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

Inclusion Criteria

• Age at the time of consent ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
• Life expectancy of > 3 months.
• Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.
• 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.
• 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.
• 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

• Known symptomatic brain metastases
• 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.
• Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment
• Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.