Inclusion Criteria:

1. Age at the time of consent ≥ 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
3. Life expectancy of > 3 months.
4. Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.
5. Progressive disease in the setting of medical or surgical castration (ie, castration- resistant prostate cancer [CRPC]) by PCWG3 criteria for study entry.
   • Evidence of disease progression by rising PSA or
   • Soft tissue progression per RECIST 1.1 or
   • Evidence of disease progression by observation of 2 new bone lesions since the initiation of last systemic therapy.
6. Metastatic prostate cancer disease, documented by imaging.
7. Must have undergone bilateral orchiectomy (surgical castration) or be willing to continue GnRH analog or antagonist (medical castration).
8. Surgically or medically castrated, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
9. Previously untreated with or progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide).
10. No prior treatment with cytotoxic chemotherapy for mCRPC is permitted. Up to six prior cycles of docetaxel received for castration-sensitive disease is permitted for those subjects prior to receiving enzalutamide or abiraterone/prednisone.
11. Subjects must refrain from donating sperm starting at the planned first dose of tazemetostat until 3 months following the last dose of tazemetostat, 3 weeks following the last dose of abiraterone/prednisone, and 3 months following the last dose of enzalutamide.
12. Subjects with a female partner of childbearing potential as defined in the protocol must:
    1. Be vasectomized, or
    2. Remain abstinent or use a condom starting at the planned first dose of tazemetostat until 3 months following the last dose of tazemetostat, 3 weeks following the last dose of abiraterone/prednisone, and 3 months following the last dose of enzalutamide. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
13. Female partners of subjects who are of child-fathering potential as defined in the protocol and who are, themselves, of childbearing potential as defined in the protocol must also adhere to one of the following:
    1. Placement of an intrauterine device or intrauterine system
    2. Established use of oral, injected, or implanted hormonal methods of contraception plus an additional barrier method
    3. Progesterone-only oral contraception, where inhibition of ovulation is not the primary mode of action.

Exclusion Criteria:

1. Known symptomatic brain metastases.
2. Untreated or impending spinal cord compression.
3. Treatment with any of the following for prostate cancer within the indicated timeframe prior to day 1 of starting study treatment:
   • First generation: AR antagonists (eg, bicalutamide, nilutamide, flutamide) within 4 weeks.
   • 5-alpha-reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol), or progesterones within 2 weeks.
   • Chemotherapy (as permitted in inclusion criteria #10) within 3 weeks.
   • Prior radionuclide therapy within 4 weeks.
   • Another interventional product or standard agent in a clinical study within 28 days prior to the first planned dose of tazemetostat
4. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
5. History of another invasive cancer within 3 years of randomization, with the exception of treated non-melanoma skin cancer, treated superficial bladder cancer, or fully treated cancers with a remote probability of recurrence in the opinion of both the Medical Monitor and Investigator.
6. History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of sub clinical seizures manifested by loss of consciousness or transient ischemic attack within 12 months of randomization. However, subjects on medications with seizure lowering threshold will be admitted.
7. Clinically significant cardiovascular disease including the following:
   • Myocardial infarction within 6 months before screening.
   • Uncontrolled angina within 3 months before screening.
   • Congestive heart failure (New York Heart Association class 3 or 4), or a history of congestive heart failure (New York Heart Association class 3 or 4), unless a screening echocardiogram or multigated acquisition scan performed within 3 months before randomization demonstrates a left ventricular ejection fraction
     • 50% (Appendix 2).
   • History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes).
   • History of Mobitz 2 second-degree or third-degree heart block without a permanent pacemaker in place.
   • Hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at screening.
   • Bradycardia as indicated by a heart rate of <45 beats per minute on the screening ECG, and upon physical examination.
   • Uncontrolled hypertension as indicated by systolic blood pressure >170 mmHg or diastolic blood pressure >105 mmHg at screening.
8. Gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer disease within 3 months before randomization).
9. Major surgery within 4 weeks of randomization.
10. For subjects taking abiraterone and prednisone, no evidence of hepatic impairment or classified as only Child-Pugh class A for hepatic impairment.
11. Hypersensitivity reaction to the active pharmaceutical ingredient of tazemetostat, abiraterone, prednisone, or enzalutamide, or any of the other components of each individual agent under study.
12. Is unwilling to exclude grapefruit juice, Seville oranges, and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study.
13. Is currently taking any prohibited medication(s) as described in Section 9.3.3.
14. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.
15. Is immunocompromised (ie, has a congenital immunodeficiency). Subjects diagnosed with human immunodeficiency virus (HIV) are eligible to participate in the study if they meet the following criteria:
    • No history of AIDS-defining opportunistic infections, or have not had an opportunistic infection within the 12 months prior to enrollment.
    • No history of AIDS-defining cancers (eg, Kaposi's sarcoma, aggressive B-cell lymphoma, and invasive cervical cancer).
    • Subjects may take prophylactic antimicrobials; however, subjects taking specific antimicrobial drugs where there may be drug-drug interaction or overlapping toxicities with study drugs must be excluded from study participation.
    • Subjects should be on established anti-retroviral therapy for ≥4 weeks with an HIV viral load of < 400 copies/mL and/or CD4+ T-cell (CD4+) count ≥ 350 cells/uL prior to enrollment.
16. Has a prior history of T-cell lymphoblastic lymphoma/ T-cell acute lymphoblastic leukemia.
17. Is unable to take oral medications or has malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea or vomiting) that might impair the bioavailability of study treatments.
18. Subjects with hepatitis B or hepatitis C are ineligible to participate in the study unless they meet the following criteria:
    • Do not have uncontrolled hepatitis B or C infection, are not on active immunosuppressive therapy, and do not have a history of autoimmune disease requiring ongoing systemic therapy.
    • Subjects taking therapy for hepatitis where there may be a drug-drug interaction or overlapping toxicities with study drugs must be excluded from study participation.