Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977.