A Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Participants With Advanced Prostate Cancer

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 the following imaging

   • Bone lesions on bone scan (per PCWG3) or by soft tissue disease (per RECIST 1.1) by CT/MRI imaging Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist.
7. Prior treatment with a second-generation androgen inhibitor as follows:

   * For phase 1b, EITHER Previously untreated with or progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second generation inhibitor (inhibitor (abiraterone, enzalutamide, or apalutamide)
   * For phase 2 randomized component (i.e, enzalutamide- containing treatment arms) of the study, previously progressed on abiraterone.

Exclusion Criteria:

1. Known symptomatic brain metastases
2. 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 (except 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
   * For phase 2 subjects to be randomized to one of the enzalutamide treatment arms only, prior treatment with the second-generation androgen antagonist including enzalutamide, apalutamide, darolutamide, and proxalutamide, etc.
3. Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment
4. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.