample collection, which contributed to differences in the number of participants analyzed across time points.

For Phase 2, PK blood samples for assessment of enzalutamide AUC0-24 were pre-specified to be collected at different time points by treatment arm. In the Phase 2: Tazemetostat 1200 mg + Enzalutamide arm, samples were collected at Cycle 1 Days 2 and 21 only. In the Phase 2: Enzalutamide arm, samples were collected at Cycle 1 Day 1 only. No PK samples were collected at other time points for these arms.

The PK population included only participants with enzalutamide PK data collected at the protocol-specified time points. During the study, participants missed few scheduled site visits for sample collection, which contributed to differences in the number of participants analyzed across time points.

FACT-P questionnaire included subscales:physical well-being(PWB) (Questions [Q] GP1 to GP7),social/family well-being subscale(SWB) (Q GS1 to GS7),emotional well-being subscale(EWB) (Q GE1 to GE6),functional well-being subscale(FWB) (Q GF1 to GF7) and prostate cancer subscale(PCS) (Q C2, C6, P1 to P8, BL2 and BL5). Each question had 5 responses, 0: "not at all", 1: "a little bit", 2: "somewhat", 3: "quite a bit" and 4: "very much". Scores ranged from 0 ("not at all") to 4 ("very much") for positively phrased questions. Negatively phrased questions had a reverse scoring, from 0 ("very much") to 4 ("not at all"). Q that were reversed (via subtraction of the response from 4) were: GP1-7, GE1, GE3-6, C2, P1-3, P6-P8 and BL2. Total FACT-P score was sum of scores of all sub-scales (PWB, SWB, EWB, FWB and PCS). Higher scores: better quality of life. Baseline: last value recorded for a variable prior to or on date of randomization. Change from baseline in FWB and PCS scores is presented.

The FACT-P population included all participants in the ITT population who completed an evaluable FACT-P questionnaire at baseline and >=1 post-baseline visit. Only those participants with data collected at specified timepoints are reported. Eventually, the participants discontinued as they progressed in the study. Hence, fewer participants at each cycle and no participants returned on Cycle 21 Day 1009, Cycle 22 Day 1093 , Cycle 23 Day 1177 and Cycle 24 Day 1261 in Phase 2: Enzalutamide arm.

TTD was defined as the interval from date of randomization until date of first clinically meaningful deterioration (3 points or more decline for subscale score, 10 points or more decline for total score) that was confirmed at subsequent visit at least 3 weeks apart with no improvement in between visits or death (by any cause) in absence of a clinically meaningful deterioration, regardless of whether participant discontinued study drug(s) prior to deterioration. PCS included Q C2, C6, P1 to P8, BL2 and BL5. Each question had 5 responses,0: "not at all",1: "a little bit",2: "somewhat",3: "quite a bit" and 4: "very much". Scores ranged from 0 ("not at all") to 4 ("very much") for positively phrased questions. Negatively phrased questions had a reverse scoring, from 0 ("very much") to 4 ("not at all"). Total FACT-P: sum of scores of all sub-scales(PWB, SWB, EWB, FWB and PCS). Higher scores: better quality of life. TDD in prostate symptoms as assessed by FACT-P: PCS score is presented.

The ITT population included all participants who were randomized into the study. Only those participants with PCS TDD event are reported.