CELLO-1: A Phase 1b/2 Open-Label Study Evaluating Tazemetostat in Combination With Enzalutamide or Abiraterone/Prednisone in Chemotherapy Naive Subjects With Metastatic Castration-Resistant Prostate Cancer
Phase: PHASE1
Conditions: Metastatic Prostate Cancer, Metastatic Castration-resistant Prostate Cancer
Sponsor: Epizyme, Inc.



Clinical Study Protocol Amendment
Protocol EZH-1101
Tazemetostat 
Amendment 6
Epizyme, Inc.
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SIGNATURE PAGE
Sponsor's Approval
The protocol has been approved by Epizyme, Inc.
Sponsor's Authorized Officer:
, MD, MPH
Senior Medical Advisor, Interim Chief Medical and Development 
Officer
Epizyme, Inc.
400 Technology Square, 4th Floor
Cambridge, MA 02139, USA
Date
Responsible Medical Officer:
, MD, MS
Senior Medical Director
Epizyme, Inc.
400 Technology Square, 4th Floor
Cambridge, MA 02139 USA
Date
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Clinical Study Protocol Amendment 
Protocol EZH-1101 
Tazemetostat  
Amendment 6 
Epizyme, Inc. 
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INVESTIGATOR'S AGREEMENT 
 
Protocol Title: CELLO-1: A PHASE 1B/2 OPEN-LABEL STUDY EVALUATING 
TAZEMETOSTAT IN COMBINATION WITH ENZALUTAMIDE OR 
ABIRATERONE/PREDNISONE IN CHEMOTHERAPY NAIVE SUBJECTS WITH 
METASTATIC CASTRATION RESISTANT PROSTATE CANCER  
Protocol Number: EZH-1101 
 
I have read the EZH-1101 protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. 
Confidentiality Statement: This protocol and any related documents from Epizyme, Inc., 
contain privileged information that is confidential and may not be disclosed unless such 
disclosure is required by federal laws or regulations. In any event, persons to whom the 
information is disclosed must be informed that it is privileged and/or confidential and may not be 
further disclosed by them. Information from this study may not be reproduced in any form 
without the written permission of Epizyme, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date (dd mmm yyyy) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name/Address of Institution 

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EMERGENCY CONTACT INFORMATION 
Protocol Title: 
CELLO-1: A PHASE 1B/2 OPEN-LABEL STUDY EVALUATING 
TAZEMETOSTAT IN COMBINATION WITH ENZALUTAMIDE OR 
ABIRATERONE/PREDNISONE IN CHEMOTHERAPY NAIVE SUBJECTS 
WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER  
Compound Name (Number): 
Tazemetostat (EPZ-6438) 
Protocol Number: 
EZH-1101 
IND Number: 
143032 
EudraCT Number: 
2019-003649-14 
Sponsor: 
Epizyme, Inc. 
400 Technology Square, 4th Floor 
Cambridge, MA 02139 USA 
Sponsor Medical Monitor: 
, MD, MS 
Senior Medical Director 
Epizyme, Inc., 400 Technology Square, 4th Floor Cambridge, MA  02139 USA 
Telephone: 
Email:
North American Medical 
Monitor: 
, MD 
Senior Medical Director, Hematology/Oncology - Medical Affairs 
PRA Health Sciences, 9755 Ridge Drive, Lenexa, Kansas  66219 
Contact numbers: 
; 
Medical Monitoring Supporting Center  
Contact numbers:
; 
 
Email:
EU Medical Monitor: 
 
 
, MD 
Medical Director - Oncology 
PRA Health Sciences, 500 South Oak Way, Green Park, Reading, Benkshire 
RG2 6AD, UK 
Medical Monitoring Supporting Center 
Contact numbers: (PHONE)
; (FAX) 
 
Email: 
 
SAE Hotline for North 
American/Australian Sites Only: 
 
Phone:  
+1-513-579-9911, dial 3; or +1-800-730-5779, dial 3; or +49 89 89 55 718 44  
Fax:  
+1-513-570-5196; or +1-866-336-5320; or +49 89 89 55 718 104  
Email: medpace-safetynotification@medpace.com  
AE Hotline for EU Sites Only: 
 
Phone: +49 89 89 55 718 44  
Fax: +49 89 89 55 718 104  
Email: medpace-safetynotification@medpace.com  
 
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Clinical Study Protocol Amendment 
Protocol EZH-1101 
Tazemetostat  
Amendment 6 
Epizyme, Inc. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 6 
31 August 2022 
Amendment 5 
14 April 2022 
Amendment 4 
27 December 2020 
Amendment 3 
05 June 2020 
Amendment 2 
10 January 2020 
Amendment 1 
29 July 2019 
Original Protocol 
11 June 2019 
 
Amendment 6 
Note: This amendment is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: 
This amendment is being made primarily for the following reasons:  
1. To update background and clinical information regarding tazemetostat to align with the 
updated tazemetostat IB (IB v12.0). 
2. To remove the requirement of scans for confirmation of progression in soft tissue at 
Week 9 based on RECIST 1.1 criteria. 
3. To update the list of responsible personnel and emergency contact information. 
4. To correct internal conflict errors introduced in Protocol Amendment #5 and clarify 
concomitant medication and supplement advice. 
 

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Section 7.7 Study Design 
Schematic and Schedule of 
Assessments 
 
Merged columns for “CXR or chest 
CT” between cycle 4 and cycle 13+ to 
clarify that they are done only if 
screening chest x-ray demonstrated 
metastatic chest disease, in line with 
the footnote ‘u.’. 
To enhance readability of table 
(no instructional information was 
changed). 
Section 2 Synopsis 
Section 13.3.2.2 Analysis of 
Secondary Efficacy Endpoints 
Removed the extraneous word “first” in 
the definition of PSA50 
To correct a minor error. 
Section 13.3.5 Health-Related 
Quality of Life Assessment 
Endpoints and Analysis 
Specified that the algorithms for 
scoring PROs and plans for the 
corresponding analyses will be 
provided in a PRO SAP. 
To clarify which SAP will 
address PRO analysis plans. 
Abbreviations: PCWG3 = Prostate Cancer Working Group 3; PRO = patient-reported outcome; RECIST = Response Evaluation 
Criteria in Solid Tumours; rPFS = radiographic progression-free survival; SAP = statistical analysis plan. 
 
 
 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Epizyme, Inc.  
Name of Investigational Product: Tazemetostat (EPZ-6438)  
Name of Active Ingredient:  Tazemetostat 
Protocol Number: EZH-1101 
Phase: 1b/2 
Country: Global 
Title of Study:  
CELLO-1: A PHASE 1B/2 OPEN-LABEL STUDY EVALUATING TAZEMETOSTAT IN COMBINATION 
WITH ENZALUTAMIDE OR ABIRATERONE/PREDNISONE IN CHEMOTHERAPY NAIVE SUBJECTS 
WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER  
Study centers: Approximately 20 centers globally 
Study period (years):  
Date first subject enrolled: November 2019 
Estimated date last subject completed: February 2024 
Phase of Development: 1b/2 
Objectives: 
Primary Objectives: 
Phase 1b: 
x 
To determine the safety and tolerability of each of the combinations (tazemetostat with 
enzalutamide or tazemetostat with abiraterone/prednisone).  
x 
To select the recommended phase 2 doses (RP2Ds) of tazemetostat for each combination treatment 
based on pharmacokinetic (PK) and pharmacodynamic parameters as well as efficacy and the 
overall tolerability of each of the combinations (tazemetostat with enzalutamide or tazemetostat 
with abiraterone/prednisone). 
Phase 2:  
x 
To determine the benefit of combining tazemetostat with enzalutamide when compared to 
enzalutamide alone as assessed by radiographic progression-free survival (rPFS) according to 
Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for progression in bone or in 
soft tissue (the latter by Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1]).  
Secondary Objectives: 
Phase 1b and Phase 2: 
x 
To determine the benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone 
(in phase 1b) and the benefit of combining tazemetostat with enzalutamide when compared to 
enzalutamide alone (in phase 2) as assessed by: 
 
Prostate-specific antigen (PSA)50 (PSA50), defined as the percentage of subjects with a 
50% decline of PSA from baseline at any time on study for subjects with a baseline PSA 
 ug/L (ng/mL) per PCWG3 criteria. 
 
Objective response rate (ORR) and best overall response (BOR) in soft tissue per RECIST 1.1 
guidelines. 
 
Disease control rate (DCR; no radiographic progression per PCWG3 criteria, and no 
unequivocal clinical progression or death) at 6 months on treatment. 
 
Time to first skeletal-related event (SRE) per PCWG3. 
 
Time to initiation of the next systemic treatment for prostate cancer  (TTNT). 
 
Time to PSA progression (TTPP), as defined as the duration from baseline to the day of PSA 
progression per PCWG3 criteria in months. 

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Protocol EZH-1101 
Tazemetostat  
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 
Reduction in circulating tumor cells (CTC) from a state of having a detectable number of 
CTCs to having an undetectable number of CTCs. 
 
&7& UHVSRQVH UDWH GHILQHG DV WKH SHUFHQWDJH RI VXEMHFWV ZLWK D  UHGXFWLRQ LQ &7&
number from baseline. 
x 
To further evaluate the safety and tolerability of the combination of tazemetostat with 
enzalutamide. 
x 
To assess the PK of tazemetostat when administered in combination with enzalutamide (phases 1b 
and 2) and abiraterone/prednisone (phase 1b only) and the PK of enzalutamide (phases 1b and 2) 
and abiraterone (phase 1b only) when administered in combination with tazemetostat.  
Phase 2 Only: 
x 
To determine the benefit of combining tazemetostat with enzalutamide when compared to 
enzalutamide alone on quality of life (QoL) as assessed by changes from baseline in FACT-P 
Functional Well-being Subscale (FWB) and Prostate Cancer Subscale (PCS) scores over the 
course of the study. 
x 
To determine the benefit of combining tazemetostat with enzalutamide when compared to 
enzalutamide alone to QoL as assessed by time to definitive deterioration (TDD) in functional 
status and in prostate symptoms as assessed by the FACT-P FWB and PCS scores, respectively. 
Exploratory Objectives: 
Phase 1b only: 
x 
To evaluate the rate of pain progression relative to the time of screening at 6 months using the 
Brief Pain Inventory (BPI)-Short Form (-SF) for tazemetostat in combination with enzalutamide or 
abiraterone/prednisone.  
Phase 2 only: 
x 
To evaluate the rate of pain progression relative to baseline at each post-baseline time point using 
the BPI-SF for tazemetostat in combination with enzalutamide versus enzalutamide alone. 
x 
To determine the benefit of combining tazemetostat with enzalutamide when compared to 
enzalutamide alone to QoL as assessed by changes from baseline in the FACT-P domains: 
Emotional, Social, and Physical Well-being over the course of the study. 
x 
To determine the benefit of combining tazemetostat with enzalutamide when compared to 
enzalutamide alone to QoL as assessed by changes from baseline in EQ-5D-5L visual analogue 
scale (VAS) and Health Utilities Index (HUI) scores over the course of the study. 
Phase 1b and 2: 
x 
To determine the benefit of tazemetostat in combination with enzalutamide or 
abiraterone/prednisone (in phase 1b) and the benefit of combining tazemetostat with enzalutamide 
when compared to enzalutamide alone (in phase 2) as assessed by PSA90.  
x 
To determine the benefit of tazemetostat in combination with enzalutamide or 
abiraterone/prednisone (in phase 1b) and the benefit of combining tazemetostat with enzalutamide 
when compared to enzalutamide alone (in phase 2) as assessed by circulating tumor DNA 
(ctDNA) burden.  
x 
To assess the pharmacodynamic modulation of EZH2 activity by tazemetostat by measuring 
H3K27me3 levels in paired pre- and on-treatment tumor biopsies, including biopsies taken at 
disease progression (in phase 2 only in responders), that may be obtained from the phase 1b and 
phase 2 portions of the study. 
x 
To assess genetic and molecular characteristics of responders as compared to non-responders, 
including mutational status of selected genes and gene expression signatures in tumor biopsies 
taken pre-treatment, on drug treatment (at cycle 2 day 1), and at disease progression (only in 
responders). 

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x 
To assess the genetic and molecular characteristics of responders as compared to non-responders, 
including the mutational status in pre- and on-treatment tumor biopsies and ctDNA in liquid 
biopsies. Expression profiling signatures of neuroendocrine prostate cancer (NEPC) and androgen 
receptor (AR) signaling in pre- and on-treatment tumor biopsies will be determined. AR-V7 and 
NEPC status (morphologically) and, possibly, selected neuroendocrine marker(s) will be 
determined in CTCs from liquid biopsies taken at baseline. Neuroendocrine status will also be 
determined in baseline serum samples by assessing serum biomarker neuron-specific enolase 
(NSE) collected pre-dosing. 
x 
To compare concordance of genetic and molecular characteristics in tumor and liquid biopsy 
samples.  
x 
To assess immunological endpoints in tumor biopsy samples, including the number and 
activation/exhaustion status of CD8+ and regulatory T-cell subtypes and other immune cells in 
tumor infiltrates from tumor biopsies taken pre-treatment, on drug treatment (at cycle 2 day 1), and 
at disease progression (only in responders). Also, to investigate circulating immune cell sub-
populations isolated from peripheral blood mononuclear cells (PBMCs) taken pre-treatment, on 
drug treatment at cycle 2 day 1, and at disease progression (only in responders) to determine the 
impact of drug treatment on immune cell numbers, antigen presentation, and immune cell 
activation status. 
Methods: 
This is a 2-part, global, multi-center, open-label, randomized phase 1b/2, active-controlled safety and efficacy 
study of oral administration of tazemetostat in combination with enzalutamide or abiraterone/prednisone (phase 
1b) and of tazemetostat in combination with enzalutamide versus enzalutamide alone (phase 2) in asymptomatic 
or mildly symptomatic subjects with progressive, metastatic castration-resistant prostate cancer (mCRPC) who 
have not received chemotherapy for mCRPC and who: for phase 1b, are EITHER previously untreated with a 
second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second 
generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide); or for phase 2, previously progressed 
on abiraterone. The phase 1b portion of this study was designed to determine the RP2D of tazemetostat in 
combination with either enzalutamide or abiraterone/prednisone, based on safety, tolerability, pharmacokinetic, 
pharmacodynamic, and efficacy profiles.  
In the phase 1b part of the study, there were 3 different tazemetostat dose levels planned to be tested in 
combination with abiraterone/prednisone and 5 different tazemetostat dose levels planned to be tested in 
combination with enzalutamide. A maximum of approximately 24 subjects (7 for the combination with 
abiraterone/prednisone, 13 for the combination with enzalutamide, and up to 4 additional subjects in the event 
of a dose-limiting toxicity [DLT]) were to be enrolled.  Dose escalations began at 400 mg tazemetostat twice 
daily, followed by 600 mg tazemetostat twice daily, followed by 800 mg tazemetostat twice daily, as tolerated 
according to occurrence of DLTs, as defined in the protocol). For the enzalutamide combination only, dose 
escalation could further proceed to 1200 mg twice daily followed by 1600 mg twice daily, as tolerated. For both 
enzalutamide and abiraterone/prednisone, prescribed doses as recommended by the respective package inserts 
are to be used throughout the study. Subjects treated in the phase 1b part of the study who did not experience a 
DLT may continue in the study after cycle 1 on the combination regimen at the assigned dose until progression 
or occurrence of unacceptable toxicity. 
Now that the RP2D of tazemetostat when administered in combination with enzalutamide is established as 
1200 mg twice daily, the Investigator may increase the dose of tazemetostat up to the RP2D for phase 1b 
subjects continuing on combination therapy with enzalutamide after consulting with the Medical Monitor. 
Treatment 
In the phase 2 part of the study, approximately 80 chemotherapy naive, qualified subjects will be enrolled and 
randomized. Subjects with mCRPC previously treated with abiraterone/prednisone will be randomized 1:1 to 
either tazemetostat combined with enzalutamide (using the newly established tazemetostat RP2D of 1200 mg 
twice daily when given in combination with enzalutamide) or enzalutamide alone. Prescribed doses of 
enzalutamide as recommended in the package insert will be used throughout the study. Subjects will not be 
treated with abiraterone in the phase 2 portion of the study. 
PSA increase without evidence of confirmed radiographic progression is strongly discouraged as a criterion to 
discontinue study therapy. Treatment should be continued for as long as the subject is tolerating the study drugs 

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and continues androgen deprivation therapy (ADT) (ie, surgical castration or ongoing gonadotropin releasing 
hormone [GnRH] analogue therapy) until confirmed radiographic disease progression by PCWG3 criteria, even 
if the subject continues to benefit clinically, or until unequivocal clinical progression if earlier than radiographic 
disease progression.  
Localized, palliative radiation therapy and initiation of bisphosphonates or other approved bone targeting agents 
are allowed and should not result in discontinuation of study drug therapy.  
The following assessments of prostate cancer status will be collected during the course of the study: overall 
survival, soft tissue disease on computed tomography (CT) scan or on magnetic resonance imaging (MRI), bone 
disease on radionuclide bone scans, SREs, health-related QoL assessments (ie, BPI-SF, FACT-P, and EQ-5D-
5L), PSA, CTC enumeration, and blood biomarkers of neuroendocrine prostate cancer. The consensus 
guidelines of RECIST 1.1 and the PCWG3 have been taken into consideration for the determination of 
radiographic disease progression. The evaluation of progression in bone will be based upon PCWG3 criteria (ie, 
the appearance of two or more new bone lesions on bone scan), and the evaluation of progression in soft tissue 
will be based on RECIST 1.1 criteria. The documentation required for the determination of radiographic disease 
progression in both bone and soft tissue is listed below in Table S1, and a flow diagram for assessment of bone 
scans to declare disease progression in bone per PCWG3 after the week 9 scan is provided in Figure S1. Tumor 
assessments will be performed every 8 weeks for the first 6 months and then every 12 weeks thereafter, starting 
after cycle 7 until radiographic disease progression is seen. 

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Table S1. 
Protocol-Specified Documentation for Radiographic Evidence of Disease Progression 
Date 
Progression 
Detected 
(Visit)a  
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(requirement and timing) 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 9 
(Cycle 3 Day 1 
[±7 days]) 
Bone lesions; 2 or more new 
lesions compared to baseline 
bone scan by PCWG3 
Timing: at least 6 weeks after 
progression identified or at 
week 17 visitb. 
Two or more new bone 
lesions on bone scan 
(compared to week 9 
scan). 
Soft tissue lesions: 
Progressive disease on CT or 
MRI by RECIST 1.1 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Week 17 
(Cycle 5 Day 1 
[±7 days]) 
Bone lesions: Two or more 
new lesions on bone scan 
compared to week 9 bone 
scan. 
Timing: at least 6 weeks after 
progression identified or at 
week 25 visit. Required for 
bone lesions observed on 
bone scanb. 
Persistentc or increase in 
number of bone lesions 
on bone scan compared 
to week 9 scan. 
Soft tissue lesions: 
Progressive disease on CT or 
MRI by RECIST 1.1. 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Week 25 
(Cycle 7 Day 1 
[±7 days]) or 
later 
Bone lesions: Two or more 
new lesions compared to 
week 9 bone scan. 
Timing: at least 6 weeks after 
progression identified. 
Required for bone lesions 
observed on bone scanb. 
Persistentc or increase in 
number of lesions on 
bone scan compared to 
week 9 scan. 
Soft tissue lesions: 
Progressive disease on CT or 
MRI by RECIST 1.1. 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Abbreviations: CT = computed tomography; RECIST = Response Evaluation Criteria in Solid Tumors; MRI = magnetic 
resonance imaging; n/a = not applicable; PCWG3 = Prostate Cancer Clinical Trials Working Group 3. 
a Progression detected by bone scan at an unscheduled visit either prior to week 9 or between scheduled visits will require a 
confirmatory scan at least 6 weeks later and should follow confirmation criteria outlined in the table for the next scheduled 
scan.  
b Confirmation must occur at the next available scan. 
c For confirmation, at least two of the lesions first identified as new must be present at that next available scan (confirmation 
scan).  
 
 

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Figure S1. Post Week 9 Bone Scan Assessment Flow Diagram
Note: Progression detected by bone scan at an unscheduled visit after week 9 will require a confirmatory scan at least 6 
weeks later and should follow confirmation criteria outlined in the diagram. 
Study films (CT/MRI and bone scan) should be read on-site using PCWG3 and RECIST 1.1 guidelines and also 
be submitted in a digital format for a blinded independent central radiology review. Radiographic imaging is not 
required after protocol-defined radiographic progressive disease is reached.
Determination of radiographic progression by central radiology review (in parallel with the Investigator’s 
primary review) will continue until at least 
 rPFS events from a total of 74 subjects (37 per arm) are 
confirmed in phase 2, as required for primary rPFS analysis between the active (tazemetostat with 
enzalutamide) and control arms (enzalutamide alone).
Throughout the study, safety and tolerability will be assessed by the recording of adverse events (AEs), 
monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead 
electrocardiograms (ECGs). Dosing interruptions and dose-level adjustments of tazemetostat and the 
combination therapy will be allowed according to protocol-defined guidelines.
In the phase 1b part of the study, a Safety Review Committee (SRC) monitored safety data on an ongoing basis, 
assessed DLTs, and determined the RP2D, as per charter (completed). 
Subjects will have a post-treatment follow-up visit 30 (±3) days after their last dose of tazemetostat or prior to 
initiation of an investigational agent or cytotoxic chemotherapy, whichever occurs first. 
All subjects with confirmed radiographic disease progression as defined in the protocol will be discontinued 
from study drug and from further follow-up after the 30-day follow-up visit, even if the subject continues to 
benefit clinically. If the Investigator elects to continue enzalutamide treatment in the commercial setting in the 
case of subject who continue to benefit clinically despite confirmed radiographic progression, it will be 
recorded as subsequent anti-cancer therapy.
For subjects who discontinue study treatment for reasons other than confirmed radiographic disease progression 
(such as unequivocal clinical or chemical progression), radiographic tumor assessment scans are required every 
12 weeks (±7 days) during long-term follow-up, and other study assessment will continue as scheduled, until 
the earlier of either: 18 months post last study drug dose; radiographic disease progression; the start of a new 
systemic anticancer therapy for prostate cancer; withdrawal of consent/loss to follow-XS GHDWK RU 
U3)6
events have been observed in the study (as communicated by the Sponsor).
CCI
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Study Design: 
This is a 2-part, global, multi-center, open-label, randomized Phase 1b/2 study with an oral administration of 
tazemetostat in combination with either enzalutamide or abiraterone/prednisone (phase 1b) and tazemetostat in 
combination with enzalutamide versus enzalutamide alone (phase 2) in male subjects with mCRPC (refer to 
Figure S2). The Phase 1b dose escalation portion of this study was designed to determine the RP2D of 
tazemetostat in combination with either enzalutamide or abiraterone/prednisone based on safety, tolerability, 
PK, pharmacodynamics, and efficacy profiles.  
Phase 1b 
The following paragraphs describe the plan for the phase 1b dose escalation and RP2D determination portion of 
the study, which has been completed). The RP2D of tazemetostat when administered in combination with 
enzalutamide was established as 1200 mg twice daily.) 
The phase 1b part of the study comprised a dose escalation to determine the RP2D for the phase 2 part and 
to establish the safety profile of the combination of tazemetostat with enzalutamide or 
abiraterone/prednisone. The selection of therapy depended on which agent the subjects were previously 
treated with and progressed on prior to enrollment into the study. Subjects who were previously treated 
with enzalutamide and/or apalutamide were to receive tazemetostat in combination with 
abiraterone/prednisone. Similarly, subjects who were previously treated with abiraterone/prednisone were 
to receive tazemetostat in combination with enzalutamide. Subjects who were previously untreated with 
either enzalutamide or abiraterone/prednisone were to be equally distributed in both dose escalation arms in 
the phase 1b part of the study. 
Dose escalation was performed using a modified 3+3 design consisting of a planned maximum of 
approximately 24 evaluable subjects (7 for the abiraterone/prednisone combination and 13 for the 
enzalutamide combination, and up to 4 additional subjects in the event of a DLT). The starting dose level of 
tazemetostat was 400 mg orally twice daily followed by 600 mg orally twice daily followed by 800 mg 
twice daily, as tolerated according to occurrence of DLTs. For the enzalutamide combination only, dose 
escalation could further proceed to 1200 mg twice daily followed by 1600 mg twice daily, as tolerated. 
For phase 1b dose escalation purposes, DLTs during the first cycle were assessed. After completion of 
cycle 1 of each combination (tazemetostat with enzalutamide or tazemetostat with abiraterone/prednisone), 
all available safety data were to be reviewed jointly by the Sponsor and Investigators (the SRC), and the 
decision to proceed to the next dose cohort was made. 
For each combination therapy, the following dose escalation procedure was followed (all dose levels of 
tazemetostat noted here are given twice daily): 
A single subject was to be enrolled at the 400 mg dose level. If the subject did not experience a DLT, 
then dose escalation would proceed to the next level of 600 mg. If the subject did experience a DLT, 
the study would stop for this combination therapy.  
At the 600 mg dose-escalated level, 3 subjects were to be enrolled. If no subjects experienced a DLT at 
the 600 mg level, then dose escalation would proceed to the next level of 800 mg.  If 1 subject 
experienced a DLT at 600 mg, then the 600 mg dose level would be expanded by 3 additional subjects; 
if there were no additional DLTs at the 600 mg level (ie, no more than 1 DLT in 6 subjects), then dose 
escalation would proceed to the 800 mg level. If, however, 2 or more subjects out of the first 3 or 6 
subjects enrolled at 600 mg experienced a DLT, then the next lower, previously tested dose of 400 mg 
would be expanded by 2 additional subjects for a total of 3 subjects. If no additional DLTs were 
observed at the 400 mg dose level, then 400 mg would be evaluated for suitability as the RP2D. If 1 
DLT was observed at the 400 mg dose level, 3 additional subjects would be enrolled; 400 mg would be 
evaluated for suitability as the RP2D if no further DLTs occur. Otherwise, the study for this 
combination therapy would stop. 
At the 800 mg dose-escalated level, 3 subjects were to be enrolled. If no subjects experienced a DLT at 
the 800 mg level, then for the abiraterone/prednisone combination, 800 mg would be evaluated for 
suitability as the RP2D. If 1 subject experienced a DLT at 800 mg, then the 800 mg dose level would 
be expanded by 3 additional subjects; if there were no additional DLTs at the 800 mg level (ie, no 
more than 1 DLT in 6 subjects), then for the abiraterone/prednisone combination 800 mg would be 
evaluated for suitability as the RP2D. 

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If another DLT was observed after expansion to 6 subjects at 800 mg (2 out of 6), then 600 mg would 
be evaluated for suitability as the RP2D. 
For the enzalutamide combination only, if none of the first 3 subjects or no more than 1 of 6 subjects 
experienced a DLT at the 800 mg dose level, then dose escalation would proceed to the next level of 
1200 mg. At the 1200 mg dose-escalated level, 3 subjects would be enrolled. If no subjects 
experienced a DLT at the 1200 mg level, then dose escalation would proceed to the next level of 1600 
mg. If 1 subject experienced a DLT at 1200 mg, then the 1200 mg dose level would be expanded by 3 
additional subjects; if there were no additional DLTs at the 1200 mg level (ie, no more than 1 DLT in 6 
subjects), then dose escalation would proceed to the 1600 mg level. If, however, 2 or more subjects out 
of the first 3 or 6 subjects enrolled at 1200 mg experienced a DLT, then the next lower, previously 
tested dose of 800 mg would be evaluated for suitability as the RP2D. 
For the enzalutamide combination only, at the 1600 mg dose-escalated level, 3 subjects were to be 
enrolled. If no subjects experienced a DLT at the 1600 mg level, then 1600 mg would be evaluated for 
suitability as the RP2D.  If 1 subject experienced a DLT at 1600 mg, then the 1600 mg dose level 
would be expanded by 3 additional subjects; if there were no additional DLTs at the 1600 mg level (ie, 
no more than 1 DLT in 6 subjects), then 1600 mg would be evaluated for suitability as the RP2D. If, 
however, 2 or more subjects out of the first 3 or 6 subjects enrolled at 1600 mg experienced a DLT, 
then the next lower, previously tested dose of 1200 mg would be evaluated for suitability as the RP2D. 
Seven subjects were enrolled in the abiraterone/prednisone combination dose escalation arm and 14 
subjects were enrolled in the enzalutamide combination dose escalation arm. Determination of the RP2D 
was informed by all available information, including PK parameters and the overall safety and tolerability 
of each combination. The RP2D of tazemetostat when administered in combination with enzalutamide was 
established as 1200 mg twice daily. Any available AR splice variant (ie, AR-V7) expression status and 
neuroendocrine (small cell NEPC) status data were also evaluated before proceeding to phase 2. 
Now that the RP2D for tazemetostat in combination with enzalutamide has been established, subjects with 
mCRPC previously treated with abiraterone/prednisone will be enrolled and randomized 1:1 in the phase 2 
part of the study to receive either tazemetostat with enzalutamide or enzalutamide alone (see below). 
Subjects in the phase 1b part of the study who did not experience a DLT could have continued in the study 
after cycle 1 on the combination regimen at the assigned dose until progression or occurrence of 
unacceptable toxicity.  For subjects who had been assigned to enzalutamide in phase 1b, the dose of 
tazemetostat may be increased to the RP2D after consultation with the Medical Monitor. 
Phase 2 
The phase 2 part of the study will include an open-label, 2-arm randomized portion. Approximately 80 
chemotherapy naive, qualified subjects with mCRPC who were previously treated with abiraterone/prednisone 
will be enrolled and randomized 1:1 to receive either tazemetostat combined with enzalutamide (using the 
established RP2D of 1200 mg orally twice daily when given in combination with enzalutamide) or 
enzalutamide alone. All subjects will receive treatment in 28-day cycles.  
Total study enrollment will be approximately 104 subjects, and the total study duration will be approximately 
12 months for phase 1b and approximately 
 months for phase 2, for a total study duration of approximately 
50 months. 
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Figure S2.  Study Design
Sample Size Justification:
For the phase 2 randomized component of the study, to compare the combination of tazemetostat with 
enzalutamide to enzalutamide alone, 
 rPFS events from a total of 74 total subjects (37 per arm) will provide 
approximately 
 power for the analysis of rPFS, with a 2-sided total type I error of 0.05 to reject the null 
hypothesis that there is no difference in rPFS between the two arms. To account for the approximate 
 
dropout, the sample size will increase to 80 (40 per arm). The sample size assumes that the combination of 
tazemetostat with enzalutamide will prolong rPFS by 
 (hazard ratio [HR] = 
) from
months for 
enzalutamide to 
 months, with 
 of subjects lost to follow-up over an 
-month enrollment period, an 9-
month follow-up period (a total follow-up time of 18 months, tmax = 18), and a total phase 2 study duration of 
approximately 
months. (The critical boundary to achieve statistical significance for the final rPFS logrank 
testing between two arms is HR=
 or 
 months of improvement in rPFS.)
Number of Subjects (planned) for whole trial: Up to 104 subjects are planned for the trial to assess 
combination therapy (up to approximately 24 in phase 1b [enrollment completed]; 80 in phase 2).
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Diagnosis and Main Criteria for Eligibility 
Inclusion Criteria: 
1. $JH DW WKH WLPH RI FRQVHQW  \HDUV 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix 1). 
3. Life expectancy of >3 months. 
4. Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or 
neuroendocrine (differentiated or with neuroendocrine features) 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.  
x 
Evidence of disease progression by rising PSA or 
x 
Soft tissue progression per RECIST 1.1 or 
x 
Evidence of disease progression by observation of 2 new bone lesions since the initiation of 
last systemic therapy.  
6. Metastatic prostate cancer disease, as documented by the following imaging.:  
x 
Bone lesions on bone scan (per PCWG3) or by soft tissue disease (per RECIST 1.1) by 
CT/MRI imaging. 
7. Must have undergone bilateral orchiectomy (surgical castration) or be willing to continue GnRH 
analog or antagonist (medical castration). 
8. 6XUJLFDOO\ RU PHGLFDOO\ FDVWUDWHG ZLWK VHUXP WHVWRVWHURQH   QJG/  QPRO/ DW Vcreening. 
9. Prior treatment with a second-generation androgen inhibitor as follows: 
x 
For phase 1b, EITHER previously untreated with a second-generation androgen inhibitor 
(abiraterone, enzalutamide, or apalutamide) OR progressed on a second-generation androgen 
inhibitor (abiraterone, enzalutamide, or apalutamide). 
x 
For phase 2 randomized component (ie, enzalutamide-containing treatment groups) of the 
study, previously progressed on abiraterone for either castration-sensitive or castration-
resistant disease; the required washout period for abiraterone is 7 days.   
10. No prior treatment with cytotoxic chemotherapy for mCRPC except as follows:  
x 
For phase 1b, more than 6 cycles of docetaxel received for castration-sensitive disease prior to 
having received enzalutamide or abiraterone/prednisone is permitted. 
x 
For the phase 2 randomized component (ie, enzalutamide-containing treatment groups) of the 
study, up to 6 prior cycles of docetaxel received for castration-sensitive disease in the 
nonmetastic and metastatic settings prior to having received abiraterone/prednisone is 
permitted.  
11. Demonstrate adequate organ function as defined below: 
x 
Absolute neutrophil count (ANC)   ȝ/ 
x 
3ODWHOHW &RXQW   ȝ/ 
x 
+HPRJORELQ   JG/ ZLWKRXW D WUDQVIXVLRQ ZLWKLQ  ZHHNV RI VFreening. 
x 
6HUXP FUHDWLQLQH   î XSSHU OLPLW RI QRUPDO 8/1 RU 
 
&UHDWLQLQH FOHDUDQFH   P/PLQ DV HVWLPDWHG E\ WKH &RFNFURIW DQG *DXOW IRUPXOD LQ
VXEMHFWV ZLWK FUHDWLQLQH !  î 8/1 
x 
%LOLUXELQ   î 8/1 XQOHVV HYLGHQFH RI *LOEHUW
V GLVHDVH LQ ZKLFK FDVH   î 8/1 
x 
Aspartate aminotransferase (AST)   î 8/1 ZLWKRXW OLYHU PHWDVWDVHV PXVW EH   î 8/1
with liver metastases. 
x 
Alanine aminotransferase (ALT)   î 8/1 ZLWKRXW OLYHU PHWDVWDVHV PXVW EH   î 8/1
with liver metastases. 

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x 
Albumin > 3.0 g/dL (30 g/L) at screening. 
12. Subjects of child-fathering potential as defined in the protocol (Section 7.4.2.1) must either practice 
complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy 
(medically confirmed azoospermia), or maintain medical castration during sexual contact with a 
pregnant female or female partner of childbearing potential (FCBP) during study treatment, for 3 
weeks following the last dose of abiraterone/prednisone, and for 3 months following the last dose 
of enzalutamide.  Male subjects with surgical castration are not required to use condoms. 
NOTE: Male subjects must not donate semen or sperm from first dose of study drug, during study 
treatment (including during dose interruptions), and for 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. 
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: 
x 
Abiraterone within 7 days. 
x 
First generation: AR antagonists (eg, bicalutamide, nilutamide, flutamide) within 4 weeks. 
x 
5-alpha-reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol), or 
progesterones within 2 weeks. 
x 
Chemotherapy (except as permitted in inclusion criterion #10) within 3 weeks. 
x 
Prior radionuclide therapy within 4 weeks. 
x 
Another interventional product or standard agent in a clinical study within 28 days prior to the 
first planned dose of tazemetostat 
x 
For phase 2 subjects to be randomized to one of the enzalutamide treatment groups only, prior 
treatment with any second-generation AR antagonist (eg, enzalutamide, apalutamide, 
darolutamide, proxalutamide, etc) other than abiraterone. 
4. Severe concurrent disease, infection, or comorbidity 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: 
x 
Myocardial infarction within 6 months before screening. 
x 
Uncontrolled angina within 3 months before screening.  
x 
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 
leIW YHQWULFXODU HMHFWLRQ IUDFWLRQ  Appendix 2). 
x 
History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, 
ventricular fibrillation, torsades de pointes). 
x 
History of Mobitz 2 second-degree or third-degree heart block without a permanent pacemaker 
in place. 

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x 
Hypotension as indicated by systolic blood pressure <86 millimeters of mercury (mmHg) at 
screening.  
x 
Bradycardia as indicated by a heart rate of <45 beats per minute on the screening ECG, and 
upon physical examination. 
x 
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, 
according to the potential to be assigned to that agent(s). 
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, including live virus 
vaccine within 30 days before the first dose of study treatment or plans to receive a live virus 
vaccine during treatment. 
14. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 
(EZH2). 
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: 
x 
No history of AIDS-defining opportunistic infections or have not had an opportunistic 
infection within the 12 months prior to enrollment. 
x 
No history of AIDS-defining cancers (eg, Kaposi’s sarcoma, aggressive B-cell lymphoma, and 
invasive cervical cancer). 
x 
Subjects may take prophylactic antimicrobials; however, subjects taking specific antimicrobial 
drugs that have a potential for drug-drug interaction or overlapping toxicities with study drugs 
must be excluded from study participation.  
x 
Subjects should be on established anti-UHWURYLUDO WKHUDS\ IRU  ZHHNV ZLWK DQ +,9 YLUDO ORDG
of < 400 copies/mL and/or CD4+ T-FHOO &' FRXQW   FHOOVX/ SULRU WR HQUROOPHQW 
16. +DV WKURPERF\WRSHQLD QHXWURSHQLD RU DQHPLD RI *UDGH  SHU 1DWLRQDO &DQFHU ,QVWLWXWH
V
Common Terminology Criteria for Adverse Events [CTCAE] 5.0 criteria) or any prior history of 
myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia 
(AML). Has abnormalities known to be associated with MDS (eg del 5q, chr 7 abn) and 
myeloproliferative neoplasms (MPN; eg, JAK2 V617F) observed in cytogenetic testing and DNA 
sequencing. 
NOTE: At screening, a complete peripheral blood count (CBC) with differential (manual or 
automated peripheral blood smear) will be performed and assessed per institutional standards to 
rule out myeloid malignancies, including but not limited to MDS/AML/MPN. A potential subject 
with a suspected or confirmed myeloid malignancy will be excluded from the study. 
17. Has a prior history of T-cell lymphoblastic lymphoma/ T-cell acute lymphoblastic leukemia (T-
LBL/T-ALL). 
18. 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. 

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19. Subjects with hepatitis B or hepatitis C are ineligible to participate in the study unless they meet 
the following criteria:  
x 
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.  
x 
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. 
Investigational product, dosage, and mode of administration:  
In the phase 1b and 2 parts of the study: 
 
Table S2. 
Phase 1b/2 Doses of Tazemetostat, Enzalutamide, Abiraterone, and Prednisone 
Treatment 
Dose 
Frequency 
Total Daily Dose 
Tazemetostat 
Phase 1ba: Per dose escalation  
Phase 2c:  
- 
1200 mg for combination 
with enzalutamide 
Twice 
daily 
Phase 1ba: Per dose escalation  
Phase 2:  
- 
2400 mg for combination 
with enzalutamide 
Enzalutamide 
160 mg 
Once daily 
160 mg 
Abirateroneb, d 
1000 mg 
Once daily 
1000 mg 
Prednisoned 
5 mg 
Twice 
daily 
10 mg 
a The starting dose was 400 mg tazemetostat twice daily. If there were no DLTs, dose escalation would continue to 600 mg 
twice daily to a maximum of 800 mg twice daily, as tolerated; for the combination with enzalutamide only, dose escalation 
may have continued to 1200 mg twice daily and to a maximum of 1600 mg twice daily, as tolerated. 
b Abiraterone must be taken on an empty stomach with water at least 1 hour before, or 2 hours after a meal. 
c  Orally twice daily in continuous 28-day cycles.  
d Abiraterone and prednisone are administered in phase 1b only.  
 
The plan for the phase 1b dose-escalation part of the study was as follows: There were 3 different tazemetostat 
dose levels planned to be tested in combination with abiraterone/prednisone and 5 different tazemetostat dose 
levels planned to be tested in combination with enzalutamide. Enzalutamide or abiraterone/prednisone was to be 
administered on cycle 1 day 1 and tazemetostat on day 2. Tazemetostat was to be escalated from a starting dose 
of 400 mg twice daily, to 600 mg twice daily, to 800 mg twice daily as tolerated, in a modified 3+3 design in 
combination with enzalutamide or abiraterone/prednisone. For the combination with enzalutamide only, 
tazemetostat could have been further escalated to 1200 mg twice daily and to a maximum of 1600 mg twice 
daily, as tolerated. 
In the randomized phase 2 part of the study, the RP2D of 1200 mg of tazemetostat when given in combination 
with enzalutamide will be administered orally twice daily in continuous 28-day cycles. Enzalutamide and 
tazemetostat will both be administered on day 1 of each cycle. 

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Duration of Treatment:  
Treatment administration should continue for as long as the subject is tolerating the study drugs and continues 
ADT (ie, surgical castration or ongoing GnRH analogue therapy) until confirmed radiographic disease 
progression by PCWG3 criteria as specified in Table S1 above, even if the subject continues to benefit 
clinically, or unequivocal clinical progression if earlier than radiographic disease progression. Enzalutamide 
treatment may be pursued in the commercial setting at the Investigator’s discretion in this case (and will be 
recorded as subsequent anti-cancer therapy). Investigators are strongly discouraged from discontinuing 
treatment due to PSA rise alone without evidence of confirmed radiographic progression. Initiation of new 
therapy for prostate cancer at the time of radiographic progression will mandate discontinuation of study drug. 
Criteria for Evaluation: 
Efficacy Assessments: 
Efficacy will be assessed through survival data, chest CT or chest X-rays, PSA levels, BPI-SF, CTC 
enumeration, and tumor assessments by radionuclide bone scan and CT or MRI, with disease progression 
defined by RECIST 1.1 for soft tissue disease or, where indicated, the appearance of two or more new bone 
lesions on bone scan (per PCWG3). The consensus guidelines of RECIST 1.1 and the PCWG3 are to be taken 
into consideration for the determination of radiographic disease progression. Study films (CT/MRI and bone 
scan) should be read on-site using PCWG3 and RECIST 1.1 guidelines (submitted in a digital format for a 
blinded independent central radiology review was removed with Amendment #5). Radiographic imaging is not 
required after protocol-defined radiographic progressive disease is reached.  
Health-related quality-of-life assessments in the phase 2 portion of the study will also include the FACT-P and 
EQ-5D-5L. Every effort should be made to ensure all subjects complete as many scheduled health-related QoL 
assessments as possible, and assessments should be administered before other interactions in the clinic during 
the visit. 
Pharmacokinetic Sampling: 
In the phase 1b part of the study, blood samples for PK analysis were collected in cycle 1 on days 1, 2, and 21 at 
pre-dose (0 hours) and at 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose; and in cycle 2 on day 1 at pre-dose (0 hours) 
and at 2 and 6 hours post-dose.  
In the randomized phase 2 part of the study, blood samples for sparse PK analysis will be collected only from 
subjects assigned to the combination arm in cycles 2, 3, 5, and 10 on day 1 at pre-dose (0 hours) and at 2- and 6-
hours post-dose. For PK assessment days, subjects will be required to take their study drug/s in the morning at 
the clinic after the pre-dose sample has been collected. The date and time of last dose on PK sampling days will 
be recorded.  
Pharmacogenetics and Biomarker Assessments: 
AR-V7 status and NEPC subgroups will be determined as follows: AR-V7 status will be determined by 
immunofluorescence (IF) detection of the splice variant in nuclei of CTCs; NEPC status will be determined in 
CTCs by assessing imaging of multiple small cell neuroendocrine parameters and may as well with 
neuroendocrine marker(s). Biomarkers, such as neuron-specific enolase (NSE), will also be determined. 
Safety Assessments: 
Safety will be assessed through summaries of adverse events, laboratory evaluations, vital signs, physical 
examinations, and ECGs. Laboratory values also will be classified by toxicity grade based on the National 
&DQFHU ,QVWLWXWH
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Statistical Methods: 
Efficacy Analyses in Phase 2: The efficacy analyses will be conducted using an Intent-to-Treat population, 
defined as all randomized subjects. Comparisons between treatment groups for secondary endpoints will occur 
only if the primary endpoint (rPFS) achieves statistical significance at an alpha level of 0.05. 
Primary Efficacy Endpoint Analysis: 
Radiographic progression-free survival (phase 2 randomized treatment groups): The rPFS of tazemetostat in 
combination with enzalutamide will be compared to the rPFS of enzalutamide alone. rPFS is defined as the time 
from the date of randomization to the date of the first objective evidence of radiographic progression or death 
from any cause, whichever occurs first. In cases where PD or death has not occurred, censoring rules will be 
provided in the SAP. Radiographic disease progression is defined by the criteria in Table S1 (and Figure S2). 

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The primary analysis of rPFS for tazemetostat in combination with enzalutamide compared with enzalutamide 
treatment alone will be based upon at least the first 
 rPFS events observed. A log-rank test will be used to 
compare tazemetostat in combination with enzalutamide to enzalutamide treatment alone at the significance 
level of 0.05 (one-sided). Conventionally, HRs with corresponding 2-sided 95% confidence intervals will be 
estimated using the Cox proportional hazards model. Graphical methods will be used to assess the Cox 
proportional hazards model assumptions. rPFS will also be summarized descriptively using the Kaplan-Meier 
(KM) method.  The KM estimate along with the corresponding 95% CI will be calculated using the Brookmeyer 
and Crowley method and will be provided for the median. The event-free rate with corresponding 95% CI will 
EH FDOFXODWHG XVLQJ *UHHQZRRG
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months. Median follow-up for rPFS will be estimated according to the KM estimate of potential follow-up. KM 
curves will also be provided. 
Secondary Efficacy Endpoint Analysis:  
x 
PSA50: 36$ LV GHILQHG DV WKH SHUFHQWDJH RI VXEMHFWV ZLWK D  UHGXFWLRQ RI 36$ IURP
EDVHOLQH DW DQ\ WLPH RQ VWXG\ IRU VXEMHFWV ZLWK D EDVHOLQH 36$  XJ/  QJP/, per PCWG3 
criteria. Confirmed PSA response is defined as a  UHGXFWLRQ LQ 36$ IURP EDVHOLQH WR SRVW-
baseline PSA result ZLWK  UHGXFWLRQ IURP EDVHOLQH, with a consecutive assessment that 
confirms  UHGXFWLRQ IURP EDVHOLQH conducted at least 3 weeks later required to confirm the 
PSA response. If a consecutive value meets the response criteria but is obtained within 3 weeks 
and the next assessment also meets response criteria and is taken after 3 weeks, then the initial 
response is considered as confirmed response as well. However, a subject with a missing 
confirmation PSA value after 3 weeks is considered as non-responder. PSA50 will be calculated 
by treatment group for subjects with PSA values at the baseline assessment (cycle 1 day 1 
predose) and at least 1 post baseline assessment. A Cochran-Mantel- Haenszel mean score test will 
be used to compare the response rates between tazemetostat in combination with enzalutamide and 
enzalutamide treatment alone. 
x 
Time to First Skeletal-Related Event (SRE): Time to first SRE is defined as the time from 
randomization to the date of the first SRE. In cases where an SRE has not occurred at the time of 
the analysis, the subject will be right-censored. Censoring rules will be provided in the SAP. An 
SRE is defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord 
compression, or change of antineoplastic therapy to treat bone pain. A log-rank test will be used to 
compare time to SREs between tazemetostat in combination with enzalutamide and enzalutamide 
treatment alone. 
x 
ORR and Best Overall Soft Tissue Response: ORR is defined per RECIST 1.1 guidelines. The 
best overall soft tissue response as assessed by Investigators using RECIST 1.1 will be 
summarized. Only subjects with measurable soft tissue disease at screening (ie, at least 1 target 
lesion per RECIST 1.1) will be included in this analysis. Clopper-Pearson exact method will be 
used to compare the proportion of subjects with an objective response (complete response or 
partial response) per RECIST 1.1 between tazemetostat in combination with enzalutamide and 
enzalutamide treatment alone.   
x 
Disease Control Rate (no radiographic progression per PCWG3, and no unequivocal clinical 
progression or death) at 6 months on study therapy. A Cochran-Mantel-Haenszel test will be used 
to compare DCR between tazemetostat in combination with enzalutamide and enzalutamide 
treatment alone, and the corresponding p-value will be provided. Also, the 95% CI will be 
provided for each treatment group and the difference in proportion between the two treatment 
groups using Clopper-Pearson exact method and Newcombe method, respectively. 
x 
Time to Initiation of the Next Systemic Treatment for Prostate Cancer (TTNT): TTNT is 
defined as the time from the date of randomization to date of first documented administration of 
systemic treatment for prostate cancer. The TTNT will be right-censored at the last study 
assessment date if the subject did not receive subsequent treatment. A log-rank test will be used to 
compare time to initiation of subsequent treatment between tazemetostat in combination with 
enzalutamide and enzalutamide treatment alone. 
x 
Time to PSA Progression: Time to PSA progression is defined as the duration from baseline to 
the date of PSA progression. PSA progresVLRQ LV GHILQHG DV D  LQFUHDVH DQG DQ DEVROXWH
CCI

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LQFUHDVH RI   ȝJ/  QJP/ DERYH WKH QDGLU RU EDVHOLQH YDOXH IRU VXEMHFWV ZKR GLG QRW KDYH D
decline in PSA value by week 17). This increase must be confirmed by a second consecutive 
assessment conducted at least 3 weeks later. The date of confirmed PSA progression is the date of 
WKH LQLWLDO  increase. Subjects without confirmed PSA progression at the time of analysis will 
be right-censored. Censoring rule will be provided in the SAP. Time from randomization to first 
observation of PSA progression will be assessed. A log-rank test will be used to compare TTPP 
between tazemetostat in combination with enzalutamide and enzalutamide treatment alone. 
x 
CTCs: In subjects who enter the study with a detectable number of CTCs, the rate of CTC 
reduction to zero is the proportion of subjects who convert to an undetectable number of CTCs. 
&7& UHVSRQVH LV GHILQHG DV D  UHGXFWLRQ LQ &7&V IURP EDVHOLQH LQ VXEMHFWV ZKR HQWHU WKH
study with a detectable number of CTCs, and the CTC response rate is the proportion of subjects 
ZLWK D  UHGXFWLRQ LQ &7&V IURP EDVHOLQH F\FOH  GD\  SUH-dose). The rate of CTC reduction 
to zero and the CTC response rate for tazemetostat in combination with enzalutamide will be 
compared with those for enzalutamide treatment alone using the Clopper-Pearson exact method. 
See also health-related quality of life (QoL) endpoints below. 
Population PK Analysis:  
x 
PK data will be combined with data from the phase 1b and phase 2 parts in a population PK 
model. 
Safety Analysis: 
Safety analyses will be based on all subjects who receive 1 dose or partial dose of any of the study drugs (ie, 
the Safety population). Safety data from the phase 1b and phase 2 portions of the study will be presented 
separately. In general, safety data from the phase 1b portion of the study will be tabulated by assigned dose 
levels and overall, and the data from the phase 2 portion of the study will be tabulated by assigned treatment 
group and overall. For all analyses, subjects who receive a dose modification will be retained and analyzed in 
the treatment group originally assigned.  
Drug exposure and compliance will be summarized by descriptive statistics. Severity of all adverse events is to 
be evaluated by the Investigator based on the CTCAE, version 5.0 and will be coded to preferred term, higher 
level term, and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA) version in 
effect at the time of the analysis. Tabular summaries of the number and percentage of subjects with adverse 
events will be presented by MedDRA system organ class and preferred term by relationship to study treatment 
and by severity.  
Deaths will be summarized and listed and will include the categorical reason for death. 
/DERUDWRU\ YDOXHV DOVR ZLOO EH FODVVLILHG E\ WR[LFLW\ JUDGH EDVHG RQ WKH 1DWLRQDO &DQFHU ,QVWLWXWH
V &7&$(
version 5.0. Separate listings and summary tables will be produced for the laboratory test groups with abnormal 
values flagged. Laboratory shift tables of changes from baseline to worst post-baseline values based on CTCAE 
toxicity grades will be produced for each parameter. Vital signs and ECG data will be listed and categorically 
summarized descriptively.  Physical examination results will be listed. 
Exploratory Analyses and Endpoints:  
x 
PSA90: Defined and analyzed similarly to PSA50. 
x 
Changes in ctDNA burden (defined as the proportion of ctDNA in the entire population of cell-
free DNA [cfDNA]) from longitudinal samples taken throughout the period of drug treatment as 
compared to baseline.  
x 
Characterization of tazemetostat combination exposure (possible example: Cmin). 
x 
Pharmacodynamic modulation of EZH2 activity by tazemetostat as assessed by measuring 
H3K27me3 levels in paired pre- and on-treatment tumor biopsies that may be obtained from the 
phase 1b and phase 2 portions of the study. Analyses will include change from screening to on-
study values plotted at cycle 2 day 1 and at progression using a waterfall plot. 
x 
The mutational landscape of pre-treatment tumor biopsies and baseline ctDNA, such as for 
loss of PTEN, TP53, and RB1, will be determined using bioinformatic analysis of whole exome 
next generation sequencing (NGS) and compared when possible to the mutational landscape in 

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biopsies taken on-treatment and at disease progression.  In addition, whole transcriptome data will 
be obtained from tumor biopsies using RNASeq, and bioinformatics analysis of NEPC and AR 
signaling pathways, including AR variant AR-V7 gene expression, and other pathways involved in 
prostate cancer biology will be performed in matched biopsies.  Finally, the state of the immune 
microenvironment in pre-treatment, on treatment (at cycle 2 day 1), and at disease progression 
(only in responders) tumor biopsies in subjects receiving tazemetostat in combination with 
enzalutamide will be evaluated by investigating the occurrence of various gene expression 
signatures of tumor inflammation and infiltrating lymphocytes available from public sources. 
x 
Circulating tumor DNA (ctDNA) obtained from liquid biopsies taken minimally at baseline prior 
to the first dose and on the same days as CT/MRI scans to ascertain first sign of response and 
disease progression based on ctDNA burden will also undergo targeted whole exome sequencing 
(WES) to determine the mutational status of genes, such as PTEN, TP53, and RB1, associated with 
clinical outcome.   
x 
Concordance of genetic characteristics of disease in tumor biopsies and ctDNA isolated from 
baseline liquid biopsies will be evaluated using regression analysis methods.   
x 
Assessment of immunological endpoints in tumor biopsies taken at pre-treatment, on-treatment 
(cycle 2 day 1), and at disease progression (only in responders) in the phase 2 portion of the study 
will be conducted to determine the level of infiltration of various T-cell lymphocyte and other 
immune cell populations (cell type number and activation status) using multiplex IF staining and 
DNA sequence analysis.  Differences in the composition of the immune microenvironment 
between responders and non-responders in each treatment cohort will be determined and compared 
to published tumor immune profiles associated with response or resistance to immunotherapy, 
such as checkpoint inhibitor blockade or enzalutamide therapy. In addition, circulating immune 
cell sub-populations isolated from PBMCs from blood taken pre-treatment, on-treatment (cycle 2 
day 1), and at disease progression (only in responders) in the phase 2 portion of the study will be 
investigated to determine the impact of drug treatment on immune cell numbers, antigen 
presentation, and activation status. 
 
Subgroup Analysis 
Subgroup analysis will be performed for rPFS by AR-V7 and NEPC (negative and positive) status. A swim lane 
plot (time on treatment) showing AR-V7 and NEPC status will be provide for each endpoint. 
 
Health-Related QoL Endpoints 
BPI-SF (phase 1 and phase 2 exploratory objectives): 
x 
In phase 1, the rate of pain progression, defined as the proportion of subjects with an increase of 
 IURP WKH WLPH RI VFUHHQLQJ LQ WKH DYHUDJH RI %3, SDLQ LQWHQVLW\ LWHP VFRUHV LWHPV   
and 6) at 6 months will be used to assess tazemetostat in combination with enzalutamide and 
tazemetostat in combination with abiraterone/prednisone. The BPI scores will be summarized 
descriptively at time of screening, at 3 months, and at 6 months. 
x 
In phase 2, the rate of pain progression, defined as the proportion of subjects with an increase of 
 IURP EDVHOLQH LQ WKH DYHUDJH RI %3, SDLQ LQWHQVLW\ LWHP VFRUHV LWHPV    DQG  DW HDFK
post-baseline time point will be used to compare tazemetostat in combination with enzalutamide to 
enzalutamide treatment alone. The BPI scores will be summarized descriptively at baseline and 
each postbaseline time point. 
The BPI mean severity score will be analyzed using mixed-effects model for repeated measures (MMRM) and 
mixed-effects models with baseline score and treatment group as covariates, and the differences in mean scores 
between treatment groups will be presented with corresponding 95% CIs at each time point and overall. 
Changes from baseline will also be presented.  The mean change from baseline will be summarized and plotted 
by treatment group. Continuous endpoints will be analyzed similarly as for BPI pain intensity score. 

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FACT-P (phase 2 secondary and exploratory objectives): 
x 
For the secondary objective, the percentage of subjects with a decline from baseline in the FWB 
VXEVFDOH VFRUH E\  SRLQWV DQG WKH SHUFHQWDJH RI VXEMHFWV ZLWK D GHFOLQH IURP baseline in the 
3URVWDWH &DQFHU 6XEVFDOH 3&6 VFRUH E\  SRLQWV DW DQ\ SRVWEDVHOLQH YLVLW ZLOO EH FRPSDUHG
between the treatment groups. 
x 
For the secondary objective, the TDD is a decline from baseline in FACT-P FWB subscale score 
RI  SRLQWV DQG WKH WLPH IURP baseline to decline in FACT-3 3&6 VXEVFDOH VFRUH RI  SRLQWV
will be compared between the treatment groups. 
x 
For exploratory objectives, scores will be summarized descriptively over the course of the study 
by treatment group, with emphasis on the following FACT-P domains: Emotional, Social, and 
Physical Well-being. 
Analyses will be conducted on the intent to-treat FACT-P population, defined as all randomized subjects who 
have completed an evaluable FACT-3 TXHVWLRQQDLUH DW EDVHOLQH DQG  SRVW-baseline visit. An evaluable 
TXHVWLRQQDLUH ZLOO KDYH VXIILFLHQW LWHPV FRPSOHWHG WR DOORZ FDOFXODWLRQ RI  )$&7-P subscale. 
In general, to estimate longitudinal changes in FACT-P scores from baseline, the primary analysis will be 
carried out using an MMRM. MMRM analysis uses all available data and assumes that any missing 
observations are missing at random. The differences in mean scores between treatment groups will be presented 
with the corresponding 95% CI at each time point and overall. To address the possibility that missing data may 
not be at random, a second analysis will be carried out using a pattern-mixture model (PMM) with placebo-
based pattern imputation. In both models, the baseline covariates may include: treatment group; time; baseline 
ECOG score (0–1 or 2); average baseline domain score. Due to the exploratory nature of the analyses, 
adjustments for multiple comparisons will not be made.  
The cumulative distribution function will be presented as a continuous plot of the numerical change in FACT-P 
scores from baseline on the horizontal axis, with the cumulative percentage of patients experiencing up to that 
change on the vertical axis. One curve for each treatment group will be plotted for each visit. 
EQ-5D-5L (phase 2 exploratory objective): 
For the exploratory objective, scores will be summarized descriptively over the course of the study by 
treatment group, with emphasis on changes from baseline in EQ-5D-5L VAS and HUI scores over the course of 
the study. The analysis method is similar to those for FACT-P. 
 

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3. 
TABLE OF CONTENTS 
Contents 
1. 
TITLE PAGE ................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
,19(67,*$725
6 $*5((0(17 ................................................................................................3 
EMERGENCY CONTACT INFORMATION ................................................................................4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................5 
2. 
SYNOPSIS ...................................................................................................................9 
3. 
TABLE OF CONTENTS ...........................................................................................27 
Contents 
27 
List of Tables .................................................................................................................................32 
List of Figures ................................................................................................................................33 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................34 
5. 
INTRODUCTION ......................................................................................................38 
5.1. 
Background .................................................................................................................38 
5.2. 
Clinical Characteristics of Prostate Cancer ................................................................39 
5.3. 
Rationale for Tazemetostat Treatment ........................................................................39 
5.4. 
Tazemetostat ...............................................................................................................43 
5.4.1. 
Nonclinical Pharmacology ..........................................................................................43 
5.4.2. 
Pharmacokinetics ........................................................................................................43 
5.4.3. 
Clinical Experience .....................................................................................................44 
5.4.4. 
Pharmacodynamics .....................................................................................................46 
5.5. 
Rationale .....................................................................................................................46 
5.5.1. 
Rationale for Studying mCRPC..................................................................................46 
5.5.2. 
Study Rationale ...........................................................................................................48 
5.5.3. 
Rationale for Dose Selected ........................................................................................49 
5.6. 
Benefit:Risk Assessments ...........................................................................................51 
5.6.1. 
Animal Toxicology .....................................................................................................51 
5.6.2. 
Photo-Reactive Potential ............................................................................................52 
5.6.3. 
CYP3A Metabolism....................................................................................................52 
5.6.4. 
Summary .....................................................................................................................53 

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6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................54 
6.1. 
Primary Objectives .....................................................................................................54 
6.2. 
Secondary Objectives .................................................................................................54 
6.3. 
Exploratory Objectives ...............................................................................................55 
7. 
INVESTIGATIONAL PLAN .....................................................................................57 
7.1. 
Overall Study Design ..................................................................................................57 
7.2. 
Number of Subjects ....................................................................................................59 
7.3. 
Treatment Assignment ................................................................................................60 
7.4. 
Restrictions During Study Treatment .........................................................................60 
7.4.1. 
Food and Sun Exposure ..............................................................................................60 
7.4.2. 
Pregnancy and Sperm Donation .................................................................................60 
7.4.2.1. 
Definition of Child-fathering Potential: Male Subjects ..............................................61 
7.4.2.2. 
Definition of Childbearing Potential: Female Partners ..............................................61 
7.4.2.3. 
Pregnancy Prevention .................................................................................................61 
7.5. 
Dose Adjustment Criteria ...........................................................................................62 
7.5.1. 
Dose-limiting Toxicities .............................................................................................62 
7.5.2. 
Dose Modifications and Stopping Rules Due to Treatment-Related 
Toxicities ....................................................................................................................65 
7.5.2.1. 
Dose Modification for Tazemetostat Toxicity ............................................................65 
7.5.2.2. 
Dose Modification for Toxicity to Abiraterone Acetate .............................................67 
7.5.2.3. 
Dose Modifications for Toxicity to Enzalutamide .....................................................68 
7.5.3. 
Tazemetostat Dose Modifications With Unavoidable Concomitant Moderate 
CYP3A Inhibitors .......................................................................................................68 
7.5.4. 
Rules for Suspension of Enrollment ...........................................................................68 
7.6. 
Criteria for Study Suspension or Termination ............................................................69 
7.7. 
Study Design Schematic and Schedule of Assessments .............................................69 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................76 
8.1. 
Subject Inclusion Criteria ...........................................................................................76 
8.2. 
Subject Exclusion Criteria ..........................................................................................77 
8.3. 
Subject Withdrawal Criteria .......................................................................................80 
8.3.1. 
Withdrawal of Subjects from Treatment/Procedures .................................................80 
8.3.2. 
Withdrawal of Subjects from Study ...........................................................................80 
8.3.3. 
Replacement of Subjects .............................................................................................81 

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9. 
TREATMENT OF SUBJECTS ..................................................................................82 
9.1. 
Study Drug Dosing .....................................................................................................82 
9.2. 
Duration of Treatment ................................................................................................82 
9.3. 
Concomitant Medications ...........................................................................................83 
9.3.1. 
Permitted Medications ................................................................................................83 
9.3.2. 
Medications to be Used with Caution .........................................................................84 
9.3.3. 
Prohibited Medications ...............................................................................................84 
9.3.4. 
Non-Drug Therapies for Disease ................................................................................85 
9.4. 
Treatment Compliance ................................................................................................85 
9.4.1. 
Treatment Compliance Procedures .............................................................................85 
9.4.2. 
Special Situations: Overdose, Misuse, Abuse and Medication Error .........................86 
9.5. 
Randomization ............................................................................................................86 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................87 
10.1. 
Study Drug ..................................................................................................................87 
10.1.1. 
Tazemetostat ...............................................................................................................87 
10.1.2. 
Enzalutamide ..............................................................................................................87 
10.1.3. 
Abiraterone/Prednisone ..............................................................................................87 
10.2. 
Study Drug Packaging and Labeling ..........................................................................88 
10.3. 
Study Drug Storage .....................................................................................................88 
10.4. 
Study Drug Preparation ..............................................................................................88 
10.5. 
Administration ............................................................................................................88 
10.6. 
Study Drug Accountability .........................................................................................89 
10.7. 
Study Drug Handling and Disposal ............................................................................89 
11. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................90 
11.1. 
Consent .......................................................................................................................90 
11.2. 
Screening Assessments ...............................................................................................90 
11.2.1. 
Demographic/Medical History ...................................................................................90 
11.3. 
Efficacy Assessments .................................................................................................90 
11.3.1. 
Prostate Cancer Status ................................................................................................90 
11.3.2. 
Radiographic Progression-Free Survival ....................................................................91 
11.3.3. 
Chest X-ray or Chest CT ............................................................................................92 
11.3.4. 
Prostate Specific Antigen (PSA) ................................................................................92 
11.3.5. 
Circulating Tumor Cell (CTC) Enumeration ..............................................................93 

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11.3.6. 
Health-Related Quality of Life ...................................................................................93 
11.3.6.1. 
Brief Pain Inventory-Short Form ................................................................................93 
11.3.6.2. 
Functional Assessment of Cancer Therapy-Prostate (FACT-P) .................................93 
11.3.6.3. 
EuroQoL 5-Dimension 5-Level (EQ-5D-5L) .............................................................93 
11.4. 
Pharmacokinetic Assessments ....................................................................................94 
11.4.1. 
Blood Sample Collection ............................................................................................94 
11.4.2. 
Urine Pharmacokinetic Sample Collection .................................................................94 
11.5. 
Pharmacogenomics, Biomarkers, and Other Assessments .........................................94 
11.5.1. 
Tumor Biopsy .............................................................................................................94 
11.5.2. 
Blood Samples for Disease Markers and Pharmacogenomics (PGx) .........................95 
11.5.2.1. 
Blood Sample for ctDNA Genotyping .......................................................................95 
11.5.2.2. 
AR-V7 and NEPC Status in Circulating Tumor Cells ................................................95 
11.5.2.3. 
Blood Biomarkers of Neuroendocrine Prostate Cancer ..............................................95 
11.5.3. 
Future Use of Biosamples ...........................................................................................96 
11.6. 
Follow-up ....................................................................................................................96 
11.6.1. 
Post-treatment Follow-up Visit...................................................................................96 
11.6.2. 
Long-Term Follow-up ................................................................................................96 
11.6.3. 
Subsequent Therapy After Discontinuation of Study Treatment ...............................96 
11.6.4. 
Evaluation of Response to Subsequent Anti-Cancer Therapy ....................................97 
12. 
ASSESSMENT OF SAFETY .....................................................................................98 
12.1. 
Safety Parameters .......................................................................................................98 
12.1.1. 
Vital Signs ..................................................................................................................98 
12.1.2. 
Weight and Height ......................................................................................................98 
12.1.3. 
Physical Examination .................................................................................................98 
12.1.4. 
Electrocardiogram (ECG) ...........................................................................................99 
12.1.5. 
Laboratory Assessments .............................................................................................99 
12.1.6. 
Creatinine Clearance .................................................................................................100 
12.1.7. 
ECOG Performance Status .......................................................................................100 
12.1.8. 
Optional Chest Ultrasound .......................................................................................100 
12.2. 
Adverse Events .........................................................................................................100 
12.2.1. 
Definitions of Adverse Events ..................................................................................100 
12.2.1.1. 
Adverse Event (AE) ..................................................................................................100 
12.2.1.2. 
Serious Adverse Event (SAE) ..................................................................................101 

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12.2.1.3. 
Laboratory Abnormalities .........................................................................................102 
12.2.1.4. 
Other Safety Assessment Abnormalities ..................................................................102 
12.2.1.5. 
Disease-Related Events ............................................................................................102 
12.2.1.6. 
Adverse Events of Special Interest (AESIs) .............................................................102 
12.2.1.7. 
Safety Signal Under Evaluation: B-cell acute lymphoblastic leukemia (B-
ALL) .........................................................................................................................104 
12.2.2. 
Reporting of Special Situations ................................................................................105 
12.2.3. 
Grading and Severity ................................................................................................106 
12.2.4. 
Relationship to Study Drug ......................................................................................106 
12.2.5. 
Outcome and Follow-Up ..........................................................................................107 
12.2.6. 
Timeframe for Collecting AEs and SAEs ................................................................107 
12.2.7. 
Recording Adverse Events and Pregnancy ...............................................................108 
12.2.8. 
Reporting of SAEs and AESIs ..................................................................................108 
12.3. 
Safety Review Committee (SRC) .............................................................................108 
12.4. 
Quarterly Safety Review (QSR) Committee ............................................................109 
13. 
STATISTICS ............................................................................................................110 
13.1. 
Analysis Sets .............................................................................................................110 
13.1.1. 
Phase 1b Analysis Sets .............................................................................................110 
13.1.2. 
Phase 2 Analysis Sets ...............................................................................................110 
13.2. 
Sample Size Justification ..........................................................................................110 
13.3. 
Analyses ....................................................................................................................111 
13.3.1. 
Disposition, Demographics, Baseline Characteristics, and Prior Cancer 
Treatments ................................................................................................................111 
13.3.2. 
Efficacy Analyses .....................................................................................................111 
13.3.2.1. 
Primary Efficacy Endpoint Analysis ........................................................................111 
13.3.2.2. 
Analysis of Secondary Efficacy Endpoints ..............................................................112 
13.3.2.3. 
Subgroup Analysis ....................................................................................................113 
13.3.3. 
Pharmacokinetic and Population Pharmacokinetic Analysis ...................................114 
13.3.4. 
Exploratory Analyses and Endpoints........................................................................114 
13.3.5. 
Health-Related Quality of Life Assessment Endpoints and Analysis ......................116 
13.3.6. 
Safety Analyses ........................................................................................................117 
13.3.6.1. 
General Considerations .............................................................................................117 
13.3.6.2. 
Study Drug Exposure and Compliance .....................................................................117 

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13.3.6.3. 
Adverse Events and Deaths ......................................................................................117 
13.3.6.4. 
Clinical Laboratory Values .......................................................................................119 
13.3.6.5. 
Other Safety Measures ..............................................................................................119 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................120 
14.1. 
Study Monitoring ......................................................................................................120 
14.2. 
Audits and Inspections ..............................................................................................120 
14.3. 
Institutional Review Boards/Independent Ethics Committees .................................121 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................122 
16. 
ETHICS ....................................................................................................................123 
16.1. 
Ethics Review ...........................................................................................................123 
16.2. 
Ethical Conduct of the Study ....................................................................................123 
16.3. 
Written Informed Consent ........................................................................................123 
17. 
DATA HANDLING AND RECORDKEEPING .....................................................124 
17.1. 
Inspection of Records ...............................................................................................124 
17.2. 
Retention of Records ................................................................................................124 
18. 
PUBLICATION POLICY ........................................................................................125 
19. 
LIST OF REFERENCES ..........................................................................................126 
 
 
List of Tables 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................34 
Table 2: 
Dose-Limiting Toxicities - Tazemetostat ...................................................................63 
Table 3: 
Dose-Limiting Toxicities - Abiraterone/Prednisone ..................................................64 
Table 4: 
Dose-Limiting Toxicities - Enzalutamide ..................................................................64 
Table 5: 
Dose Modifications for Tazemetostat Treatment-Related Toxicities .........................66 
Table 6: 
Dose Modification for Abiraterone-Related Toxicity ................................................67 
Table 7: 
Recommended Dose Reductions of Tazemetostat for Moderate CYP3A 
Inhibitors .....................................................................................................................68 
Table 8: 
Schedule of Assessments ............................................................................................71 
Table 9: 
Phase 1b/2 Doses of Tazemetostat, Enzalutamide, Abiraterone, and 
Prednisone ...................................................................................................................82 

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Table 10: Protocol-Specified Documentation for Radiographic Evidence of Disease 
Progression .................................................................................................................91 
 
List of Figures 
Figure 1: Study Design ..............................................................................................................70 
Figure 2: 
Post Week 9 Bone Scan Assessment Flow Diagram ..................................................92 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or 
Specialist Term 
Definition/Explanation 
ADT 
androgen deprivation therapy 
AE 
adverse event 
AESI 
adverse event of special interest 
ANC 
absolute neutrophil count 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AST 
aspartate aminotransferase 
AR 
androgen receptor 
AR-V7 
androgen-receptor splice variant 7 
ASIs 
androgen-signaling inhibitors 
ATRT 
atypical teratoid rhabdoid tumor 
AUC 
area under the concentration versus time curves 
B-ALL 
B-cell acute lymphoblastic leukemia  
BOR 
best overall response 
BPI 
Brief Pain Inventory 
BPI-SF 
Brief Pain Inventory-Short Form 
CI 
confidence interval 
Cmax 
peak plasma concentration 
Cmin 
minimum/trough plasma concentrations 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CSR 
clinical study report 
CT 
computed tomography 
CTC 
circulating tumor cells 
CTCAE 
1DWLRQDO &DQFHU ,QVWLWXWH
V &RPPRQ 7HUPLQRORJ\ &ULWHULD IRU $GYHUVH (YHQWV 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interaction 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
Emax 
maximal effect 
ES 
epithelioid sarcoma 
ESC 
External Safety Committee 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level questionnaire 
EZH2 
enhancer of zeste homologue-2 

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Abbreviation or 
Specialist Term 
Definition/Explanation 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FACT-P 
Functional Assessment of Cancer Therapy – Prostate  
FDA 
United States Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FL 
follicular lymphoma 
FWB 
functional well-being 
GCP 
Good Clinical Practices 
GnRH 
gonadotropin releasing hormone 
GOF 
gain-of-function 
H3K27 
lysine 27 of histone H3 
H3K27me3 
H3K27 trimethylation 
HIV 
human immunodeficiency virus 
HMT 
histone methyltransferase 
HR 
hazard ratio 
HUI 
Health Utilities Index 
IB 
,QYHVWLJDWRU
V %URFKXUH 
IBW 
ideal body weight 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IF 
immunofluorescence 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
INI1 
integrase interactor 1 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
LN 
lymph nodes 
LSLV 
last subject’s last visit 
mCRPC 
metastatic castration-resistant prostate cancer 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeter of mercury 
MPN 
myeloproliferative neoplasm 
QTcF 
QT interval corrected by Fridericia’s formula 
RECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MMRM 
mixed-effects model for repeated measures 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NE 
not evaluable 
NEPC 
neuroendocrine prostate cancer 

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Abbreviation or 
Specialist Term 
Definition/Explanation 
NGS 
next-generation sequencing 
NHL 
non-Hodgkin lymphoma 
NSE 
neuron-specific enolase 
NYHA 
New York Heart Association 
OATP 
organic anion transporting polypeptide 
ORR 
objective response rate 
PBMC 
peripheral blood mononuclear cell 
PCS 
Prostate Cancer Subscale 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PET 
positron-emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PGx 
pharmacogenetic(s) 
PK 
pharmacokinetic(s) 
PMM 
pattern-mixture model 
PO 
oral(ly) 
PR 
partial response 
PRC2 
polycomb repressive complex 2 
PSA 
prostate-specific antigen 
PSA50 
the percentage of participants who had a PSA decline of at least 50% from 
baseline 
PSA90 
the percentage of participants who had a PSA decline of at least 90% from 
baseline 
QoL 
quality of life 
QSR 
Quarterly Safety Review 
RECIST 
response evaluation criteria in solid tumors 
RP2D 
recommended phase 2 doses 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SAM 
S-adenosyl methionine 
SD 
stable disease 
SET 
sun(var)3-9, enhancer-of-zeste and trithorax 
SMARCA4 
SWItch/Sucrose non-fermentable related, matrix associated, actin dependent 
regulator of chromatin, subfamily a, member 4 
SRC 
Safety Review Committee 
SRE 
skeletal-related event 
SUSAR 
suspected unexpected serious adverse reaction 
SWI/SNF 
SWItch/Sucrose Non-Fermentable 
t1/2 
apparent elimination half-life 
T-ALL 
T-cell acute lymphoblastic leukemia 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TGI 
tumor growth inhibition 
T-LBL 
T-cell lymphoblastic lymphoma 
tmax 
maximum plasma concentration 
TSP1 
thrombospondin-1 

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Abbreviation or 
Specialist Term 
Definition/Explanation 
TTNT 
time to initiation of the next systemic treatment 
TTPP 
time to PSA progression 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WBC 
white blood cells 
WES 
whole exome sequencing 
WT 
wild-type 
 

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5. 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according 
to: United States and international standards of Good Clinical Practices, Food and Drug 
Administration (FDA) Title 21 Part 312, and International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines; applicable 
government regulations; and institutional research policies and procedures. 
5.1. 
Background 
Post-translational modifications of histones, the core proteins of chromatin, play an important 
role in controlling the fidelity of cellular gene transcription patterns. One of the critical 
transcription-controlling histone modifications is methylation of specific lysine and arginine 
residues, catalyzed by histone methyltransferases (HMTs) which all use S-adenosyl methionine 
(SAM) as a co-factor for the methylation reaction (Copeland, 2013). 
Genetic alterations in a number of HMTs or associated regulatory proteins have been identified 
in several human cancers where they are purported to be oncogenic. Enhancer of zeste 
homologue 2 (EZH2) is the catalytic subunit of the multi-protein polycomb repressive complex 2 
(PRC2) that catalyzes the mono-, di-, and trimethylation of lysine 27 of histone H3 (H3K27) 
(Margueron, 2011). 
Enhancer of zeste homologue-2 mutation and/or over-expression has been observed in several 
cancer types, leading to an aberrant H3K27 trimethylation (H3K27me3) state which is oncogenic 
(Chase, 2011).  
For instance, somatic EZH2 gain-of-function (GOF) mutations at three hotspots (Y646, A682, 
and A692 [NM_001203247]) are found in 10% to 20% of follicular lymphoma (FL) and diffuse 
large B-cell lymphoma (DLBCL). These GOF mutations result in an oncogenic dependency on 
EZH2 production of abnormally high H3K27me3 levels, and resultant transcriptional 
reprogramming of the cell (Morin, 2010). 
In addition to the EZH2 GOF activation mutations described above, overexpression or 
amplification of EZH2 has been described in numerous tumor types, including but not limited to 
bladder, breast cancer, colorectal, lung, pancreatic, ovarian, prostate, mesothelioma, uveal 
melanoma, renal carcinoma, cholangiocarcinoma, and stomach cancer (Kuroki, 2014; LaFave, 
2015; Comet, 2016). 
This is partially explained by the regulation of EZH2 gene expression by the pRB-E2F pathway, 
which is dysregulated in many tumor types (Bracken, 2003). In many of these tumors, EZH2 has 
been demonstrated to function as an oncogene (Comet, 2016). For instance, EZH2 
overexpression promotes anchorage-independent growth and cell invasion in breast cancer 
(Kleer, 2003), proliferation and epithelial-mesenchymal transition in lung cancer (Takawa, 2011; 
Tiwari, 2013), and tumorigenesis and metastasis in prostate cancer (Min, 2010). In addition, a 
gene expression profiling study shows that overexpression of EZH2 in metastatic castration-
resistant prostate cancer (mCRPC) (Varambally, 2002) and decreased expression of target genes 
are correlated with disease stage and poor prognosis (Yu, 2007). 
These data suggest that inhibition of EZH2 might also be beneficial in solid tumors that 
overexpress EZH2 or contain amplifications of the EZH2 gene. 

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5.2. 
Clinical Characteristics of Prostate Cancer 
Worldwide, prostate cancer ranks third in cancer incidence and sixth in cancer mortality in men 
(Bray, 2018). Prostate cancer growth is dependent on androgens and depleting or blocking 
androgen action has been a mainstay of treatment for over 6 decades. Hormonal therapies 
include gonadotropin-releasing hormone (GnRH) analogues, anti-androgens, ketoconazole, and 
estrogenic compounds. Despite the early sensitivity of tumors to hormonal strategies, tumors that 
progress despite androgen deprivation generally represent a transition to the lethal variant of the 
illness, and most patients ultimately succumb to this disease (Petrylak, 2004; Pienta, 2006). 
Results of clinical investigations and studies on the molecular profiles of these progressing 
tumors show that the androgen receptor (AR) remains functional and that the tumors should 
respond to strategies directed at the AR signaling axis. Overexpression of the AR has been 
documented in upwards of 50% of such prostate cancer specimens and is believed to contribute 
to tumor progression (Chen, 2004; Scher, 2004). In addition, currently approved anti-androgens 
have the potential to act as a partial agonist and stimulate AR signaling in the setting of AR 
overexpression, therefore exacerbating or accelerating tumor growth. The decline in serum levels 
of prostate-specific antigen (PSA) seen upon discontinuation of these agents is consistent with 
the agonist effects ("anti-androgen withdrawal syndrome"). 
In clinical practice, treatment of advanced prostate cancer is therefore limited by the 
development of resistance to anti-androgen therapies. Enzalutamide, a potent AR antagonist, and 
abiraterone acetate (administered in combination with prednisone and hereafter referred to as 
abiraterone), a potent inhibitor of cytochrome P450 (CYP17A1) that suppresses androgen 
synthesis, induce declines in PSA in up to 90% of patients when administered alone to men with 
mCRPC. Both improve survival and are approved for the first-line treatment of chemotherapy-
naive mCRPC. However, resistance develops after a median of approximately 18 months, and 
strategies that prolong treatment benefit are urgently required. A rise in PSA, suggesting 
reactivation of AR target genes, is often associated with clinical progression. Several 
mechanisms have been implicated in driving resistance and can be broadly divided into 
categories that are either dependent on or independent of ligand-binding domain-driven 
reactivation of AR signaling. The former can include an adaptive feedback loop of increased 
serum and tissue androgens and AR levels after AR antagonism with enzalutamide that in vitro 
modeling suggests could result in outcompeting of enzalutamide at the AR.  
5.3. 
Rationale for Tazemetostat Treatment 
Prostate cancer is the second leading cause of cancer death for men in the United States with an 
estimated 174,650 new cases and 31,620 deaths expected (Siegel, 2019). Prostate cancer 
clinically manifests at different stages with or without associated metastases. Disease 
development and progression are driven by elevated testosterone (and dihydrotestosterone), 
through induction of AR signaling (Scher, 2000). 
In 1941, Charles Huggins demonstrated that androgen deprivation therapy (ADT) by means of 
surgical castration offered benefit to men with advanced metastatic prostate cancer (Huggins, 
2002).  
Current available therapies consist of medical castration by depletion of testicular androgens or 
by targeting AR signaling pathways. Although initial response to ADT occurs, tumors often 

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relapse after castration, in what is termed castration resistant prostate cancer (CRPC). This stage 
is defined by an increase in PSA, a target of AR signaling activation. When the disease 
progresses, prostate cancer metastasizes to the bone and other organs. Patients with mCRPC 
have poor overall survival of about 2 years from disease progression.  
Two of the newer approved androgen-signaling inhibitors (ASIs) in prostate cancer target the AR 
signaling pathway: abiraterone acetate diminishes androgen levels derived from the adrenal 
glands and the tumor itself by inhibiting the enzyme CYP17A1 and thus steroidogenesis (Barrie, 
1994), and enzalutamide, an AR antagonist, prevents AR translocation to the nucleus for 
subsequent gene activation (Tran, 2009). Even though responses are observed to these two 
inhibitors, most patients relapse in 1 to 2 years (Vander Ark, 2018; Einstein, 2019) with a variety 
of resistance mechanisms to these drugs being observed.  
Leading research in prostate cancer is now focused on understanding the mechanisms of 
resistance to these newer ASIs. Abiraterone and enzalutamide resistance is believed to be driven 
by similar mechanisms found in resistance to first-line ADTs, with one of the main resistance 
mechanisms observed being the preservation of AR signaling. One of such mechanisms is 
increased expression of the AR. In several studies of mCRPC cohorts, amplification of the AR 
was found to be present in up to 70% of cases (Robinson, 2015; Abida, 2017; Armenia, 2018; 
Quigley, 2018; Wedge, 2018). In particular, there is evidence that AR amplification may be 
caused by an intergenic enhancer region upstream of the AR (Quigley, 2018; Takeda, 2018; 
Viswanathan, 2018) found present in 81% of cases (Quigley, 2018) that strongly correlates with 
increased AR expression and possibly drives progression to mCRPC. Another mechanism of 
resistance observed in certain abiraterone and enzalutamide resistant tumors is the presence of 
recurrent GOF mutations in the AR gene responsible for the switch of the function of these 
molecules from antagonist to agonist. This switch was also observed in tumors from patients that 
relapsed after first-line AR therapies (Azad, 2015; Robinson, 2015; Lallous, 2016). These 
mutations have been found in 10 to 20% of cases in mCRPC studies (Robinson, 2015; Abida, 
2017; Armenia, 2018; Quigley, 2018; Wedge, 2018). 
In addition, expression of AR splice variants that lack the ligand binding domain (Hu, 2009) 
have been recognized as a major mechanism of resistance. Studies performed in circulating 
tumor cells have associated androgen-receptor splice variant 7 (AR-V7) expression, the most 
common of the variants, with abiraterone and enzalutamide resistance (Antonarakis, 2014; 
Antonarakis, 2015; Scher, 2016). AR-V7 is rarely expressed in primary prostate cancer tumors 
but is detected in 75% of cases in CRPC and even following ADT (Sharp, 2019). 
Based on the several mechanisms of resistance described above, it is clear that AR signaling is a 
key driver in prostate cancer even after treatment with AR-targeted therapies. Cotreatment with 
therapies that modulate alternative signaling pathways involved in oncogenesis in prostate cancer 
have been proposed as a modality to overcome resistance, including epigenetic modifiers such as 
EZH2. 
Enhancer of zeste homologue-2 is the catalytic subunit of the multi-protein PRC2 that catalyzes 
the mono-, di-, and trimethylation of H3K27 (Margueron, 2011). Enhancer of zeste homologue-2 
mutation and/or over-expression have been observed in several cancer types, leading to an 
aberrant H3K27me3 state which is oncogenic (Chase, 2011). Somatic GOF mutations within 
EZH2, found within subsets of non-Hodgkin lymphoma, result in an oncogenic dependency on 
EZH2 (Morin, 2010; Sneeringer, 2010), production of abnormally high H3K27me3 levels, and 

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resultant transcriptional reprogramming of the cell. In addition, genetic changes in proteins of the 
SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex that acts at many 
loci in opposition to PRC2, can lead to oncogenesis. Mutation or loss of the SWI/SNF subunit 
integrase interactor 1 (INI1), has been demonstrated to generate an over-activation of the PRC2 
pathway and tumor cell proliferation (Wilson, 2010). Tumors in which INI1 protein is absent 
include tumor types such as MRT, atypical teratoid rhabdoid tumor, RTK and other rare tumors 
such as epithelioid sarcoma (ES), epithelioid malignant peripheral nerve sheath tumor, extra-
skeletal myxoid chondrosarcoma; myoepithelial carcinoma, and renal medullary carcinoma 
(Margol, 2014). Inhibition of EZH2 activity by either knock-down or small molecule inhibition 
induces tumor cell killing and durable tumor regressions in preclinical models of rhabdoid 
tumors (Alimova, 2013; Knutson, 2014). Based on the strong implication of EZH2 in specific 
genetically-defined cancer types, efforts were undertaken by Epizyme and others to discover 
small molecule inhibitors of EZH2. Tazemetostat (EPZ-6438) is a selective, reversible, SAM-
competitive small molecule inhibitor of the EZH2 HMT enzymatic activity (Knutson, 2013) 
Several other EZH2 inhibitors have been described in the literature (McCabe, 2012; Qi, 2012; 
Bradley, 2014). 
In prostate cancer, increasing EZH2 messenger RNA and protein expression correlates with 
advancing disease progression. Patients with clinically localized prostate cancers with higher 
expression of EZH2 show a worse prognosis (Varambally, 2002). It has been proposed that 
EZH2 plays an oncogenic role through two different functions in androgen-driven prostate 
cancer. Enhancer of zeste homologue-2 plays its conventional role of transcriptional repressor 
that is dependent on its methyl transferase activity, and it is also proposed that it acts as a 
transcriptional activator targeting the AR and its downstream signaling pathway in a PRC2 and 
catalytic activity-independent manner (Xu, 2012; Kim, 2018). Consistent with these findings, 
enzymatic inhibitors of EZH2, including GSK126, GSK503, and tazemetostat, have been shown 
to enhance the activity of AR antagonists when tested in preclinical models of AR-dependent 
prostate cancer (Kim, 2018). For instance, GSK126 in combination with enzalutamide inhibited 
the growth of LNCaP cells in vitro and the antiproliferative effect observed with the combination 
treatment was greater than that of the single agents alone. Similar effect was observed when 
LNCaP and C4-2B (an AR-expressing, metastatic CRPC cell line) were treated with tazemetostat 
in combination with enzalutamide for 8 days in vitro. Moreover, the drug combination also 
showed synergistic suppression of LNCaP and C4-2B cell colony formation. Combination of 
tazemetostat and enzalutamide, reduced tumor growth in an in vivo xenograft model of C4-2B.  
Additionally, neuroendocrine prostate cancer (NEPC), a subtype of CRPC characterized by 
independence from AR signaling, has been associated with aggressive clinical features and poor 
overall survival (Wang, 2014). The transition of adenocarcinoma to NEPC is recognized as one 
of the mechanisms of treatment resistance in prostate cancer in which the tumors undergo lineage 
plasticity through epigenetic reprogramming in defined genetic contexts (RB1, PTEN and TP53 
loss, MYCN amplification, among others) (Beltran, 2011; Beltran, 2016) and in settings defined 
by other functional markers including delta-like 3 protein (Puca, 2019). In extreme cases, tumors 
may reprogram towards alternative pathways adopting features of neuroendocrine, neuronal, or 
other lineages. One of the key epigenetic factors driving the process of trans-differentiation to a 
neuroendocrine subtype is EZH2, which is highly expressed in this setting (Beltran, 2016; 
Davies, 2018; Puca, 2018). 

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EZH2 inhibition has been shown to reverse the reprogramming of these tumors back to a luminal 
state (Ku, 2017). Studies conducted in genetically-engineered mouse models demonstrated that 
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and anti-
androgen therapy resistance by repressing reprogramming factors such as EZH2 and SOX2 (Ku, 
2017). Dual knock-out of these tumor suppressors in vivo increased expression of SOX2 and 
EZH2, and treatment with EZH2 inhibitors led to re-expression of AR and sensitized the models 
to enzalutamide including significantly inhibited tumor growth by combination of the EZH2 
inhibitor GSK503 with enzalutamide (Ku, 2017). Overexpression and copy number amplification 
of N-Myc are also observed in clinical NEPCs tumor samples (Beltran, 2011). N-Myc has been 
proposed as a driver of the NEPC phenotype that promotes tumorigenesis by abrogating AR 
signaling and inducing EZH2-driven transcriptional repression. Using N-Myc transgenic mouse 
cell lines and human cell lines overexpressing N-Myc, EZH2 inhibitors elicited anti-tumor 
activity preclinically both in vitro and in vivo (Dardenne, 2016). Additionally, studies conducted 
in neuroendocrine patient-derived organoids demonstrated dose dependent decrease in organoid 
formation in vitro by the EZH2 inhibitor GSK343 (Puca, 2018).  
In studies conducted by Epizyme, tazemetostat dose-dependently inhibited H3K27 methylation 
in all prostate cancer cell lines tested after 4-day treatment. Tazemetostat also dose-dependently 
inhibited proliferation in vitro over the course of 14 days of treatment, especially, in cell lines 
that depend on AR signaling LNCaP, C4-2B and in 22Rv1, a cell line that in addition expresses 
the splice variant AR-V7. Furthermore, tazemetostat elicited antiproliferative activity in a cell 
line of the neuroendocrine subtype (NCI-H660). Combination treatment of LNCaP and C4-2B 
cell lines in vitro showed synergistic antiproliferative activity when tazemetostat was combined 
with enzalutamide or abiraterone. Enzalutamide synergistically enhanced the in vitro activity of 
tazemetostat in the 22Rv1 cell line, although this effect did not manifest in the in vivo xenograft 
setting performed in this model. 
Tazemetostat (125 mg/kg oral [PO] administered twice daily) enhanced the antitumor activity of 
enzalutamide administered at two different doses (10mg/kg and 30 mg/kg PO once daily) in a 
subcutaneous LNCaP prostate cancer cell line xenograft mouse model after 14 days of dosing. 
respectively. The combination treatment of tazemetostat and enzalutamide at the highest dose 
tested achieved a tumor growth inhibition (TGI) of 72%, which was greater than the individual 
drug treatments alone. The combination of abiraterone and tazemetostat showed a TGI of 35%, 
which was greater than the antitumor activity observed for the single agent treatments. 
Taken together, the studies performed at Epizyme and those reported in the literature support a 
combination approach of tazemetostat with second-generation ASI therapies in the second-line 
mCRPC setting in treatment-naive patients or following progression on abiraterone acetate or 
enzalutamide. 
Following progression on second generation anti androgens, the last resort is currently initiation 
of treatment with chemotherapy such as docetaxel or cabazitaxel. At that stage, patients in the 
third-line setting are more difficult to treat by virtue of advanced age, aggressive nature of the 
disease, and depleted end organ reserves. For docetaxel, aside from the fact it is intravenously 
administered every 2 weeks requiring frequent clinic visits, it is also associated with a black box 
warning that includes toxic death, hepatotoxicity, neutropenia, hypersensitivity reactions, and 
fluid retention. Furthermore, it must be administered with prednisone twice daily continuously 
and requires premedication with oral steroids (please refer to the current, publicly available 

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package insert). For cabazitaxel, it is administered intravenously every 3 weeks in combination 
with prednisone and requires premedication with antihistamines, corticosteroids, and H2 
antagonists. Cabazitaxel has a black box warning which includes neutropenic deaths, 
hypersensitivities including rash, hypotension, and bronchospasm (refer to the current, publicly 
available package insert). 
As such, the need for effective chemotherapy-free combination therapies like tazemetostat is 
warranted for patients in the first- and second-line setting. 
5.4. 
Tazemetostat 
5.4.1. 
Nonclinical Pharmacology 
Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine 
methyltransferase EZH2 gene (Knutson, 2013). Tazemetostat inhibits both wild-type (WT) 
EZH2 and mutated EZH2 residues Y641, A677G and A687 with half maximal inhibitory 
concentrations (IC50) ranging from 2-38 nmol/L. The compound shows a 36-fold selectivity over 
the most closely related HMT, EZH1, and greater than a 4500-fold selectivity over other HMTs. 
It selectively inhibits intracellular H3K27 methylation in a concentration- and time- dependent 
manner in all cell lines tested in vitro to date. 
Additional details are provided in the most current version of the tazemetostat ,QYHVWLJDWRU
V
Brochure (IB). 
5.4.2. 
Pharmacokinetics  
Tazemetostat is orally bioavailable in patients with hematological and solid tumor malignancies. 
The absorption is rapid with a median time to maximum plasma concentration (tmax) of 1 to 2 
hours. The mean absolute bioavailability was approximately 33% (Study EZH-103). In dose 
escalation studies in patients with hematological and solid tumor malignancies, tazemetostat 
exhibited a more than dose-proportional increase in exposure (area under the concentration-time 
curve [AUC] and maximum concentration [Cmax]). At the recommended therapeutic dose of 800 
mg twice daily, the mean steady state Cmax was 829 ng/mL and area under the concentration-time 
curve from 0 to 12 hours (AUC0-12) was 3340 ng•hr/mL. The consistent tmax and apparent 
elimination half-life (t1/2) across the range of doses evaluated (100 to 1600 mg twice daily) 
suggest overall dose-independent absorption and clearance. 
There was no difference in relative bioavailability between low-fat and high-fat meal conditions. 
A high-fat meal exhibited a negligible effect on the extent and rate of absorption. A high-fat 
meal showed a 24% and 18% decrease in tazemetostat Cmax and AUC exposures, while the 
geometric mean ratios for Cmax and AUC for the major metabolite EPZ-6930 were close to 1, 
thereby demonstrating that a similar overall systemic exposure was seen after a high-fat meal 
compared to dosing in the fasted state. 
There was little to no accumulation (Cmax and AUC) of plasma tazemetostat following repeat 
dosing, likely due to auto-induction. The metabolite EPZ-6930 had minimal accumulation 
following multiple dosing. Tazemetostat is eliminated primarily via hepatic metabolism in 
humans, with approximately 88% bound to plasma proteins. Following administration of a single 
oral 800 mg dose of radiolabeled tazemetostat, the average percent recovery of the administered 

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dose was 15.4% in urine and 87.8% in feces. Unchanged tazemetostat accounted for 1.39% of 
the administered dose recovered in urine and was not detected in feces. 
5.4.3. 
Clinical Experience 
Across the clinical development program, tazemetostat has been or is being studied in clinical 
trials for the treatment of: 
x non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) 
and follicular lymphoma (FL). 
x mantle cell lymphoma 
x multiple myeloma  
x mesothelioma 
x integrase interactor 1 (INI1) or switch/sucrose nonfermentable (SWI/SNF)-related, 
matrix-associated, actin-dependent regulator of chromatin (SMARC), subfamily A, 
member 4 (SMARCA4)-deficient tumors in both adult and pediatric populations 
(including synovial sarcoma, rhabdoid tumors, renal medullary carcinoma, ES, other 
INI1- or SMARCA4deficient tumors). 
x prostate cancer 
x ovarian cancer 
More than 1105 clinical study subjects have received tazemetostat as monotherapy or in 
combination with other drugs in Epizyme-sponsored trials. The majority of adverse events 
observed in these studies are consistent with known adverse reactions of the drugs under 
investigation and/or comorbidity, are generally mild to moderate in severity, respond to dose 
modification, and resolve without sequelae.  
The most common  treatment-emergent AEs, regardless of causality, observed in adult 
subjects across monotherapy clinical studies were nausea and fatigue. The most common TEAEs 
that have led to interruption of tazemetostat monotherapy dosing in  RI the adult population 
were thrombocytopenia and neutropenia. The most common TEAEs leading to tazemetostat 
monotherapy dose reduction in  RI the adult population were thrombocytopenia and 
neutropenia. 
The safety profile of tazemetostat is well characterized and stable. The benefit-risk remains 
positive.  
Adverse events of special interest include T-LBL/T-ALL, AML, MDS, and other myeloid 
malignancies like MPN and have been reported in patients administered tazemetostat. 
Epizyme considers the risk for T-LBL/T-ALL in tazemetostat clinical trials to be largely 
concentrated in pediatric patients. The risk of myeloid neoplasia as a result of EZH2 inhibition is 
considered uncertain based on available literature and Epizyme clinical data.  
In addition, B-cell acute lymphoblastic leukemia (B-ALL) has been reported to occur following 
tazemetostat exposure.  Refer to the IB for further details. 

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Measures are in place to exclude potential subjects who may be predisposed to developing a 
myeloid/lymphoid neoplasia from participation as well as dose modification guidelines and 
laboratory monitoring for early identification of subjects who may be developing a second 
primary hematologic malignancy. 
 
The degree of risk of second hematologic malignancies remains uncertain based on paradoxical 
preclinical literature data, and the risk may be no greater than that expected in this subject 
population in general.  Refer to the current IB for further descriptions of adverse events, AESIs 
and other potential risks.  
The anticipated safety profiles of abiraterone, prednisone, and enzalutamide are as stated in their 
respective IB, SmPC, or USPI. 
 
x Tazemetostat is in late-stage clinical development and has shown clinical activity in 
subjects across the tazemetostat program, including objective responses and sustained 
disease stabilization. Tazemetostat has received accelerated approval in the US for ES 
and FL, as noted below. 
x Tazemetostat is considered to be a clinically active drug that has the potential to 
benefit both adult and pediatric oncology subjects across different tumor types where 
there are unmet medical needs. 
Tazemetostat (TAZVERIK®) received accelerated approvals for marketing in the US: 
x On 23 January 2020, tazemetostat was approved for the treatment of adults and 
pediatric subjects aged 16 years and older with metastatic or locally advanced 
epithelioid sarcoma (ES) not eligible for complete resection. 
x On 18 June 2020, tazemetostat was approved for the treatment of:  
 adult subjects with relapsed or refractory (R/R) follicular lymphoma (FL) whose 
tumors are positive for an enhancer of zeste homolog 2 (EZH2) mutation as 
detected by a US Food and Drug Administration (FDA)-approved test and who 
have received at least 2 prior systemic therapies 
 adult subjects with R/R FL who have no satisfactory alternative treatment options. 
In June 2021, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) granted approval 
of TAZVERIK for the treatment of subjects with R/R EZH2 gene mutation-positive FL (limited 
to use when difficult to treat with standard treatments) to Epizyme’s development partner, Eisai. 
Further details of study designs, tazemetostat exposure, and the safety profile in monotherapy 
and combination therapy clinical trials AEs are outlined in the current IB. 
Tazemetostat has, thus far, shown clinical activity in subjects across the tazemetostat program, 
including objective responses and sustained disease stabilization in a number of hematologic and 
solid tumor malignancies in adults and children as outlined in the current tazemetostat IB. As 
noted above, the FDA granted accelerated approval for tazemetostat in 2020 in 2 disease states, 
ES and FL. 

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Tazemetostat is considered to be a clinically active drug that has the potential to benefit both 
adult and pediatric oncology subjects across different tumor types where there are unmet medical 
needs.  
5.4.4. 
Pharmacodynamics 
In the adult Phase I study, the pharmacodynamics of H3K27 methylation following tazemetostat 
dosing was measured in skin to provide evidence for on-target methylation inhibition in a 
surrogate tissue. In that study, IHC analysis of skin biopsies collected pre- dose and after 28 days 
of tazemetostat treatment revealed a post-dose decrease in H3K27me3-positive cells across all 
doses explored (100-1600 mg twice daily), with a maximum reduction in the percentage of 
H3K27me3-positive cells to 50% of baseline. Interestingly differences were observed in the 
tazemetostat induced reduction in H3K27me3 levels in different skin layers potentially pointing 
to different kinetics for H3K27me3 turnover in the cells that occupy different skin layers. 
In this study, pre- and post-treatment tumor biopsies will be evaluated to enable the assessment 
of tazemetostat dosing on H3K27me3 levels in tumor tissue. H3K27me3 IHC data will provide 
mechanistic insight into the impact of EZH2 inhibition on H3K27me3 levels in cell populations 
within tumor. In addition, these data will be evaluated in the context of tazemetostat exposure 
data to explore PK-pharmacodynamics relationships. 
A robust reduction in H3K27me3 by IHC staining was observed in a limited number of paired 
pre- and post-dose tumor biopsies collected thus far in Study EZH-202 and EZH-203. In addition 
to monitoring H3K27me3, expression profiles of immune markers PD-L1 and CD8 also were 
assessed. To date, two of six subjects from EZH-202 tested had increased tumor PD-L1 
expression while undergoing treatment with tazemetostat. The increased expression of tumor 
PD-L1 was associated with an increased number of CD8-positive cells infiltrating the tumor 
stroma. These data are supportive of an observation made in the Phase 1 study E7438-G000-101 
in which biopsies from a subject with ES demonstrated increased PD-L1 expression and 
evidence of T-cell infiltration. Given the limited number of tumor biopsies collected to date and 
the variability of time points assessed, it is difficult to draw conclusions regarding the immune-
priming effects of tazemetostat. 
5.5. 
Rationale 
5.5.1. 
Rationale for Studying mCRPC 
After exposure to antiandrogens, whether first or second generation, a rise in PSA, suggesting 
reactivation of AR target genes, is often associated with clinical progression. Several 
mechanisms have been implicated in driving resistance and can be broadly divided into 
categories that are either dependent on or independent of ligand-binding domain-driven 
reactivation of AR signaling. The former can include an adaptive feedback loop of increased 
serum and tissue androgens and AR levels after AR antagonism with enzalutamide that in vitro 
modeling suggests could result in outcompeting of enzalutamide at the AR. 
In an attempt to overcome resistance (Attard, 2018), a study was conducted to investigate 
enzalutamide resistance, which is thought to be attributable to ligand-binding domain 
reactivation of AR signaling. It was hypothesized that cross-resistance may exist between single-
agent enzalutamide and abiraterone, making their use in sequence of limited benefit, and that a 

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rise in androgens in patients receiving enzalutamide may result in reactivation of AR, so that 
disrupting this adaptive feedback loop by combining with abiraterone would re-induce 
enzalutamide sensitivity, resulting in prolonged patient benefit and tumor responses versus 
abiraterone alone. 
Abiraterone effectively inhibits androgen synthesis, but it was hypothesized that raised levels of 
progesterone, synthetic glucocorticoids, and other potential ligands with abiraterone in the 
presence of high AR levels after enzalutamide treatment would result in continued AR activity 
and primary resistance. For that matter, in this study patients received open-label enzalutamide 
and at predefined PSA progression were randomly assigned to receive abiraterone plus placebo 
or abiraterone plus enzalutamide. Combining abiraterone with enzalutamide would not inhibit 
reactivation of AR independent of the ligand-binding domain, including resistance mediated by 
AR splice variants or glucocorticoid receptors. A total of 509 patients enrolled in period one at 
51 sites worldwide and received open-label single-agent enzalutamide. Three hundred seventy 
(73%) of 509 patients had received a first-generation antiandrogen, 151 (30%) were receiving a 
stable dose of bisphosphonates or denosumab, and 421 (83%) had bone metastases on bone scan. 
Median duration of treatment with single-agent enzalutamide in period one was 9.1 months; 377 
 DQG  SDWLHQWV  KDG D 36$ GHFOLQH RI  DQG  UHVSHFWLYHO\ DW ZHHN 
Overall, 408 patients had stable or decreased PSA levels at weeks 13 and 21 and were therefore 
eligible to enter period two when they developed PSA progression. Of these, 251 patients had 
confirmed PSA progression, met period two eligibility criteria, and were randomly assigned to 
one of the two treatment groups before the cutoff date of October 7, 2016. A total of 126 were 
assigned to enzalutamide plus abiraterone and prednisone (combination group), and 125 were 
assigned to placebo plus abiraterone and prednisone. All except one patient in each treatment 
group received study treatment. At the data cutoff for the primary analysis, of the 258 patients 
who were not randomly assigned, 84 (33%) continued enzalutamide and 174 (67%) discontinued 
period one, primarily because of disease progression. Of the 251 patients randomly assigned, 27 
(21%) of 126 patients in the combination group and 18 (14%) of 125 patients in the control 
group continued treatment. Median treatment duration in period two was 5.6 months for both 
groups. Median progression-free survival (PFS) was 5.7 and 5.6 months for the combination and 
control groups, respectively (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.61 to 1.12; 
P = .22). A predefined analysis of the PFS event by unequivocal clinical or radiographic 
progression or death suggested a difference in the proportion of events by treatment group, with 
a higher rate of clinical progression events in the combination group and a higher rate of 
radiologic events in the control group.  
This study evaluated reinduction of sensitivity to AR antagonism by combining enzalutamide 
with abiraterone to treat patients with a rising PSA while receiving enzalutamide. Because the 
study design randomly assigned patients who had received single-agent enzalutamide until 
confirmed PSA progression, a primary endpoint was used that included unequivocal clinical 
progression. This differed from the regulatory COU-AA-302 and PREVAIL studies, which 
mandated radiographic progression and was considered necessary because of the ethical and 
pragmatic challenges of continuing AR-targeting therapy in men with a rising PSA and 
worsening symptoms, given the risk of patients becoming too unwell for the next proven 
effective line of treatment with docetaxel. In fact, approximately one fifth of patients at screening 
before random assignment in period two had a pain score of 3 on question three (worst pain in 
the previous 24 hours) of the Brief Pain Inventory (BPI)-Short Form(-SF). This study did not 

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meet its primary end point. Consequently, the gatekeeping procedure was not used, and 
secondary analyses were not adjusted for multiplicity and were considered exploratory. These 
included a sensitivity analysis for radiographic PFS (rPFS) that showed a nominally significant 
difference benefiting the combination group. 
Most patients receive two or more hormonal manipulations and are then offered chemotherapy as 
they continue to progress and develop symptoms. (Lam, 2006). A randomized study comparing 
docetaxel administered every 3 weeks vs. docetaxel weekly vs. mitoxantrone has shown a 
modest survival benefit for docetaxel every 3 weeks, but this response is not durable (Tannock, 
2004). In addition, cytotoxic chemotherapy has significant treatment-related toxicities when 
compared to hormonal and other non-cytotoxic therapies (see Section 5.3).  
Because of resistance to second generation anti androgen therapies and due to overexpression of 
the AR being a common feature of progressive prostate cancer, therapies that are targeted to 
reverse or prevent resistance may be effective when added to second generation antiandrogens in 
these patients.  
5.5.2. 
Study Rationale 
The clinical benefit of tazemetostat has not yet been established in patients with progressive, 
mCRPC. This study will characterize the safety, efficacy, and PK in this population. There is a 
reasonable expectation based upon nonclinical data that clinical activity may be observed in 
patients with progressive, mCRPC. 
Data has recently been reported to suggest that a sequencing strategy of abiraterone followed by 
enzalutamide may provide greater clinical benefit to subjects with mCRPC than the reverse 
sequence. Enzalutamide showed activity as a second-line androgen receptor pathway inhibitor, 
whereas abiraterone acetate did not, leading to a longer time to second PSA progression for the 
sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence. 
(Khalaf, 2019) Given that PSA is a gold standard surrogate endpoint in measuring the early 
signals of clinical activity, the data suggest that using a sequencing strategy of abiraterone 
acetate followed by enzalutamide provides the greatest clinical benefit in patients with metastatic 
CRPC. Acquired changes in the androgen receptor signaling axis has been proposed as a 
mechanistic explanation as to why patients given enzalutamide had a higher second-line 
response. While there are known resistance mechanisms common to both drugs, enzalutamide 
retains androgen receptor inhibitory activity against 2 well-described mutations associated with 
abiraterone plus prednisone resistance. (Khalaf, 2019) The hypothesis of this optimal sequencing 
strategy, however, is being tested in the phase 1b component of the trial with enrollment of 
subjects previously treated with enzalutamide and/or apalutamide who received tazemetostat in 
combination with abiraterone/prednisone. Subjects are not planned to be treated with abiraterone 
in the phase 2 portion of this study. 
This is a 2-part, global, multi-center, open-label, randomized phase 1b/2, active-controlled safety 
and efficacy study of oral administration of tazemetostat in combination with either enzalutamide 
or abiraterone/prednisone (phase 1b) and of tazemetostat in combination with enzalutamide 
versus enzalutamide alone (phase 2) in asymptomatic or mildly symptomatic subjects with 
progressive mCRPC and who: for phase 1b, are EITHER previously untreated with a second 
generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a 

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second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide); or for phase 2, 
previously progressed on abiraterone.  
5.5.3. 
Rationale for Dose Selected 
Recommended Tazemetostat Dose Determination from Previous Clinical Trial 
The primary objective of a previously conducted trial, E7438-G000-101 (Phase 1 portion), was 
to determine the MTD and/or RP2D of tazemetostat as a single agent administered orally twice 
daily, continuously in 28-day cycles, in subjects with advanced solid tumors or relapsed and/or 
refractory B-cell lymphomas.  In the dose escalation part, subjects with advanced solid tumors or 
B-cell lymphomas received oral tazemetostat continuously in 28-day cycles. The starting dose 
was 100 mg twice daily, with subsequent dose cohorts evaluated at 200 mg, 400 mg, 800 mg, 
and 1,600 mg twice daily. Each cohort was permitted to enroll up to 6 subjects (3+3 design), 
with escalation proceeding until 2 or more subjects of a cohort of 3 to 6 subjects experienced a 
DLT during cycle 1 of treatment. The selection of the 800 mg twice daily dose as the RP2D of 
tazemetostat as a single agent is supported by all available efficacy, PK/pharmacodynamics and 
safety data. Briefly, among subjects with advanced solid tumors, 2 (5%) of the 43 subjects 
achieved an objective response, including CR in 1 subject with INI1-negative malignancy at the 
tazemetostat 800 mg twice daily dose level and 1 PR in a subject with SMARCA4-negative 
malignancy at the tazemetostat 1600 mg twice daily dose. Of the 2 responders in the advanced 
solid tumor subgroup, the DOR was 16.1 weeks for the subject with PR and 112.1+ weeks for 
the subject with CR; the latter subject was ongoing in response as of the data cutoff date (Study 
E7438-G000-101). 
In-addition, predose and postdose skin punch biopsies were successfully collected in 32 subjects 
enrolled in the dose escalation part of this study to determine target inhibition, as measured by 
downregulation of H3K27me3. A dose-dependent reduction in H3K27me3 was observed across 
the stratum spinosum layer of the skin, with a marked decrease in H3K27me3 as tazemetostat 
AUC0-12 increased after administration of doses ranging from 100 mg to 800 mg twice 
daily.  The reduction in H3K27me3 levels appeared to reach a plateau in the AUC0-12 observed in 
the 800 mg twice daily dose cohort. An inhibitory Emax model–predicted decrease in H3K27me3 
at the observed mean AUC0-12 on day 15 in the 800 mg twice daily dose cohort was more than 
80% of the maximum effect, indicating that target inhibition in the skin was near maximal and 
that doubling the dose to 1,600 mg twice daily resulted in only a modest incremental increase in 
the inhibition of H3K27 methylation. Furthermore, based on the safety data one subject in the 
dose escalation part of the study experienced a DLT (Grade 4 thrombocytopenia) while receiving 
tazemetostat 1,600 mg twice daily, which was the highest dose administered.  
Taken together these data support the selection of the 800 mg twice daily as the recommended 
Phase 2 dose (RP2D) of tazemetostat as a single agent.  
Current Trial Phase 1 Dose Escalation Plan for Combination RP2D Determination 
In order to define the optimal dose of tazemetostat to be used in combination in the proposed 
multicenter, phase 1b/2, open label, randomized, active-controlled safety and efficacy study of 
oral tazemetostat in combination with enzalutamide or abiraterone/prednisone (phase 1b) and 
tazemetostat in combination with enzalutamide versus enzalutamide alone (phase 2) in 
asymptomatic or mildly symptomatic subjects with progressive, mCRPC who have not received 

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chemotherapy for mCRPC and who: for phase 1b, are EITHER previously untreated with a 
second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed 
on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide); or for 
phase 2, previously progressed on abiraterone, a phase 1b dose escalation part was included to 
evaluate the efficacy, safety, and PK of the tazemetostat in combination  with either 
enzalutamide or abiraterone/prednisone. Dose escalation was performed using a modified 3+3 
design consisting of a planned maximum of approximately 24 evaluable subjects (7 for the 
combination with abiraterone/prednisone and 13 for the combination with enzalutamide, and up 
to 4 additional subjects in the event of a DLT). 
In the phase 1b part of the study, there were to be 3 different tazemetostat dose levels planned to 
be tested in combination with abiraterone/prednisone and 5 different tazemetostat dose levels 
planned to be tested in combination with enzalutamide. A maximum of approximately 24 
subjects (7 for the combination with abiraterone/prednisone, 13 for the combination with 
enzalutamide, and up to 4 additional subjects in the event of a dose-limiting toxicity [DLT]) 
could have been enrolled.  Dose escalations began at 400 mg tazemetostat twice daily, followed 
by 600 mg tazemetostat twice daily, followed by 800 mg tazemetostat twice daily, as tolerated 
according to occurrence of DLTs, as defined in this protocol. For the enzalutamide combination 
only, dose escalation could have further proceed to 1200 mg twice daily followed by 1600 mg 
twice daily, as tolerated. Enzalutamide (a strong CYP3A4 inducer) was expected to lower study 
drug exposure because tazemetostat is metabolized by CYP3A4; previous PK data showed that 
exposure lower than 800 mg twice daily could lead to substantially less target engagement. 
Based on emerging PK and safety data from the phase 1b portion of the study, a higher dose than 
800 mg twice daily in the phase 2 portion of the study may provide for more optimal efficacy.  
For both enzalutamide and abiraterone/prednisone, prescribed doses as recommended by the 
respective package inserts will be used throughout the study.  
Intensive PK sampling was included in the dose escalation (phase 1b) of the study to explore the 
potential of a drug-drug interaction between tazemetostat and enzalutamide or 
abiraterone/prednisone. These data, for the combination with enzalutamide, was to help further 
guide the dose selection for the phase 2 part of the study. 
Recommended Phase 2 Dose Determination for Combination with Enzalutamide 
(Complete) 
The phase 1b dose escalation and RP2D determination of tazemetostat when given in 
combination with enzalutamide has been completed.  
Seven subjects were enrolled in the abiraterone/prednisone combination dose escalation arm and 
14 subjects were enrolled in the enzalutamide combination dose escalation arm. As described 
above in Section 5.5.2, subjects were not planned to be treated with abiraterone in the phase 2 
portion of this study because of recently reported data suggesting that a sequencing strategy of 
abiraterone followed by enzalutamide may provide greater clinical benefit to subjects with 
mCRPC than the reverse sequence (Khalaf, 2019), a hypothesis being examined in the phase 1b 
component of the trial. 
All available phase 1b data concerning safety, tolerability, and PK in the combination with 
enzalutamide were considered in making the RP2D determination. 

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No DLTs were observed at any dose of tazemetostat given in the planned dose escalation phase 
with enzalutamide. The SRC considered the totality of safety and tolerability information of the 
combination and endorsed doses of tazemetostat up to 1600 mg twice daily when administered in 
combination with enzalutamide to be considered for the RP2D. 
In addition to the safety analysis, PK data were also considered in the determination of the 
RP2D.  
As described in Section 5.6.3, tazemetostat is extensively metabolized by CYP3A4, and 
enzalutamide is a strong CYP3A4 inducer.  As a result, it was expected that concentrations of 
tazemetostat in the presence of enzalutamide would be lower than concentrations of tazemetostat 
administered as monotherapy.  Accordingly, the objective of the dose escalation phase of the 
study was to identify a tazemetostat dose level when used in combination with enzalutamide that 
delivers comparable steady-state exposure to that of the 800 mg twice daily dose of tazemetostat 
when administered as monotherapy. 
Tazemetostat steady-state AUC was used as a metric to guide RP2D dose selection. The 
tazemetostat 1200 mg twice daily dosing regimen, when administered in combination with 
enzalutamide, produced a mean steady-state Cmax of 568 ng/mL and AUC(0-Ĳ of 5643 ng*h/mL, 
which was found to be comparable to the steady-state AUC of tazemetostat 800 mg twice daily 
when administered as monotherapy (6620 ng*h/mL). Therefore, because tazemetostat exposure 
at 1200 mg twice daily when administered in combination with enzalutamide is similar to 
tazemetostat exposure at 800 mg twice daily when administered as monotherapy, tazemetostat 
1200 mg twice daily was endorsed as the RP2D when administered in combination with 
enzalutamide. This dose will be further explored in the phase 2 portion of the study. 
5.6. 
Benefit:Risk Assessments 
5.6.1. 
Animal Toxicology 
Nonclinical safety assessments of tazemetostat included in vitro and monkey safety 
pharmacology studies, genotoxicity studies, and single- and repeat-dose toxicity studies in 
Sprague-Dawley rats and cynomolgus monkeys of 4- and 13-weeks duration. No notable 
cardiovascular, central nervous system (CNS), or respiratory risks were identified in nonclinical 
safety pharmacology assessments. Tazemetostat was not genotoxic in standard in vitro and in 
vivo assays. The following potential risks were identified for tazemetostat based on nonclinical 
safety data: T-cell lymphoblastic lymphoma (T-LBL) (rat), increased bone formation in bone and 
teeth (rat), non-progressive bile duct hyperplasia (monkey), teratogenicity (rat and rabbit), 
lymphoid depletion (rat and monkey), and phototoxic potential (in vitro). Other effects at high, 
non-tolerated doses, toxicities included bone marrow effects (hypocellularity, rat), and 
gastrointestinal toxicity (distention, ulceration, and degeneration, rat). 
Steady-state exposures (AUC0-24) in rats at the lowest dose (100 mg/kg/day) at which no T-LBL 
occurred in the 13-week adolescent rat study were 2.5- to 8-fold greater than that observed in 
humans at the recommended Phase 2 dose (RP2D; 800 mg twice daily) from the ongoing Phase 
1/2 Study E7438-G000-101. No incidences of abnormal bone formation have been observed in 
the ongoing clinical study. All subjects of child-fathering potential and their partners of 
childbearing potential must agree to use a reliable birth control method during the study, and for 

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3 months after the last tazemetostat dose, and additionally will be actively monitored for signs or 
symptoms of abnormal bone formation. 
Additional animal toxicology is provided in the IB for tazemetostat. 
5.6.2. 
Photo-Reactive Potential 
There are nonclinical data supporting a potential for tazemetostat phototoxicity, which has not 
been seen in human studies to date. Hence, prolonged exposure to sunlight should be avoided 
during treatment. In addition, subjects should take other measures to avoid ultraviolet exposure 
such as wearing sunscreen and sunglasses, wearing protective clothing, and avoiding tanning 
beds. Refer to the tazemetostat IB for details. 
5.6.3. 
CYP3A Metabolism 
Effect of Other Drugs on Exposure to Tazemetostat 
A thorough investigation for drug interaction potential was done by conducting a series of in 
vitro studies which included CYP phenotyping, metabolic stability, substrate, and inhibition 
assessment of metabolic transporters, and inhibition of major human CYP enzymes. Based on 
the results from the population PK analyses, the impact of concomitant drugs on tazemetostat 
exposure was evaluated. These results demonstrate that CYP3A4 inhibitors, CYP3A4 inducers, 
CYP2D6 inhibitors, CYP2D6 inducers, and pH modifiers had no clinically significant effect on 
tazemetostat exposure, suggesting that these drugs may be co-administered with tazemetostat 
(EZH-P101). With respect to potential DDI associated with drug transporters, tazemetostat is a 
P-glycoprotein (P-gp) substrate but not a substrate for other drug transporters studied, including 
breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1 and 1B3, 
organic anion transporters 1 and 3, organic cation transporter 2, and multidrug and toxin 
extrusion 1. However, P-gp does not seem to limit tazemetostat absorption in subjects, 
presumably due to the relatively good passive permeability at the therapeutic dose of 800 mg 
twice daily. This suggests that tazemetostat is not susceptible to transporter-mediated DDI as a 
victim drug. 
As stated above, enzalutamide (a strong CYP3A4 inducer) was expected to lower study drug 
exposure because tazemetostat is metabolized by CYP3A4; the previous PK data showed that 
exposure at a lower dose than 800 mg twice daily could lead to substantially less target 
engagement. Refer to Section 5.5.3 for the dose rationale for this combination to achieve a 
therapeutic dose level of tazemetostat. 
Effect of Tazemetostat on Exposure to Other Drugs 
Tazemetostat is eliminated primarily via hepatic metabolism in humans. In vitro test systems 
using hepatic preparations from mice, rats, dogs, rabbits, monkeys, and humans suggest that 
tazemetostat forms similar metabolites across species. The results of in vitro phenotyping studies 
indicate that CYP3A4 is the predominant enzyme responsible for tazemetostat metabolism in 
humans. With respect to tazemetostat as a perpetrator, although tazemetostat inhibits several 
CYPs in vitro, based on the inhibitory constant (Ki) and the observed tazemetostat exposure in 
subjects at the therapeutic dose of 800 mg twice daily, the potential clinical implications due to 
the inhibitory potential of tazemetostat on drugs that are substrates of CYP3A4, CYP2C8, or 
CYP2C19 is limited. Notably, the effect of tazemetostat on CYP3A4 is complicated with 

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opposing induction and time-dependent inhibition of the enzyme. The net clinical DDI outcome 
is a weak induction of CYP3A as indicated by an approximately 40% reduction of midazolam 
AUC following 800 mg twice daily dosing for 15 days (Study E7438-G000-101). While 
tazemetostat may potentially inhibit P-gp, OATP1B1, and OATP1B3, there is limited potential 
for clinically significant DDI with substrates of these transporters, based on in vitro transporter 
inhibition assessment and observed exposures at the recommended dose regimen of 800 mg 
twice daily. The 3 major metabolites are not expected to affect the activities of the major human 
CYPs and major drug transporters. 
5.6.4. 
Summary 
In vitro and in vivo nonclinical xenograft experiments suggest the potential for clinical antitumor 
activity in INI1-negative tumors, thus providing a rationale for the potential benefit of 
tazemetostat in the aforementioned tumors. Furthermore, in the adult phase 1 study of 
tazemetostat in adults, 3 subjects with MRT treated with tazemetostat 800 mg twice daily have 
been enrolled to the ongoing roll-over maintenance study and have demonstrated clinical 
activity. The nonclinical studies utilizing in vitro and in vivo prostate cancer model systems 
performed at Epizyme and those shown in the literature support a combination approach of 
tazemetostat with second generation ASI therapies in the second-line setting for patients who 
have not responded to or who have progressed on abiraterone acetate or enzalutamide treatment.  
Given the available safety and initial activity data of tazemetostat monotherapy and combination 
therapy in more than 2280 adult and pediatric subjects from both clinical and post-marketing 
sources , there is a reasonable expectation that the safety profile observed will be substantially 
unchanged in patients with progressive mCRPC. 
The safety profiles of the drugs to be used in combination with tazemetostat in this study 
(enzalutamide, abiraterone, and prednisone) are described in their respective Prescribing 
Information summaries. 

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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
Phase 1b: 
x To determine the safety and tolerability of each of the combinations (tazemetostat 
with enzalutamide or tazemetostat with abiraterone/prednisone).  
x To select the RP2Ds of tazemetostat for each combination treatment based on PK and 
pharmacodynamic parameters as well as efficacy and the overall tolerability of each 
of the combinations (tazemetostat with enzalutamide or tazemetostat with 
abiraterone/prednisone). 
Phase 2:  
x To determine the benefit of combining tazemetostat with enzalutamide when 
compared to enzalutamide alone, as assessed by rPFS according to Prostate Cancer 
Clinical Trials Working Group 3 (PCWG3) criteria for progression in bone or in soft 
tissue (the latter by Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1]). 
6.2. 
Secondary Objectives 
Phase 1b and Phase 2: 
x To determine the benefit of combining tazemetostat with enzalutamide or 
abiraterone/prednisone (in phase 1b) and the benefit of combining tazemetostat with 
enzalutamide when compared to enzalutamide alone (in phase 2) as assessed by: 
 PSA50, defined as the percentage of subjects with a 50% decline of PSA from 
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per PCWG3 criteria. 
 ORR and best overall response (BOR) in soft tissue per RECIST 1.1 guidelines. 
 DCR (no radiographic progression per PCWG3 criteria, and no unequivocal 
clinical progression or death) at 6 months on treatment. 
 Time to first skeletal-related event (SRE) per PCWG3. 
 Time to initiation of the next systemic treatment for prostate cancer (TTNT). 
 Time to PSA progression (TTPP), as defined as the duration from baseline to the 
day of PSA progression per PCWG3 criteria in months. 
 Reduction in circulating tumor cells (CTC) from a state of having a detectable 
number of CTCs to having an undetectable number of CTCs. 
 CTC response rate, defined as the percentage of subjects with D 0% reduction 
in CTC number from baseline. 
x To further evaluate the safety and tolerability of the combination of tazemetostat with 
enzalutamide. 

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x To assess the PK of tazemetostat when administered in combination with 
enzalutamide (phases 1b and 2) and abiraterone/prednisone (phase 1b only) and the 
PK of enzalutamide (phases 1b and 2) and abiraterone (phase 1b only) when 
administered in combination with tazemetostat.  
Phase 2 Only: 
x To determine the benefit of combining tazemetostat with enzalutamide when 
compared to enzalutamide alone on quality of life (QoL) as assessed by changes from 
baseline in FACT-P Functional Well-being Subscale (FWB) and Prostate Cancer 
Subscale (PCS) scores over the course of the study. 
x To determine the benefit of combining tazemetostat with enzalutamide when 
compared to enzalutamide alone to QoL as assessed by time to definitive 
deterioration (TDD) in functional status and in prostate symptoms as assessed by the 
FACT-P FWB and PCS scores, respectively. 
6.3. 
Exploratory Objectives 
Phase 1b Only: 
x To evaluate the rate of pain progression relative to the time of screening at 6 months 
using the Brief Pain Inventory (BPI)-Short Form (-SF) for tazemetostat in 
combination with enzalutamide or abiraterone/prednisone.  
Phase 2 Only: 
x To evaluate the rate of pain progression relative to baseline at each post-baseline time 
point using the BPI-SF for tazemetostat in combination with enzalutamide versus 
enzalutamide alone. 
x To determine the benefit of combining tazemetostat with enzalutamide when 
compared to enzalutamide alone to QoL as assessed by changes from baseline in the 
FACT-P domains: Emotional, Social, and Physical Well-being over the course of the 
study. 
x To determine the benefit of combining tazemetostat with enzalutamide when 
compared to enzalutamide alone to QoL as assessed by changes from baseline in EQ-
5D-5L visual analogue scale (VAS) and Health Utilities Index (HUI) scores over the 
course of the study. 
Phase 1b and 2: 
x To determine the benefit of tazemetostat in combination with enzalutamide or 
abiraterone/prednisone (in phase 1b) and the benefit of combining tazemetostat with 
enzalutamide when compared to enzalutamide alone (in phase 2) as assessed by 
PSA90.  
x To determine the benefit of tazemetostat in combination with enzalutamide or 
abiraterone/prednisone (in phase 1b) and the benefit of combining tazemetostat with 
enzalutamide when compared to enzalutamide alone (in phase 2) as assessed by 
ctDNA burden. 

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x To assess the pharmacodynamic modulation of EZH2 activity by tazemetostat by 
measuring H3K27me3 levels in paired pre- and on-treatment tumor biopsies, 
including biopsies taken at disease progression (in phase 2 only in responders), that 
may be obtained from the phase 1b and phase 2 portions of the study. 
x To assess genetic and molecular characteristics of responders as compared to non-
responders, including mutational status of selected genes and gene expression 
signatures in tumor biopsies taken pre-treatment, on drug treatment (at cycle 2 day 1), 
and at disease progression (only in responders). 
x To assess the genetic and molecular characteristics of responders as compared to non-
responders, including the mutational status in pre- and on-treatment tumor biopsies 
and ctDNA in liquid biopsies. Expression profiling signatures of neuroendocrine 
prostate cancer (NEPC) and androgen receptor (AR) signaling in pre- and on-
treatment tumor biopsies will also be determined. AR-V7 and NEPC status 
(morphologically) and, possibly, selected neuroendocrine marker(s) will be 
determined in CTCs from liquid biopsies taken at baseline. Neuroendocrine status 
will also be determined in baseline serum samples using serum biomarker neuron-
specific enolase (NSE) collected pre-dosing. 
x To compare concordance of genetic and molecular characteristics in tumor and liquid 
biopsy samples. 
x To assess immunological endpoints in tumor biopsy samples, including the number 
and activation/exhaustion status of CD8+ and regulatory T-cell subtypes and other 
immune cells in tumor infiltrates from tumor biopsies taken pre-treatment, on drug 
treatment (at cycle 2 day 1), and at disease progression (only in responders). Also, to 
investigate circulating immune cell sub-populations isolated from PBMCs taken pre-
treatment, on drug treatment (at cycle 2 day 1), and at disease progression (only in 
responders) to determine the impact of drug treatment on immune cell numbers, 
antigen presentation, and immune cell activation status. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a 2-part, global, multi-center, open-label, randomized phase 1b/2, active-controlled safety 
and efficacy study of oral administration of tazemetostat in combination with enzalutamide or 
abiraterone/prednisone (phase 1b) and tazemetostat in combination with enzalutamide versus 
enzalutamide alone (phase 2) in asymptomatic or mildly symptomatic subjects with progressive, 
metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for 
mCRPC and who: for phase 1b, are EITHER previously untreated with a second generation 
androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second 
generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide); or for phase 2, 
previously progressed on abiraterone. The phase 1b portion of this study was designed to 
determine the RP2D of tazemetostat in combination with either enzalutamide or 
abiraterone/prednisone, based on safety, tolerability, pharmacokinetic, pharmacodynamic, and 
efficacy profiles. The study design is displayed in Figure 1. 
Up to 104 subjects are planned to enroll in the trial to assess combination therapy (up to 
approximately 24 subjects in phase 1b; 80 subjects in randomized phase 2). 
Phase 1b 
The following paragraphs describe the plan for the phase 1b dose escalation and RP2D 
determination portion of the study, which has been completed (see Section 5.5.3). The RP2D of 
tazemetostat when administered in combination with enzalutamide was established as 1200 mg 
twice daily. 
The phase 1b part of the study comprised dose escalations to determine the RP2D for the 
phase 2 part and to establish the safety profile of the combination of tazemetostat with 
enzalutamide or abiraterone/prednisone. The selection of therapy depended on which agent 
the subjects were previously treated with and progressed on prior to enrollment into the 
study. Subjects who were previously treated with enzalutamide and/or apalutamide were to 
receive tazemetostat in combination with abiraterone/prednisone. Similarly, subjects who 
were previously treated with abiraterone/prednisone were to receive tazemetostat in 
combination with enzalutamide. Subjects who were previously untreated with either 
enzalutamide or abiraterone/prednisone were to be equally distributed in both dose escalation 
arms of the phase 1b part of the study. 
In the phase 1b part of the study, there were 3 different tazemetostat dose levels planned to 
be tested in combination with abiraterone/prednisone and 5 different tazemetostat dose levels 
planned to be tested in combination with enzalutamide. Dose escalation was performed using 
a modified 3+3 design consisting of a planned maximum of approximately 24 evaluable 
subjects (7 for the combination with abiraterone/prednisone and 13 for the combination with 
enzalutamide, and up to 4 additional subjects in the event of a DLT). Dose escalations began 
at 400 mg tazemetostat twice daily, followed by 600 mg tazemetostat twice daily, followed 
by 800 mg tazemetostat twice daily, as tolerated according to occurrence of DLTs, as defined 
in the protocol). For the enzalutamide combination only, dose escalation could further 
proceed to 1200 mg twice daily followed by 1600 mg twice daily, as tolerated. For both 

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enzalutamide and abiraterone/prednisone, prescribed doses as recommended by the 
respective package inserts are to be used throughout the study. 
For phase 1b dose escalation purposes, DLTs (as defined in Table 2, Table 3, and Table 4) 
during the first cycle were assessed. After completion of cycle 1 of each combination 
(tazemetostat with enzalutamide or tazemetostat with abiraterone/prednisone), all available 
safety data were reviewed jointly by the Sponsor and Investigators (the SRC) and the 
decision to proceed to the next dose cohort was made.  
For each combination therapy, the following dose escalation procedure was followed (all 
dose levels of tazemetostat noted here are given twice daily): 
A single subject was to be enrolled at the 400 mg dose level. If the subject did not 
experience a DLT, then dose escalation would proceed to the next level of 600 mg. If 
the subject did experience a DLT, the study would stop for this combination therapy.  
At the 600 mg dose-escalated level, 3 subjects were to be enrolled. If no subjects 
experienced a DLT at the 600 mg level, then dose escalation would proceed to the 
next level of 800 mg. If 1 subject experienced a DLT at 600 mg, then the 600 mg 
dose level would be expanded by 3 additional subjects; if there were no additional 
DLTs at the 600 mg level (ie, no more than 1 DLT in 6 subjects), then dose escalation 
would proceed to the 800 mg level. If, however, 2 or more subjects out of the first 
3 or 6 subjects enrolled at 600 mg experienced a DLT, then the next lower, previously 
tested dose of 400 mg would be expanded by 2 additional subjects for a total of 
3 subjects. If no additional DLTs were observed at the 400 mg dose level, then 400 
mg would be evaluated for suitability as the RP2D. If 1 DLT was observed at the 400 
mg dose level, 3 additional subjects would be enrolled; 400 mg would be evaluated 
for suitability as the RP2D if no further DLTs occur. Otherwise, the study for this 
combination therapy would stop. 
At the 800 mg dose-escalated level, 3 subjects were to be enrolled. If no subjects 
experienced a DLT at the 800 mg level, then for the abiraterone/prednisone 
combination, 800 mg would be evaluated for suitability as the RP2D. If 1 subject 
experienced a DLT at 800 mg, then the 800 mg dose level would be expanded by 
3 additional subjects; if there were no additional DLTs at the 800 mg level (ie, no 
more than 1 DLT in 6 subjects), then for the abiraterone/prednisone combination, 
800 mg would be evaluated for suitability as the RP2D. 
If another DLT was observed after expansion to 6 subjects at 800 mg (2 out of 6), 
then 600 mg would be evaluated for suitability as the RP2D. 
For the enzalutamide combination only, if none of the first 3 subjects or no more than 
1 of 6 subjects experienced a DLT at the 800 mg dose level, then dose escalation 
would proceed to the next level of 1200 mg. At the 1200 mg dose-escalated level, 
3 subjects would be enrolled. If no subjects experienced a DLT at the 1200 mg level, 
then dose escalation would proceed to the next level of 1600 mg. If 1 subject 
experienced a DLT at 1200 mg, then the 1200 mg dose level would be expanded by 
3 additional subjects; if there were no additional DLTs at the 1200 mg level (ie, no 
more than 1 DLT in 6 subjects), then dose escalation would proceed to the 1600 mg 
level. If, however, 2 or more subjects out of the first 3 or 6 subjects enrolled at 

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1200 mg experienced a DLT, then the next lower, previously tested dose of 800 mg 
would be evaluated for suitability as the RP2D. 
For the enzalutamide combination only, at the 1600 mg dose-escalated level, 
3 subjects were to be enrolled. If no subjects experienced a DLT at the 1600 mg level, 
then 1600 mg would be evaluated for suitability as the RP2D. If 1 subject 
experienced a DLT at 1600 mg, then the 1600 mg dose level would be expanded by 
3 additional subjects; if there were no additional DLTs at the 1600 mg level (ie, no 
more than 1 DLT in 6 subjects), then 1600 mg would be evaluated for suitability as 
the RP2D. If, however, 2 or more subjects out of the first 3 or 6 subjects enrolled at 
1600 mg experienced a DLT, then the next lower, previously tested dose of 1200 mg 
would be evaluated for suitability as the RP2D.  
Seven subjects were enrolled in the abiraterone/prednisone combination dose escalation arm 
and 14 subjects were enrolled in the enzalutamide combination dose escalation arm. 
Determination of the RP2D was informed by all available information, including PK 
parameters and the overall safety and tolerability of each combination. The RP2D of 
tazemetostat when administered in combination with enzalutamide was established as 
1200 mg twice daily. Any available AR splice variant expression status (ie, AR-V7) and 
neuroendocrine (small cell NEPC) status data were also evaluated before proceeding to phase 
2. 
Now that the RP2D for tazemetostat in combination with enzalutamide has been established, 
subjects with mCRPC previously treated with abiraterone/prednisone will be enrolled and 
randomized 1:1 in the phase 2 part of the study to receive either tazemetostat with 
enzalutamide or enzalutamide alone. 
Subjects treated in the phase 1b part of the study who did not experience a DLT may 
continue in the study after cycle 1 on the combination regimen at the assigned dose until 
progression or occurrence of unacceptable toxicity. For subjects who had been assigned to 
the enzalutamide combination in phase 1b, the dose of tazemetostat may be increased to the 
RP2D after consultation with the Medical Monitor. 
Phase 2 
The phase 2 part of the study will include an open-label, 2-arm randomized component. 
Approximately 80 chemotherapy naive, qualified subjects with mCRPC who were previously 
treated with abiraterone/prednisone will be enrolled and randomized 1:1 to receive either 
tazemetostat combined with enzalutamide ( using the newly established RP2D of 1200 mg orally 
twice daily when given in combination with enzalutamide) as determined in phase 1b part of the 
study) or enzalutamide alone. All subjects will receive treatment in 28-day cycles.  
Study Duration 
Study duration will be approximately 12 months for phase 1b and approximately 
 months for 
phase 2, for a total study duration of approximately 50 months. 
7.2. 
Number of Subjects 
It is expected that approximately 104 subjects will be enrolled: a maximum of approximately 
24 subjects in the phase 1b part of the study (enrollment completed); approximately 80 
CCI

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chemotherapy naïve, qualified subjects in the randomized phase 2 part of the study. See 
Section 13.2 for sample size assumptions. 
7.3. 
Treatment Assignment 
The plan for treatment assignment in the phase 1b part of the study (completed) was as follows: 
In the phase 1b part of the study, there were 3 different tazemetostat dose levels planned to be 
tested in combination with abiraterone/prednisone and 5 different tazemetostat dose levels 
planned to be tested in combination with enzalutamide. A maximum of approximately 24 
chemotherapy naïve, qualified subjects were to be enrolled in one of the combination treatments 
as described above in Section 7.1. The starting dose level of tazemetostat was 400 mg orally 
twice daily followed by 600 mg orally twice daily followed by 800 mg twice daily, as tolerated 
according to occurrence of DLTs. For the enzalutamide combination only, dose escalation could 
further proceed to 1200 mg twice daily followed by 1600 mg twice daily, as tolerated.  
For both enzalutamide and abiraterone/prednisone, prescribed doses as recommended by the 
respective package inserts will be used throughout the study. 
In the phase 2 part of the study, approximately 80 chemotherapy naïve, qualified subjects with 
mCRPC who were previously treated with and progressed on abiraterone/prednisone will be 
randomized 1:1 to either tazemetostat combined with enzalutamide (using the newly established 
tazemetostat RP2D of 1200 mg twice daily when given in combination with enzalutamide) or 
enzalutamide alone. Prescribed doses of enzalutamide as recommended by the package insert 
will be used throughout the study. Subjects will not be treated with abiraterone/prednisone in the 
phase 2 portion of the study. 
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.  
7.4. 
Restrictions During Study Treatment 
7.4.1. 
Food and Sun Exposure 
Subjects will abstain from ingesting Seville oranges, grapefruit or grapefruit juice, and 
foods/beverages that contain those, for 24 hours prior to the first dose of study treatment until the 
last dose of study treatment. 
Subjects should avoid prolonged exposure to sunlight while receiving study treatment. In 
addition, subjects should take other measures to avoid ultraviolet exposure such as wearing 
sunscreen and sunglasses, wearing protective clothing, and avoiding tanning beds. 
7.4.2. 
Pregnancy and Sperm Donation 
There has been no experience to date of the use of tazemetostat during pregnancy or lactation. In 
an ongoing embryofetal development study, evidence of increased skeletal developmental 
abnormalities in fetuses from the pregnant rats relative to fetuses from control rats was observed. 
Consequently, there is a potential risk for teratogenicity, and precautions must be taken to avoid 
any pregnancy that could potentially be conceived during exposure to tazemetostat by EITHER 
male OR female subjects. 

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7.4.2.1. 
Definition of Child-fathering Potential: Male Subjects 
A male subject is considered to be of child-fathering potential if he: 
x Is anatomically and physiologically capable of causing a pregnancy in a female 
partner, and 
x Will be or could possibly be sexually active with a female (who is or may become 
pregnant) while undergoing study treatment with the possibility of posing harm to a 
fetus. 
A male subject is not considered to be of child-fathering potential if he: 
x Has undergone surgical castration. 
7.4.2.2. 
Definition of Childbearing Potential: Female Partners 
A female partner is considered to be a female of childbearing potential (FCBP) if she: 
x Is anatomically and physiologically capable of becoming pregnant, and 
x Will be or could possibly be sexually active with the male subject while undergoing 
study treatment with the possibility of posing harm to a fetus. 
A female partner is considered to be of non-childbearing potential (ie, physiologically incapable 
of becoming pregnant) if she: 
x Is post-PHQRSDXVDO  PRQWKV FRQVHFXWLYH DPHQRUUKHLF 
x Is surgically sterilized (ie, bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy) with surgery at least 1 month before the male partner’s (subject’s) 
first dose of study treatment, or 
x Has a documented congenital or acquired disorder that is incompatible with 
pregnancy. 
7.4.2.3. 
Pregnancy Prevention 
Subjects must refrain from donating sperm from first dose of study drug, during study treatment 
(including during dose interruptions), and for 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. 
Subjects of child-fathering potential must either practice complete abstinence or agree to use a 
latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia) 
or maintain medical castration during sexual contact with a pregnant female or FCBP during 
study treatment and for 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. Male 
subjects with surgical castration are not required to use condoms. 
Epizyme recommends that FCBP as defined in Section 7.4.2 who are partners of male study 
subjects also either practice complete abstinence or use a highly effective method of 
contraception. It is recommended that contraception begin at least 4 weeks prior to male 
partner’s first dose of study drug, continue during study treatment (including during dose 

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interruptions), and continue for 3 months following the male subject’s last dose of tazemetostat, 
3 weeks following his last dose of abiraterone/prednisone, and 3 months following his last dose 
of enzalutamide. If the below contraception methods are not appropriate for the FCBP, it is 
recommended she be referred to a qualified contraception provider to determine the medically 
effective contraception method appropriate for her. The following are examples of highly 
effective contraception: 
- 
Intrauterine device (IUD) 
- 
Bilateral tubal ligation 
- 
Hormonal (ovulation inhibitory combined [estrogen and progesterone] birth control pills 
or intravaginal/transdermal system, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, ovulation 
inhibitory progesterone-only pills [eg, desogestrel]) 
NOTE: Female partners who are using hormonal contraceptives are recommended to have been 
on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to the 
male subject’s first dose of study treatment and continue to use the same contraceptive during 
study treatment and for 3 months after the subject’s final dose of tazemetostat, 3 weeks following 
his last dose of abiraterone/prednisone, and 3 months following his last dose of enzalutamide. 
Female partners exempt from contraceptive recommendations are those who practice true 
abstinence when this is in line with their preferred and usual lifestyle (periodic abstinence [eg, 
calendar, ovulation, sympto-thermal, post-ovulation methods], declaration of abstinence for the 
duration of the trial, and withdrawal are not acceptable methods of contraception). If currently 
abstinent, the female partner is recommended to use a highly effective method of contraception 
as described above if she becomes sexually active during the subject’s study treatment, and for 
3 months after the subject’s final dose of tazemetostat, 3 weeks following his last dose of 
abiraterone/prednisone, and 3 months following his last dose of enzalutamide. 
7.5. 
Dose Adjustment Criteria 
7.5.1. 
Dose-limiting Toxicities 
Phase 1b (Dose Escalation, Cycle 1 [Completed]) 
Study drugs for a subject who experiences a DLT were to be stopped. Events were assessed as 
DLTs according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0), as 
shown in Table 2, Table 3, and Table 4. Refer to Section 7.1 (Overall Study Design) for a 
description of the dose escalation process. 

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Table 2: 
Dose-Limiting Toxicities - Tazemetostat 
Toxicity Category 
Toxicity/CTCAE Grade 
Hematological 
Grade 4 neutropenia for >5 days, or grade 3 neutropenia with fever 
(>38.5°C in axilla) 
Grade 4 thrombocytopenia, or grade 3 thrombocytopenia with bleeding or 
ODVWLQJ  GD\V 
Other Non-hematological 
Toxicity 
 
Grade 3 fatigue, or a 2-point decline in Eastern Cooperative Oncology 
*URXS (&2* SHUIRUPDQFH VWDWXV WKDW SHUVLVWV IRU  GD\V 
Elevation of hepatic enzymes, including bilirubin to meet the definition of 
Hy’s Law (per FDA Guidance for Industry Drug-Induced Liver Injury: 
Premarketing Clinical Evaluation, July 2009) 
*UDGH  QHXURWR[LFLW\ RU FDUGLRWR[LFLW\ 
Grade 2 hypersensitivity reaction 
Nausea, vomiting, or diarrhea that persists at grade 3 or 4 despite maximal 
medical therapy 
Any grade 3 or higher non-hematological laboratory abnormalities that 
require hospitalization 
$Q\ RWKHU JUDGH  QRQ-hematological toxicity not listed above that 
SHUVLVWV IRU  GD\V GHVSLWH EHVW LQVWLWXWLRQDO VWDQGDUG Rf care. 
Abbreviations:  CTCAE= Common Terminology Criteria for Adverse Events. 
Note: Dose-limiting toxicities resulting from the combination of tazemetostat with either enzalutamide or 
abiraterone/prednisone will take into account change or increase of risks known to be associated with these 
products in addition to any new toxicities resulting from the combination of tazemetostat with the compounds. 
 

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Table 3: 
Dose-Limiting Toxicities - Abiraterone/Prednisone 
Toxicity Category 
Toxicity/CTCAE Grade 
Mineralocorticoid excess 
6HYHUH V\PSWRPV LQFOXGLQJ grade 3 hypokalemia and/or hypertension 
UHTXLULQJ KRVSLWDOL]DWLRQ ODVWLQJ  GD\V ZLWKRXW UHVROXWLRQ LQ VSLWH RI
cessation of study therapy and application of best institutional standard 
of care.  
Adrenocortical insufficiency 
*UDGH  VHYHUH V\PSWRPV UHTuiring hospitalization, uncontrolled for 
 GD\V LQ VSLWH RI GLVFRQWLQXDWLRQ RI VWXG\ WKHUDS\ DQG EHVW
institutional standard of care.   
Hepatotoxicity 
x 
Elevation of hepatic enzymes including bilirubin to meet the 
definition of Hy’s Law (per FDA Guidance for Industry Drug-
Induced Liver Injury: Premarketing Clinical Evaluation, July 
2009) 
x 
,VRODWHG JUDGH  HOHYDWLRQ RI $/7 RU $67 RI  GD\V LQ VSLWH
of discontinuation of study therapy, and application of best 
institutional standard of care. Isolated grade 3 elevation of total 
ELOLUXELQ ZLWKRXW HYLGHQFH RI ELOLDU\ REVWUXFWLRQ WKDW SHUVLVWV 
days, in spite of discontinuation of study therapy, and best 
institutional standard of care. 
x 
Grade 4 AST or ALT of any duration. 
x 
ALT and/or AST >5x ULN or total bilirubin >3x ULN. 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common 
Terminology Criteria for Adverse Events; ULN = upper limit of normal. 
Note: Dose-limiting toxicities resulting from the combination of tazemetostat with abiraterone/prednisone will take 
into account change or increase of risks known to be associated with these products in addition to any new 
toxicities resulting from the combination of tazemetostat with abiraterone/prednisone. 
 
Table 4: 
Dose-Limiting Toxicities - Enzalutamide 
Toxicity Category 
Toxicity/CTCAE Grade 
Hypersensitivity 
6HYHUH V\PSWRPV JUDGH  DOOHUJLF UHDFWLRQ UHTXLULQJ SURORQJHG
treatment (e.g. not rapidly responsive to symptomatic medication, and 
withoXW UHVROXWLRQ IRU  GD\V LQ VSLWH RI interruption of enzalutamide 
and best institutional standard of care.  
Ischemic Heart Disease 
5DSLG RQVHW RI VHYHUH DFXWH JUDGH  FDUGLDF GLVRUGHU UHTXLULQJ
hospitalization, and unresponsive to treatment for  GD\V, in spite of 
interruption of enzalutamide and best institutional standard of care.  
Seizure 
Grade 4 seizures, despite medical intervention, lasting  GD\V OHDGLQJ
to discontinuation of study therapy. 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events. 
Note: Dose-limiting toxicities resulting from the combination of tazemetostat with enzalutamide will take into 
account change or increase of risks known to be associated with both products in addition to any new toxicities 
resulting from the combination of tazemetostat with enzalutamide. 
 

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7.5.2. 
Dose Modifications and Stopping Rules Due to Treatment-Related Toxicities 
7.5.2.1. 
Dose Modification for Tazemetostat Toxicity 
Tazemetostat dose reductions and interruptions will be allowed in phase 1b (during which 
tazemetostat dose reductions are allowed only after completion of cycle 1) and are allowed in 
phase 2; however, an interruption in the administration of tazemetostat for more than 14 days 
must be discussed with the Medical Monitor before treatment can be resumed.  Dose-limiting 
toxicities are covered in Section 7.5.1. 
Dose reductions occur in a step-wise fashion and include only the previously tested doses.  For 
examples, refer to Table 7. There can be no dose level reductions below 400 mg twice daily in 
the phase 1b portion of the study, and any reductions below 600 mg twice daily in the phase 2 
portion of the study will be discussed with the Medical Monitor.   
Toxicity will be managed by concomitant medication (as appropriate), treatment interruption, 
dose reduction, and treatment discontinuation, or a combination of these. During treatment with 
tazemetostat, dose interruption and reduction for subjects who experience tazemetostat-related 
toxicity will be done in accordance with the instructions in Table 5.  
For any case of T-ALL/T-LBL, MDS/AML, or other myeloid malignancies like MPN, 
tazemetostat treatment for the subject will be discontinued. If an adult case of T-LBL/T-ALL 
occurs in this study, enrollment in this study will be suspended. Refer also to Section 7.5.4 
concerning suspension of enrollment and Section 12.2.1.6.3 for review of these cases by the 
tazemetostat safety committees. 
For subjects who require dose interruption due to tazemetostat-related toxicity in phase 1b or in 
phase 2, the treatment may re-VWDUW RQFH WKH WR[LFLW\ KDV EHHQ UHVROYHG WR *UDGH  RU EDVHOLQH
according to the instructions in Table 5. 
For continuation of treatment for cycle 2 and beyond, subjects must meet the following 
retreatment criteria: 
x 3ODWHOHW FRXQW PXVW EH  î 9/L 
x Absolute neutrophil count (ANC) PXVW EH   î 9/L, and  
x Any Grade 3 or higher toxicity must have resolved to Grade 1 or baseline, unless 
otherwise noted. 
For tazemetostat, other toxicities that, in the opinion of the Investigator are possibly, probably, or 
definitely related to study treatment, should be managed per Table 5. Toxicities that are felt by 
the Investigator to be unrelated to tazemetostat but clinically significant should be discussed with 
the Medical Monitor. In the event of an urgent unrelated toxicity, study treatment should be 
interrupted as per Table 5. Dose re-escalation is not permitted. 
 

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Table 5:
Dose Modifications for Tazemetostat Treatment-Related Toxicities
Toxicitya
During Therapy
Approximate Dose 
Adjustmentb
Grade 1
All occurrences
Continue study treatment
Maintain dose level
Grade 2c
1st occurrence
Interrupt tazemetostat until resolved to Grade  1 or baselineb
Maintain dose level
2nd occurrence 
(same or new toxicity)
Restart at 1 dose level below 
assigned dosee
3rd occurrence 
(same or new toxicity)
Discuss with Medical 
Monitor
Grade 3 - not including anemiad, and not including neutropenia and thrombocytopenia (see below)
1st occurrence
Interrupt tazemetostat until resolved to Grade  1 or baselineb
Restart at 1 dose level below 
assigned dosee
2nd occurrence 
(same or new toxicity)
Discuss with Medical 
Monitor
3rd occurrence 
(same or new toxicity)
Discontinue tazemetostat
Not applicable
Grade 3 neutropenia (ANC: <1 – 0.5 × 109/L)
$1&   î 9/L 
1st occurrence
Interrupt WD]HPHWRVWDW XQWLO UHVROYHG WR $1&   î 9/L
Restart at 1 dose level below 
assigned dosee
2nd occurrence
Discuss with Medical 
Monitor
3rd occurrence
Discontinue tazemetostat
Not applicable
Grade 3 thrombocytopenia
1st occurrence
,QWHUUXSW WD]HPHWRVWDW XQWLO UHVROYHG WR *UDGH   RU EDVHOLQHb
Restart at 1 dose level below 
assigned dosee
2nd occurrence
Discuss with Medical 
Monitor
3rd occurrence
Discontinue tazemetostat
Not applicable 
Grade 4
All occurrences
Interrupt study drug until resolved to Grade 2 or less
Discuss with Medical 
Monitor 
Abbreviations: ANC = absolute neutrophil count. 
a Excluding alopecia and nausea, vomiting, or diarrhea not receiving adequate treatment.
b An interruption of tazemetostat for more than 14 days due to any toxicity must be discussed with the Medical 
Monitor before treatment can be resumed.
c Any case of Grade 2 toxicity for which the investigator deems an interruption or dose modification is warranted 
should be discussed with the Medical Monitor
d Exclude Grade 3 anemia: Subjects are allowed to continue tazemetostat at their current dose level with transfusion 
per Investigator discretion. 
e Step-wise dose reduction levels for tazemetostat-related toxicities depend on the assigned dose and may include 
only previously tested doses; there can be no dose level reductions below 400 mg twice daily in the phase 1b 
portion of the study, and any reductions below 600 mg twice daily in the phase 2 portion of the study must be 
discussed with the Medical Monitor. If the assigned dose in phase 1b is 400 mg twice daily, only grade 1 toxicities 
and a first occurrence of any grade 2 toxicity will be considered tolerable.
The same set of rules of treatment interruption and resumption will be applied to the cohorts 
receiving combination therapy of tazemetostat and enzalutamide and tazemetostat and 

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abiraterone/prednisone dose modifications. Both enzalutamide and abiraterone/prednisone are 
considered as companion drugs to tazemetostat in this trial. There is no known overlapping 
toxicity between tazemetostat and the companion drugs used in this trial. 
3OHDVH UHIHU WR PDQXIDFWXUHU
V ODWHVW SDFNDJH LQVHUW IRU HQ]DOXWDPLGH DQG DELUDWHURQHSUHGQLVRQH
dose modifications for treatment-related toxicities. 
A discussion with the SSRQVRU
V PHGLFDO PRQLWRU LV QHHGHG LI GRVH LQWHUUXSWLRQ RU UHGXFWLRQ LV
considered, either for both or only one of the drugs.  
7.5.2.2. 
Dose Modification for Toxicity to Abiraterone Acetate 
The suggested initial dose reduction of abiraterone, if deemed necessary by the Investigator, is 
25%. If further dose reduction of abiraterone is considered necessary, the suggested step-down is 
an additional 25%, for a total of 50% reduction in abiraterone dosage at step 2. A discussion with 
WKH 6SRQVRU
V PHGLFDO PRQLWRU LV QHHGed before the 2nd dose reduction of abiraterone. If a dose 
reduction is required, the Investigator will follow the guidelines in Table 6.  
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In 
a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 
substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with 
abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of 
abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (eg, 
thioridazine). If alternative treatments cannot be used, consider a dose reduction of the 
concomitant CYP2D6 substrate drug. 
If the following conditions are observed, refer to the most current package insert for proper 
management. 
x Mineralocorticoid excess characterized by hypertension, hypokalemia, low renin, and 
hypoaldosteronism. 
x Hepatotoxicity characterized by rising transaminases and/or bilirubin. 
x Adrenocortical insufficiency characterized by worsening fatigue, hyperpigmentation 
DQG V\PSWRPV RI $GGLVRQ
V GLVHDVH 
 
Table 6: 
Dose Modification for Abiraterone-Related Toxicity 
 
1,000 mg orally once daily with prednisone 5 mg orally twice daily 
1st reduction 
25% (750 mg once daily) and prednisone 5 mg twice daily 
2nd reductiona 
5% (500 mg once daily) and prednisone 5 mg twice daily 
3rd reduction 
Stop treatment 
a Discussion with the medical monitor is needed before the second dose reduction. 
 

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7.5.2.3. 
Dose Modifications for Toxicity to Enzalutamide 
There is no recommended step down for enzalutamide. Co-administration of another strong 
CYP2C8 inhibitor (gemfibrozil) increased the composite AUC of enzalutamide plus N-
desmethyl enzalutamide in healthy volunteers (see the most current enzalutamide package 
insert). Co-administration of enzalutamide with other strong CYP2C8 inhibitors should be 
avoided if possible. If co-administration of enzalutamide with a strong CYP2C8 inhibitor cannot 
be avoided, refer to the most current package insert for adjustment of the dose of enzalutamide.  
If the following conditions are observed: 
x Hypersensitivity 
x Worsening of ischemic cardiovascular disease 
x Posterior reversible encephalopathy syndrome 
x New onset seizures not due to metastasis 
discontinue treatment and discuss with medical monitor immediately. 
7.5.3. 
Tazemetostat Dose Modifications With Unavoidable Concomitant Moderate 
CYP3A Inhibitors 
As described in Sections 9.3.2 and 9.3.3, after the completion of cycle 1 in the phase 1b portion 
of the study and at any time during the phase 2 portion of the study for subjects receiving 
tazemetostat, if coadministration with a moderate CYP3A inhibitor cannot be avoided, the 
recommended tazemetostat dose reductions are shown in Table 7.  After discontinuation of the 
moderate CYP3A inhibitor for 3 elimination half-lives, resume the tazemetostat dose that was 
being taken prior to initiating the inhibitor.   
Examples of moderate CYP3A inhibitors include, but are not limited to, those listed in 
Appendix 6. This list of medications is not exhaustive; refer to product information and the 
source websites in the appendix for the most up-to-date information. 
Table 7: 
Recommended Dose Reductions of Tazemetostat for Moderate CYP3A 
Inhibitors 
Current Dosage 
Adjusted Dosage 
1600 mg twice daily 
800 mg twice daily 
1200 mg twice daily 
600 mg twice daily 
800 mg twice daily 
400 mg twice daily 
600 mg twice daily 
400 mg for first dose and 200 mg for second dose 
400 mg twice daily 
200 mg twice daily 
 
7.5.4. 
Rules for Suspension of Enrollment 
The Investigators, Institutional Review Boards (IRBs)/Independent Ethics Committees (ECs), 
regulatory agencies, and an ad hoc Quarterly Safety Review (QSR) committee will convene to 

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review the data and to make recommendations for potential changes in study conduct if one or 
more subjects develops any of the following AEs deemed to be definitely related to study 
treatment by the Investigator and/or Medical Monitor, based upon close temporal relationship or 
other factors: 
x Death 
x Hepatotoxicity 
x T-LBL/T-ALL 
x Hypersensitivity 
x Posterior reversible encephalopathy syndrome 
x New onset seizures not due to metastasis 
In the event that study enrollment is suspended, the study will not be restarted until all parties 
have agreed to the course of action to be taken and the IRBs/IECs have been notified. 
If a case of adult T-LBL/T-ALL occurs, study enrollment will be suspended and the benefit-risk 
of the drug will be assessed by the QSR Committee and the External Safety Committee (ESC). 
Refer also to Section 12.2.1.6.3.  
7.6. 
Criteria for Study Suspension or Termination 
Should conditions requiring further clarification arise before the decision to proceed with or 
terminate the study can be reached, the study will be suspended until the situation has been 
resolved.  
The sponsor has the right to terminate this study and remove all study material from the site at 
any time. Examples of where this might occur include, but are not limited to:  
x When it becomes apparent that subject enrollment is unsatisfactory with respect to 
quality and/or quantity or data recording is inaccurate and/or incomplete on a chronic 
basis.  
x When the incidence and/or severity of AEs in this study indicates a potential health 
hazard caused by treatment with tazemetostat.  
7.7. 
Study Design Schematic and Schedule of Assessments 
The study design is displayed in Figure 1, and the Schedule of Assessments is shown in Table 8. 
 

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Figure 1: Study Design 

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Table 8: 
Schedule of Assessments  
Cycle Screening 
C1 
C2 
C3 C4 
C5 
C6 
C7 C8-9b C10 C11-12b 
C13+ 
Unsched-
uled 
Visitsd 
Post-
treat-
ment 
Follow-
up 
Long-
term 
Follow 
Upe 
Study Day -28 to -1 
1 
2a 
21a 
29 
57 
85 
113 141 169 
197b 
and 
225b  
253 
281b 
and 
309b 
337 and every 
subsequent 84 
daysc 
Week -4 to -1 
(28 days) 
1 
1 
3 
5 
9 
13 
17 
21 
25 
29b 
and 
33b 
37 41b and 
45b 
49 and every 
subsequent 12 
weeks 
As needed 
during 
study 
30 days 
after 
last 
dosef 
Every 12 
weeks 
Window (days) 
 
 
 
 
± 2 
± 2 ± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
 
± 3 
± 7 
Informed consentg 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
(IVRS/IWRS) 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Physical examination 
including weighth 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGi 
X 
Xi 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Xj 
X 
 
Clinical Laboratory 
Assessmentsk 
Xk 
Xk 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Xj 
X 
 
Assess CBC with 
differential for myeloid 
malignanciesk 
X 
 
 
 
Xk 
 
X 
 
Blood draw for NEPC 
markers in bloodl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood sample for 
ctDNA genotype analysis 
and PBMC isolationm 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Tumor biopsyn 
Xn 
 
 
 
Xn 
Xn 

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Cycle Screening 
C1 
C2 
C3 C4 
C5 
C6 
C7 C8-9b C10 C11-12b 
C13+ 
Unsched-
uled 
Visitsd 
Post-
treat-
ment 
Follow-
up 
Long-
term 
Follow 
Upe 
Study Day -28 to -1 
1 
2a 
21a 
29 
57 
85 
113 141 169 
197b 
and 
225b  
253 
281b 
and 
309b 
337 and every 
subsequent 84 
daysc 
Week -4 to -1 
(28 days) 
1 
1 
3 
5 
9 
13 
17 
21 
25 
29b 
and 
33b 
37 41b and 
45b 
49 and every 
subsequent 12 
weeks 
As needed 
during 
study 
30 days 
after 
last 
dosef 
Every 12 
weeks 
Window (days) 
 
 
 
 
± 2 
± 2 ± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
 
± 3 
± 7 
PSAo 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
CTCso 
X 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
PK (phase 1b; completed)p 
 
X 
X 
X 
X 
 
 
 
  
 
 
 
  
 
 
 
 
PK (phase 2)q 
 
 
 
 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
CT/MRI and bone scan 
Xr 
 
 
 
 
Xs 
 
Xst 
 
Xst 
 
Xst 
 
Xst 
 
 
Xe 
CXR or chest CTu 
Xu 
 
 
 
 
(X)u 
 
 
 
ECOG performance status 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Xb 
X 
Xb 
X 
X 
X 
 
BPI-SF (phase 1b)v 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
BPI-SF (phase 2)v 
 
Xv 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
FACT-Pv 
 
Xv 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5Lv 
 
Xv 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
AEs/SAEsw 
 X 
 X 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Xb 
X 
Xb 
X 
X 
X 
Xe 
Optional chest ultrasoundx 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Concomitant medications 
X 
X 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Xb 
X 
Xb 
X 
X 
X 
 
Study drug dispensing 
 
X 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Study drug treatmenty 
 
X 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Annual Assessmentsz 
 
X 
 
 
 
Disease assessment and 
survival statuse 
 
 
X 
X 
Abbreviations: AE = adverse event; BPI-SF = Brief Pain Inventory-Short Form; CT = computed tomography; CTCs = circulating tumor cells; CXR = chest x-
ray; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EQ-5D-5L = EuroQol 5-Dimension 5-Level questionnaire; FACT-P = 
Functional Assessment of Cancer Therapy – Prostate; MRI = magnetic resonance imaging; F/U = Follow-up; PD = progressive disease; NEPC = 

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neuroendocrine prostate cancer; NSE = neuron-specific enolase; PK = pharmacokinetic; PSA = Prostate-Specific Antigen; QoL = quality of life; SAE = serious 
adverse event; SRE = skeletal-related event. 
a In cycle 1, the day 2 and day 21 visits apply only to subjects in phase 1b (completed). 
b These visits/assessment may be completed by telephone. 
c Starting at cycle 13, subjects will have a clinic visit every 12 weeks. 
d Unscheduled visits may be performed at any time during the study whenever necessary to assess for or follow-up on adverse events, upon discontinuation of 
treatment, at tKH VXEMHFW
V UHTXHVW RU LI GHHPHG QHFHVVDU\ E\ WKH ,QYHVWLJDWRU 
e Long-term follow-up Beginning after study drug discontinuation:  
x 
All subjects with confirmed radiographic disease progression as defined in the protocol will be discontinued from study drug and from further follow-up 
after the 30-day follow-up visit, even if the subject continues to benefit clinically. If the Investigator elects to continue enzalutamide treatment in the 
commercial setting in the case of subject who continue to benefit clinically despite confirmed radiographic progression, it will be recorded as 
subsequent anti-cancer therapy. 
x 
For subjects who discontinue study treatment for reasons other than confirmed radiographic disease progression (such as unequivocal clinical or 
chemical progression), radiographic tumor assessment scans are required every 12 weeks (±7 days) during long-term follow-up, and other study 
assessment will continue as scheduled, until the earlier of either: 18 months post last study drug dose; radiographic disease progression; the start of a 
new systemic anticancer therapy for prostate cancer; withdrawal of consent/loss to follow-XS GHDWK RU  U3)6 HYHQWV KDYH EHHQ REVHUYHG LQ WKH VWXG\
(as communicated by the Sponsor). 
f Post-treatment follow up, or prior to initiation of an investigational agent or new anti-cancer therapy, whichever occurs first. The post-treatment/early 
termination assessments will be required and, in the event of a continuing AE, the subject will be asked to return for follow-up until the AE has resolved or is 
deemed to be continuing indefinitely. 
g Informed consent must be signed within 4 weeks before randomization; otherwise, the screening visit must be repeated. 
h A brief physical examination is required at each visit, with the exception of the screening visit during which a complete physical examination will be 
completed. 
i A single ECG will be taken at specified study visits. A single ECG will be recorded unless there is an abnormality, such as prolonged QT interval corrected for 
heart UDWH XVLQJ )ULGHULFLD¶V IRUPXOD 47F)  PVHF QHZ DUUK\WKPLD RU RWKHU FOLQLFDOO\ VLJQLILFDQW ILQGLQJ ,I DQ DEQRUPDOLW\ is observed, the ECG is to be 
performed in triplicate at least 2 minutes apart. 
j If medically indicated. 
k Clinical laboratory assessments (see Appendix 3) will include:  
x 
Serum chemistries, urinalysis, hematology and coagulation (as well as testosterone at screening), and  
x 
CBC with differential assessment as follows:  
During Screening and within 30 days following the end of study treatment (before initiation of subsequent antineoplastic therapy), a complete blood count 
(CBC) with differential (manual or automated peripheral blood smear) will be performed and assessed per institutional standards to rule out myeloid 
malignancies, including but not limited to MDS/AML/MPN. A potential subject with a suspected or confirmed myeloid malignancy will be excluded 
from the study. 
During the study treatment period, the Investigator will monitor subjects for the development of myeloid malignancies as medically indicated. 
Any suspected or confirmed AESIs identified during and following the study treatment period will be reported as delineated in Section 12.2. 
l Blood draw for NEPC markers in blood: neuron-specific enolase (NSE; 1mL) at screening. (Note: serum chromogranin A [1 mL] was removed with 
Amendment 

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m Samples for ctDNA genotype analysis will be collected from subjects at baseline before administration of the first dose, and at all times commensurate with 
CT/MRI and bone scans in both the phase 1b and phase 2 parts of the study for genotype analysis.  Sample collection is mandatory for both phase 1b and phase 
2 part of the study. Refer to the laboratory manual for processing of the PBMC samples to be isolated from whole blood for gene expression profiling. 
n Tumor biopsies: For subjects in phase 1b, optional tumor biopsies will be collected during baseline, disease progression, and first sign of response only from 
subjects who agree to provide optional tumor biopsy as documented on the informed consent form. In the phase 2 part of the study, tumor biopsies (primary 
and metastatic, including from lymph node and bone) will be collected when safe and feasible from 12-20 subjects randomized only to the combination arm of 
tazemetostat plus enzalutamide at: 1) pre-treatment,  2) cycle 2 day 1 during treatment, and 3) at the time of disease progression (only in responders); in order 
to ascertain which treatment group a phase 2 subject is assigned to in advance of organizing a pre-treatment tumor biopsy, randomization of phase 2 subjects 
who consent to provide the biopsy may occur up to 3 days before cycle 1 day 1. Randomization of phase 2 subjects not providing a pre-treatment biopsy should 
occur on cycle 1 day 1 but may occur up to 3 days earlier. In both phases, the baseline biopsy can be taken from archival tumor, provided the sample was 
REWDLQHG  \HDU EHIRUH HQUROOPHQW A separate laboratory manual will be provided for instructions on providing biopsy from bone. For both phases, Epizyme 
will request available archival tumor samples from all subjects (5 to 20 slides per subject) who do not provide matched biopsies from Screening (added with 
Amendment #5). Longitudinal biopsies should be taken whenever feasible form the same lesions. 
o All protocol-specified PSA and CTC measurements are to be done at a central laboratory 
p PK (Phase 1b; completed): In the phase 1b part of the study blood samples for PK analysis were to be collected in cycle 1 on days 1, 2, and 21 prior to dosing 
(0 hours) and post-dose at 30 minutes (±5 minutes), at 1, 2, 4, 6, and 8 hours (±15 minutes), and at 24 hours (±30 minutes).  In cycle 2 on day 1 samples were to 
be drawn pre-dose and 2- and 6- hours post-dose (±15 minutes). Subjects should have been instructed not to take their dose of study drug on these visit days 
before they went to the clinic and should have been instructed to take their study drug in the clinic after the PK sample is drawn. For PK assessment days, 
subjects were required to take their study drug/s in the morning at the clinic after the pre-dose sample has been collected.  The date and time of the last dose 
were to be recorded. 
q Sparse PK (Phase 2): in the phase 2 part of the study in cycles 2, 3, 5, and 10 on day 1, blood samples will be drawn only from subjects assigned to the 
combination arm for sparse PK analysis before dosing (0 hours) and at 2 and 6 hours post-dose (±15 minutes).  For PK assessment days, subjects will be 
required to take their study drug/s in the morning at the clinic after the pre-dose sample has been collected.  The date and time of the last dose will be recorded. 
r Screening timeframe for CT scan or MRI, bone scan, chest X-ray, or chest CT must occur within 4 weeks before randomization; otherwise, the screening 
visit must be repeated. 
s Visit windows for CT/MRI, bone scan, chest X-ray, or chest CT: Window for radiological assessments is ±7 days and are performed every 8 weeks for the 
first 6 months and then every 12 weeks thereafter. At all visits where radiological assessment is performed, all other procedures must be completed within the 
±2-day window as specified in the schedule. 
t CT/MRI: Disease progression observed by CT or MRI for soft tissue disease does not require a confirmatory scan. 
u Chest CT is required at all imaging time points, if screening chest x-ray demonstrated metastatic chest disease. 
v Health-Related Quality of Life (QoL) Assessments (BPI-SF, FACT-P, and EQ-5D-5L) should be administered before other interactions in the clinic. In 
phase 2, assessments at baseline are administered on cycle 1 day 1 before other interactions in the clinic. Every effort should be made to ensure all subjects 
complete as many scheduled health-related QoL assessments as possible. The BPI-SF instrument should assess pain related to prostate cancer only. 
w AEs/SAEs will be collected from the time the subject signs the consent form until the earlier of either screen failure, the end of the safety reporting period 
(30 days after the last dose of study drug), or initiation of an investigational agent or cytotoxic chemotherapy. In addition, SAEs occurring beyond 30 days post 
treatment that are considered to be related to study drug will be collected. All nonserious AEs will be followed to resolution or other outcome is reached until 
study closure and database lock.  All SAEs will be followed by Epizyme to resolution or other outcome is reached, regardless of study closure/database lock. 
(Refer to Sections 12.2.5 and 12.2.6). Where appropriate, medical tests and examinations will be performed to document resolution or other outcome of the 
event(s).  

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x An optional chest ultrasound may be performed at screening and every 8 weeks at the Investigator’s discretion to monitor for early signs of T-LBL/T-ALL, 
thymus enlargement. 
y Study Drug Treatment: For study visit days, subjects will self-administer study drug upon instruction from the staff. 
z Annual assessments will be conducted only for subjects who remain on tazemetostat treatment to review for AEs of special interest at a clinic visit (±30 days). 
 

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
1. $JH DW WKH WLPH RI FRQVHQW  \HDUV 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 
(Appendix 1). 
3. Life expectancy of >3 months. 
4. Histologically or cytologically confirmed adenocarcinoma of the prostate. Small 
cell or neuroendocrine (differentiated or with neuroendocrine features) tumors of 
the prostate are also permitted. 
5. Progressive disease in the setting of medical or surgical castration (ie, CRPC) by 
PCWG3 criteria for study entry.  
x Evidence of disease progression by rising PSA or 
x Soft tissue progression per RECIST 1.1 or  
x 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: 
x Bone lesions on bone scan (per PCWG3) or by soft tissue disease (per 
RECIST 1.1) by CT/MRI 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 WHVWRVWHURQH  QJG/ 
nmol/L) at screening. 
9. Prior treatment with a second-generation androgen inhibitor as follows: 
x For phase 1b, EITHER previously untreated with a second-generation 
androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed 
on a second-generation androgen inhibitor (abiraterone, enzalutamide, or 
apalutamide).  
x For phase 2 randomized component (ie, enzalutamide-containing treatment 
groups) of the study, previously progressed on abiraterone for either 
castration-sensitive or castration-resistant disease; the required washout period 
for abiraterone is 7 days. 
10. No prior treatment with cytotoxic chemotherapy for mCRPC, except as follows:  
x For phase 1b, more than 6 cycles of docetaxel received for castration-sensitive 
disease prior to having received enzalutamide or abiraterone/prednisone is 
permitted.  

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x For the phase 2 randomized component (ie, enzalutamide-containing 
treatment groups) of the study, up to 6 prior cycles of docetaxel received for 
castration-sensitive disease in the nonmetastic and metastatic settings prior to 
having received abiraterone/prednisone is permitted.   
11. Demonstrate adequate organ function as defined below: 
x $1&   ȝ/ 
x 3ODWHOHW &RXQW   ȝ/ 
x +HPRJORELQ   JG/ without a transfusion within 2 weeks of screening. 
x 6HUXP FUHDWLQLQH   î XSSHU OLPLW RI QRUPDO 8/1 RU 
- 
&UHDWLQLQH FOHDUDQFH   P/PLQ DV HVWLPDWHG E\ WKH &RFNFURIW DQG
*DXOW IRUPXOD LQ VXEMHFWV ZLWK FUHDWLQLQH !  î 8/1 
x %LOLUXELQ   î 8/1 XQOHVV HYLGHQFH RI *LOEHUW
V GLVHDVH LQ ZKLFK FDVH  
î 8/1 
x $67   î 8/1 ZLWKRXW OLYHU PHWDVWDVHV PXVW EH   î 8/1 ZLWK OLYHU
metastases. 
x $/7   î 8/1 ZLWKRXW OLYHU PHWDVWDVHV PXVW EH   î 8/1 ZLWK OLYHU
metastases. 
x Albumin >3.0 g/dL (30 g/L) at screening. 
12. Subjects of child-fathering potential as defined in the protocol (Section 7.4.2.1) 
must either practice complete abstinence or agree to use a latex or synthetic 
condom, even with a successful vasectomy (medically confirmed azoospermia), 
or maintain medical castration during sexual contact with a pregnant female or 
female partner of childbearing potential (FCBP) during study treatment, for 3 
weeks following the last dose of abiraterone/prednisone, and for 3 months 
following the last dose of enzalutamide.  Male subjects with surgical castration 
are not required to use condoms. 
NOTE: Male subjects must not donate semen or sperm from first dose of study 
drug, during study treatment (including during dose interruptions), and for 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. 
8.2. 
Subject 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: 
x Abiraterone within 7 days. 

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x First generation AR antagonists (eg, bicalutamide, nilutamide, flutamide) within 
4 weeks. 
x 5-alpha reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol), 
or progesterones within 2 weeks. 
x Chemotherapy (except as permitted in inclusion criterion #10) within 3 weeks. 
x Prior radionuclide therapy within 4 weeks. 
x Another interventional product or standard agent in a clinical study within 28 days 
prior to the first planned dose of tazemetostat 
x For phase 2 subjects to be randomized to one of the enzalutamide treatment groups 
only, prior treatment with any second-generation AR antagonist (eg, enzalutamide, 
apalutamide, darolutamide, proxalutamide, etc) other than abiraterone. 
4. Severe concurrent disease, infection, or comorbidity 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: 
x Myocardial infarction within 6 months before screening. 
x Uncontrolled angina within 3 months before screening.  
x 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 
 Appendix 2).  
x History of clinically significant ventricular arrhythmias (eg, sustained ventricular 
tachycardia, ventricular fibrillation, torsades de pointes). 
x History of Mobitz 2 second-degree or third-degree heart block without a 
permanent pacemaker in place. 
x Hypotension as indicated by systolic blood pressure <86 millimeters of mercury 
(mmHg) at screening.  
x Bradycardia as indicated by a heart rate of <45 beats per minute on the screening 
electrocardiogram (ECG), and upon physical examination. 

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x 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. 
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, according to the potential to be assigned to the agent(s). 
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, including 
live virus vaccine within 30 days before the first dose of study treatment or plans to 
receive a live virus vaccine during treatment. 
14. Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2. 
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: 
x No history of AIDS-defining opportunistic infections or have not had an opportunistic 
infection within the 12 months prior to enrollment. 
x No history of AIDS-defining cancers (eg, Kaposi’s sarcoma, aggressive B-cell 
lymphoma, and invasive cervical cancer). 
x Subjects may take prophylactic antimicrobials; however, subjects taking specific 
antimicrobial drugs that have a potential for drug-drug interaction or overlapping 
toxicities with study drugs must be excluded from study participation.  
x Subjects should be on established anti-UHWURYLUDO WKHUDS\ IRU  ZHHNV ZLWK DQ +,9
viral load of < 400 copies/mL and/or CD4+ T-FHOO &' FRXQW  FHOOVX/ SULRU
to enrollment. 
16. Has thrombocytopenia, QHXWURSHQLD RU DQHPLD RI *UDGH  SHU &7&$(  FULWHULD RU
any prior history of myeloid malignancies, including MDS and AML. Has abnormalities 
known to be associated with MDS (eg, del 5q, chr 7 abn) and MPN (eg, JAK2 V617F) 
observed in cytogenetic testing and DNA sequencing. 
NOTE:  At screening, a complete peripheral blood count (CBC) with differential 
(manual or automated peripheral blood smear) will be performed and assessed per 
institutional standards to rule out myeloid malignancies, including but not limited to 
MDS/AML/MPN. A potential subject with a suspected or confirmed myeloid malignancy 
will be excluded from the study. 
17. Has a prior history of T-LBL/T-ALL. 

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18. 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. 
19. Subjects with hepatitis B or hepatitis C are ineligible to participate in the study unless 
they meet the following criteria:  
x 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.  
x 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. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Withdrawal of Subjects from Treatment/Procedures 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to future medical care by the physician or institution. 
Subjects (or legally authorized representatives) can decline to continue receiving tazemetostat 
and/or other protocol-required procedures at any time during the study but can continue 
participation in the study (eg, for follow-up information). If this occurs the Investigator is to 
discuss with the subject appropriate processes for discontinuation and the options for procedures 
that may continue such as collection of data, including endpoints and AEs. The Investigator must 
document the agreement in the procedures that the subject will continue with and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of the 
medical records.) 
Reasons for removal from protocol-required treatment or procedures might include the 
following: 
x Disease progression 
x Subject request to end study treatment and/or procedures 
x Safety concern (eg, AE, failure to follow contraception or pregnancy, excluded 
medication required) 
8.3.2. 
Withdrawal of Subjects from Study 
Withdrawal of full consent for the study means that the subject does not wish to receive further 
protocol-required treatment or procedures and does not wish to or is unable to continue further 
study participation. Subject data up to withdrawal of consent will be included in the analysis of 
the study, and where permitted, publicly available data can be included after withdrawal of 
consent (eg, death records). The Investigator must document this agreement regarding 
withdrawal of full consent as well as discuss appropriate procedures for withdrawal from the 
study. 
Reasons for removal of a subject from the study might include the following: 

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x Death 
x Decision by Sponsor to terminate the study 
x Subject request to withdraw from study 
x Lost to follow-up 
8.3.3. 
Replacement of Subjects 
Subjects in phase 1b of the study were to be replaced if there were not a sufficient number of 
samples to calculate PK parameters. 
Subjects in phase 2 will not be replaced in this study. 

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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug Dosing 
Study drug dosing is described in Table 9 below.  Dose adjustment criteria are discussed in 
Section 7.5. 
Table 9: 
Phase 1b/2 Doses of Tazemetostat, Enzalutamide, Abiraterone, and 
Prednisone 
Treatment 
Dose 
Frequency 
Total Daily Dose 
Tazemetostat 
Phase 1ba: Per dose escalation  
Phase 2c:  
RP2D of 1200 mg for combination 
with enzalutamide  
Twice daily 
Phase 1ba: Per dose escalation  
Phase 2:  
2400 mg for combination with 
enzalutamide 
Enzalutamide 
160 mg 
Once daily 
160 mg 
Abirateroneb, d 
1000 mg 
Once daily 
1000 mg 
Prednisoned 
5 mg 
Twice daily 
10 mg 
Abbreviations: RP2D = recommended phase 2 dose. 
a The starting dose was 400 mg tazemetostat twice daily. If there were no DLTs, dose escalation would continue to 
600 mg twice daily and to a maximum of 800 mg twice daily; for the combination with enzalutamide only, dose 
escalation may have continued to 1200 mg twice daily and to a maximum of 1600 mg twice daily, as tolerated. 
b Abiraterone must be taken on an empty stomach with water at least 1 hour before, or 2 hours after a meal. 
c  Orally twice daily in continuous 28-day cycles. 
d  Abiraterone and prednisone are administered in phase 1b only 
 
The plan for the phase 1b part of the study was as follows: There were 3 different tazemetostat 
dose levels planned to be tested in combination with abiraterone/prednisone and 5 different 
tazemetostat dose levels planned to be tested in combination with enzalutamide. Enzalutamide or 
abiraterone/prednisone was to be administered orally on cycle 1 day 1 and tazemetostat 
administered orally on day 2. Tazemetostat was to be escalated from a starting dose of 400 mg 
twice daily, to 600 mg twice daily, to 800 mg twice daily as tolerated, in a modified 3+3 design 
in combination with enzalutamide or abiraterone/prednisone. For the combination with 
enzalutamide only, tazemetostat could have been further escalated to 1200 mg twice daily and to 
a maximum of 1600 mg twice daily, as tolerated. 
In the randomized phase 2 part of the study, the RP2D of 1200 mg of tazemetostat when given in 
combination with enzalutamide will be administered orally twice daily in continuous 28-day 
cycles. Enzalutamide and tazemetostat will both be administered on day 1 of each cycle.  
9.2. 
Duration of Treatment 
Prostate-specific antigen increase without evidence of confirmed radiographic progression is 
strongly discouraged as a criterion to discontinue study therapy. Initiation of new therapy for 
prostate cancer at the time of radiographic progression will mandate discontinuation of study 
drug.  

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Treatment administration should continued for as long as the subject is tolerating the study drugs 
and continues ADT (ie, surgical castration or ongoing GnRH analogue therapy) until confirmed 
radiographic disease progression by PCWG3 criteria (see Table 10 and Figure 2), even if the 
subject continues to benefit clinically, or until unequivocal clinical progression if earlier than 
radiographic disease progression.   
NOTE: If the Investigator elects to continue enzalutamide treatment in the commercial setting in 
the case of subject who continue to benefit clinically despite confirmed radiographic disease 
progression, it will be recorded as subsequent anti-cancer therapy. 
9.3. 
Concomitant Medications 
Documentation of all concomitant medication administered during study treatment will be 
recorded in the electronic Case Report Form (eCRF) at each visit. 
Coadministration of tazemetostat with a strong or moderate CYP3A inhibitor increases 
tazemetostat plasma concentrations, which may increase the frequency or severity of adverse 
reactions. Coadministration of tazemetostat with a strong or moderate CYP3A inducer may 
decrease tazemetostat plasma concentrations, which may decrease the efficacy of tazemetostat. 
Because there is a potential for interaction of tazemetostat with other concomitantly administered 
drugs through the cytochrome P450 system, all over-the-counter medications and alternative 
therapies, in addition to prescribed medications, must be recorded in the eCRF. The Investigator 
should be alerted if the subject is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes. 
9.3.1. 
Permitted Medications 
The following medications are permitted as specified: 
x Supportive care measures and symptomatic treatment for any treatment-related 
toxicity, including short courses of glucocorticoids, if clinically indicated. (See also 
Section 9.3.2 Section 9.3.3 below.) 
x Glucocorticoids may be taken by subjects with CNS tumors, under the following 
conditions: 
 For control of neurological symptoms that may continue at a tapering dose. 
 Intermittent use for control of nausea (not to exceed 0.3 mg/kg/dose 
dexamethasone, maximum of 20 mg) every 12 hours as needed. 
x Non-enzyme inducing anti-epileptic drugs. 
x Prophylactic use of standard anti-emetics. 
x Blood and platelet transfusions, as needed per the judgment of the Investigator. 
x Initiation of bisphosphonates or other approved antiresorptive medications are 
allowed and should not result in discontinuation of study drug therapy. 
x Over-the-counter medications, nutritional supplements, vitamins, and herbal 
preparations (including CBD oil) are permitted, except those to be used with caution 

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or that are prohibited for reasons stated in Sections 9.3.2 and 9.3.3 below (for 
example, St. John’s wort). 
9.3.2. 
Medications to be Used with Caution 
The following medications are to be used with caution in subjects receiving tazemetostat: 
x CYP3A sensitive substrates 
x Moderate CYP3A inhibitors. After the completion of cycle 1 in the phase 1b 
(completed) portion of the study or at any time during the phase 2 portion of the study 
for subjects receiving tazemetostat, if coadministration with a moderate CYP3A 
inhibitor cannot be avoided, reduce the dose of tazemetostat as shown in Section 7.5.3 
(Dose Modifications With Unavoidable Concomitant CYP3A Inhibitors). After 
discontinuation of the moderate CYP3A inhibitor for 3 elimination half-lives, resume 
the tazemetostat dose that was being taken prior to initiating the inhibitor. 
NOTE: Examples of medications that are moderate inhibitors of CYP3A or are CYP3A 
sensitive substrates include, but are not limited to, those listed in Appendix 6. This list of 
medications is not exhaustive; refer to product information and the source websites in the 
appendix for the most up-to-date information. 
For guidance on medications to be used with caution in subjects receiving enzalutamide, 
abiraterone, or prednisone, Investigators are instructed to follow the local labels. 
For all subjects, the following medications may be used with caution (and are to be listed as 
concomitant medications in the CRF, if used): 
x Over-the-counter medications, nutritional supplements, vitamins, and herbal 
preparations are permitted under physician recommendation and with the agreement 
of the Investigator only, with the exception of those that are prohibited for reasons 
stated in Section 9.3.3 below (for example, St. John’s wort). Aspirin, nonsteroidal 
anti-inflammatory drugs, and low-molecular-weight heparin or prophylactic doses of 
heparin are permissible but should be used with caution.  
x Medical marijuana is permitted only under physician recommendation and with the 
agreement of the Investigator. 
x Any alternative therapies should be discussed with the Investigator prior to 
enrollment in the study or prior to initiating them during the study. 
9.3.3. 
Prohibited Medications 
Prohibited medications include: 
x Antineoplastic therapy or other investigational therapy for the treatment of 
cancer, unless otherwise noted here  
x Any other experimental or unapproved drugs. 
x Prophylactic use of hematopoietic colony stimulating factors 
NOTE: Therapeutic use of hematopoietic colony stimulating factors is discouraged 
and should be discussed with the Medical Monitor and should be conducted 

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according to the 2006 American Society for Clinical Oncology Guideline for use of 
white blood cell (WBC) growth factors (Smith, 2006). 
x Strong inhibitors of CYP3A and strong and moderate inducers of CYP3A within 
14 days prior to first dose of study treatment and concomitantly with tazemetostat or 
in the absence of tazemetostat for the duration of study, except for assigned study 
treatment with enzalutamide (a strong inducer of CYP3A4).  
Moderate CYP3A inhibitors were prohibited during cycle 1 of the phase 1b 
(completed) portion of the study, starting from 14 days prior to first dose of 
tazemetostat. 
NOTE: Examples of medications that are moderate or strong inhibitors and moderate 
or strong inducers include, but are not limited to, those listed in Appendix 6 (for 
example, St. John’s wort, which is a strong CYP3A inducer). This list of medications 
is not exhaustive; refer to product information and the source websites in the 
appendix for the most up-to-date information. 
x Enzyme inducing anti-epileptic drugs including, but not limited to, carbamazepine, 
phenobarbital, phenytoin, and barbiturates, should not be taken within 14 days prior 
to the first dose of study treatment and for the duration of study treatment. 
x Live virus vaccine within 30 days before the first dose of study treatment or during 
treatment. 
x For guidance on medications contraindicated with enzalutamide, abiraterone, or 
prednisone, Investigators are instructed to follow the local labels. 
9.3.4. 
Non-Drug Therapies for Disease 
Radiation Therapy: Localized, palliative radiation therapy and potential concurrent dose 
interruptions will be permitted for pain or severe symptom control after discussion with the 
Medical Monitor. Radiation will be limited to non-target lesions only and documented in the 
eCRF. 
Other Palliative Procedures: Other procedures intended for symptom control and potential 
concurrent dose interruptions may be permitted after discussion with the Medical Monitor. These 
procedures will be limited to non-target lesions only and documented in the eCRF. 
9.4. 
Treatment Compliance 
9.4.1. 
Treatment Compliance Procedures 
For study visit days, the subject will self-administer drug upon instruction from the study staff. 
The subject will be requested to maintain a medication diary of each dose of tazemetostat as well 
as the combination drugs (either enzalutamide or abiraterone/prednisone). The dosing diary will 
be returned to the site staff at each visit. 
Compliance for doses taken outside of the clinic may be assessed by a count of the tablets 
returned to the study site by the subject and review of doses taken with the subject. This will be 

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recorded in the source documents, which may include the use of a subject medication diary per 
institutional practice. 
9.4.2. 
Special Situations: Overdose, Misuse, Abuse and Medication Error 
Definitions, reporting, and management of overdose, misuse, abuse, and medication errors are 
presented below and refer to tazemetostat, enzalutamide, or abiraterone/prednisone. 
x Overdose: An overdose is defined, regardless of any associated AEs or sequelae, as: 
 On a per-dose basis, any amount of the orally administered drug(s) that is over the 
protocol-specified dose assigned to a given subject. 
 On a schedule or frequency basis, anything taken more frequently than the 
protocol-required schedule or frequency. 
x Misuse: Intentional and inappropriate use of study drug not in accordance with the 
protocol. 
x Abuse: Sporadic or persistent intentional excessive use of study drug accompanied 
by harmful physical or psychological effects. 
x Medication error: Any unintentional event that causes or leads to inappropriate 
study drug use or subject harm while the study drug is in the control of site personnel 
or the subject. 
These occurrences must be reported on the dosing administration eCRF. Adverse events 
associated with these occurrences are to be captured on the AE eCRF.  
All instances of special situations are to be reported using the paper Special Situation Form 
regardless of presence or absence of an associated AE.  Refer to Section 12.2.1.7 for detailed 
instructions on how to handle the reporting of special situations.  
In the event of a special situation, the Investigator should immediately contact the Medical 
Monitor or their designee and closely monitor the subject for AEs/SAEs and laboratory 
abnormalities. 
9.5. 
Randomization 
In the phase 2 part of the study, approximately 80 chemotherapy naïve, qualified subjects with 
mCRPC who previously progressed on abiraterone/prednisone will be randomized 1:1 to receive 
either tazemetostat combined with enzalutamide or enzalutamide alone.  
No blinding will be used in this part of the study.  
 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug  
10.1.1. 
Tazemetostat 
Tazemetostat (EPZ-6438) is an Epizyme investigational product (IP) and is defined as an 
Investigational Medicinal Product (IMP) under the European Union Clinical Trials Directive 
(EU CT Dir).  Refer to Section 10.5 for instructions on administration of tazemetostat. 
 
Investigational Product 
Product Name: 
Tazemetostat (EPZ-6438) 
Formulation Description: 
200-mg tablets 
Dosage Form: 
Tablet 
Physical Description: 
Round, red, biconvex, film-coated tablets  
Dosea/Route/Schedule/Duration: 
Oral/twice daily/continuous 
a Dose is dependent on dose escalation level in phase 1b (completed) and will be the declared RP2D of 1200 mg 
when given in combination with enzalutamide in phase 2. See Section 9.1 for details. 
Abiraterone/prednisone (tablets) and enzalutamide (capsules) will be provided by Epizyme. 
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10.1.2. 
Enzalutamide 
In the phase 1b and phase 2 parts of the study, enzalutamide will be administered on day 1 of 
each cycle.  
Subjects enrolled the study will receive enzalutamide 160 mg (four 40 mg capsules) orally once 
daily. The subject is to be instructed to swallow capsules whole. Enzalutamide can be taken with 
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V ODWHVW SDFNDJH LQVHUW IRU DGGLWLRQDO GHWDLOV 
10.1.3. 
Abiraterone/Prednisone 
In the phase 1b part of the study, abiraterone/prednisone will be administered on day 1 of each 
cycle.  
The recommended dose for mCRPC of abiraterone is 1,000 mg (two 500 mg tablets or four 
250 mg tablets) orally once daily in combination with prednisone 5 mg (in tablet form) 
administered orally twice daily (for a total daily dose of prednisone 10 mg). 
Abiraterone must be taken on an empty stomach, either 1 hour before or 2 hours after a meal. 
The subject should be instructed that the tablets should be swallowed whole with water and not 
crushed or chewed.  
3OHDVH UHIHU WR WKH PDQXIDFWXUHU
V ODWHVW SDFNDJe inserts for abiraterone and prednisone for 
additional details. 

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10.2. 
Study Drug Packaging and Labeling 
Tazemetostat tablets are packaged in a white high- density polyethylene bottle with a child-
resistant, tamper-evident polypropylene screw cap. The contents of the package label will be in 
accordance with all applicable regulatory requirements. The expiry date will be printed on the 
label. 
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V ODWHVW SDFNDJH
insert for further details.  
10.3. 
Study Drug Storage 
Tazemetostat must be stored in a secure area, in compliance with storage requirements listed on 
the label, with access limited to the Investigator and authorized site staff only. 
For abiraterone/prednisone and enzalutamide, please refer WR WKH PDQXIDFWXUHU
V ODWHVW SDFNDJH
insert for further details.  
10.4. 
Study Drug Preparation 
No preparation for tazemetostat is needed.  
)RU DELUDWHURQHSUHGQLVRQH DQG HQ]DOXWDPLGH SOHDVH UHIHU WR WKH PDQXIDFWXUHU
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insert for further details.  
10.5. 
Administration 
Tazemetostat must be dispensed or administered only to subjects enrolled in the study and in 
accordance with the protocol. Standard institutional procedures for administering an oral agent 
will be followed. An adequate supply will be provided with instructions on home administration. 
Tazemetostat will be taken orally twice daily with or without food. Subjects should be instructed 
to swallow tablets whole and not to cut, crush, or chew tablets. 
Tazemetostat doses should be taken at least 8 hours apart. If a dose is missed (eg, missed 
morning or evening dose and did not re-dose within an appropriate amount of time), or if the 
subject vomits a dose, the dose should be skipped. All doses given, missed, and vomited are to 
be recorded. 
Refer to Section 10.1.2, Section 10.1.3, as well as the prescribing information for enzalutamide, 
abiraterone, and prednisone for drug administration instructions. 
In the phase 1b dose escalation part of the study (completed), enzalutamide or 
abiraterone/prednisone was administered on cycle 1 day 1 and tazemetostat on day 2. 
Tazemetostat was escalated from a starting dose of 400 mg twice daily to 600 mg twice daily to 
800 mg twice daily as tolerated, in a modified 3+3 design in combination with enzalutamide or 
abiraterone/prednisone. For the enzalutamide combination only, dose escalation could further 
proceed to 1200 mg twice daily followed by 1600 mg twice daily, as tolerated. 
In the phase 2 part of the study, the RP2D of 1200 mg of tazemetostat when given in 
combination with enzalutamide will be administered orally twice daily in continuous 28-day 
cycles. Enzalutamide and tazemetostat will both be administered on day 1 of each cycle. 

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10.6. 
Study Drug Accountability 
The Investigator/designee will be responsible for taking an inventory of each shipment of 
tazemetostat received and comparing it with the accompanying shipment form. The 
Investigator/designee will verify the accuracy of the information on the form, sign and date it, 
and acknowledge the shipment receipt according to the instructions provided. 
The Investigator/designee must keep accurate written records of all tazemetostat received from 
the Sponsor. Additionally, the Investigator/designee must keep accurate records of the 
tazemetostat dispensed to subjects enrolled in this study including the quantity of tablets, lot 
number, date dispensed, subject initials and identification number, dose administered, balance 
forward, and the initials of the person dispensing the IP. Based on the entries in the site 
accountability forms, it must be possible to reconcile IP delivered with that used and returned. 
All IP must be accounted for and all discrepancies investigated and documented appropriately. 
Tazemetostat stock may not be removed from the investigative site where originally shipped 
without prior knowledge and consent of the Sponsor or its designee. When authorized, all 
applicable local, state, and national laws must be adhered to for the transfer. 
This will also apply to Epizyme supplied abiraterone/prednisone and enzalutamide. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all unused tazemetostat will be destroyed by the investigative site or sent 
to a designated contractor for disposal on behalf of the Sponsor, per the instructions at that time. 
Any IP returned to the Sponsor-designated contractors must be counted and verified by site 
personnel and the Sponsor or its designee. All certificates of delivery/receipts and/or return 
forms must be signed prior to shipment. The IP for return must be packed in a tamper-evident 
manner to ensure integrity is maintained during return. All IP returned must be in accordance 
with local, state, and national laws and must first be authorized by the Sponsor prior to shipment.  
This will also apply to Epizyme supplied abiraterone/prednisone and enzalutamide. 

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11. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and their timing are summarized in the Schedule of Assessment and 
Procedures (Table 8). 
11.1. 
Consent 
All subjects must take part in the informed consent process. Adequate time must be allowed for 
the subject to review the informed consent form, ask questions, and make a voluntary decision. 
No protocol-specific procedures, including screening procedures are to be performed until the 
subject has signed and dated an IRB/IEC-approved informed consent form (ICF). 
11.2. 
Screening Assessments 
A signed, written informed consent must be obtained prior to any study-specific assessments or 
procedures being performed. 
All screening assessments, including tumor assessment, must be performed within 28 days 
before enrollment. 
3URFHGXUHV FRQGXFWHG DV SDUW RI WKH VXEMHFW
V URXWLQH FOinical management (eg, blood counts, 
chemistries, imaging studies) and obtained prior to consent may be used for screening provided 
the procedure meets the protocol-defined criteria and has been performed in the screening 
timeframe for the study (up to 28 days before enrollment). 
11.2.1. 
Demographic/Medical History 
The following demographic information will be collected: date (or year, where appropriate) of 
birth, race, and ethnicity. These will be documented in source documents and captured in the 
relevant eCRF. 
The investigator or designee will obtain detailed information regarding all past medical history 
and surgical events. The dates and descriptions of past history and events will be documented in 
source documents and captured in the relevant eCRF. 
11.3. 
Efficacy Assessments 
For study assessments not included in the sections below, refer to the Schedule of Assessments 
(Table 8) for details. 
11.3.1. 
Prostate Cancer Status 
As described in subsequent sections, the following assessments of prostate cancer status will be 
collected during the course of the study: overall survival, soft tissue disease on CT scan or on 
MRI, bone disease on radionuclide bone scans, SREs, health-related QoL assessments (ie, BPI-
SF, FACT-P, and EQ-5D-5L), PSA, CTC enumeration and blood biomarkers of neuroendocrine 
prostate cancer. The consensus guidelines of RECIST 1.1 and the PCWG3 (Scher, 2016) have 
been taken into consideration for the determination of radiographic disease progression. 

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11.3.2. 
Radiographic Progression-Free Survival 
Primary efficacy will be assessed in the phase 2 part of the study by rPFS. The consensus 
guidelines of RECIST 1.1 and the PCWG3 have been taken into consideration for the 
determination of radiographic disease progression. The evaluation of progression in bone will be 
based upon PCWG3 criteria (ie, the appearance of two or more new bone lesions on bone scan), 
and the evaluation of progression in soft tissue will be based on RECIST 1.1 criteria. 
The documentation required for the determination of radiographic disease progression in both 
bone and soft tissue is listed in Table 10, and a flow diagram for assessment of bone scans to 
declare disease progression in bone per PCWG3 after the week 9 scan is provided in Figure 2 . 
Tumor assessments will be performed every 8 weeks for the first 6 months and then every 
12 weeks thereafter, starting after cycle 7 until radiographic disease progression is seen. 
Table 10: 
Protocol-Specified Documentation for Radiographic Evidence of Disease 
Progression 
Date 
Progression 
Detected 
(Visit)a  
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(requirement and timing) 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 9 
(Cycle 3 Day 1 
[±7 days]) 
Bone lesions; 2 or more new 
lesions compared to baseline 
bone scan by PCWG3 
Timing: at least 6 weeks after 
progression identified or at 
week 17 visitb. 
Two or more new bone 
lesions on bone scan 
(compared to week 9 
scan). 
Soft tissue lesions: 
Progressive disease on CT or 
MRI by RECIST 1.1 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Week 17 
(Cycle 5 Day 1 
[±7 days]) 
Bone lesions: Two or more 
new lesions on bone scan 
compared to week 9 bone 
scan. 
Timing: at least 6 weeks after 
progression identified or at 
week 25 visit. Required for 
bone lesions observed on 
bone scanb. 
Persistentc or increase in 
number of bone lesions 
on bone scan compared 
to week 9 scan. 
Soft tissue lesions: 
Progressive disease on CT or 
MRI by RECIST 1.1. 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Week 25 
(Cycle 7 Day 1 
[±7 days]) or 
later 
Bone lesions: Two or more 
new lesions compared to 
week 9 bone scan. 
Timing: at least 6 weeks after 
progression identified. 
Required for bone lesions 
observed on bone scanb. 
Persistentc or increase in 
number of lesions on 
bone scan compared to 
week 9 scan. 
Soft tissue lesions: 
Progressive disease on CT or 
MRI by RECIST 1.1. 
No confirmatory scan 
required for soft tissue 
disease progression. 
n/a 
Abbreviations: CT = computed tomography; RECIST = Modified Response Evaluation Criteria in Solid Tumors; MRI = 
magnetic resonance imaging; n/a = not applicable; PCWG3 = Prostate Cancer Clinical Trials Working Group 3. 
a Progression detected by bone scan at an unscheduled visit either prior to week 9 or between scheduled visits will require a 
confirmatory scan at least 6 weeks later and should follow confirmation criteria outlined in the table for the next scheduled 
scan. 
b Confirmation must occur at the next available scan. 
c For confirmation, at least two of the lesions first identified as new must be present at that next available scan (confirmation 
scan). 

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Figure 2:
Post Week 9 Bone Scan Assessment Flow Diagram
Note: Progression detected by bone scan at an unscheduled visit after week 9 will require a confirmatory scan at least 6 weeks 
later and should follow confirmation criteria outlined in the diagram. 
Study films (CT/MRI and bone scan) should be read on-site using PCWG3 and RECIST 1.1 
guidelines and also be submitted in a digital format for a blinded independent central radiology 
review. 
Radiographic imaging is not required after protocol-defined radiographic progressive disease is 
reached. 
Determination of radiographic progression by central radiology review (in parallel with the 
Investigator’s primary review) will continue until at least 
 rPFS events from a total of 
74 subjects (37 per arm) are confirmed in phase 2, as required for primary rPFS analysis between 
the active (tazemetostat with enzalutamide) and control arms (enzalutamide alone). See 
Section 13.2 for sample size justification.
11.3.3.
Chest X-ray or Chest CT
Chest CT is required at all imaging time points, if screening chest x-ray demonstrated metastatic 
chest disease.
11.3.4.
Prostate Specific Antigen (PSA)
All PSAs are to be done at a central laboratory. A laboratory manual detailing sample collection, 
preparation, storage, and shipping process will be provided.
CCI

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11.3.5. 
Circulating Tumor Cell (CTC) Enumeration 
Enumeration of CTC levels are to be done at a central laboratory. A laboratory manual detailing 
sample collection, preparation, storage, and shipping process will be provided.  
11.3.6. 
Health-Related Quality of Life 
The assessment of health-related QoL measures is an important aspect of this study as it will 
provide added information on the choice of treatment. Every effort should be made to ensure all 
subjects complete as many scheduled health-related QoL assessments as possible. Assessments 
should be administered before other interactions in the clinic during the visit. 
11.3.6.1. Brief Pain Inventory-Short Form 
The BPI, developed by the Pain Research Group of the World Health Organization Collaborating 
Centre for Symptom Evaluation in Cancer Care, is a validated patient-reported outcome 
instrument (Cleeland, 2009).  It is a self-administered, multidimensional pain assessment 
questionnaire used to rapidly assess the severity of pain and its impact on functioning. The 
BPI-SF contains front and back body diagrams, and 4 pain severity and 7 pain interference items 
that are rated on an ordinal numerical scale with anchors of 0 (no pain/interference) to 
10 (maximum pain/interference).  
In this study, a composite of the four pain items (a mean severity score) from the BPI-SF will be 
used to assess the rate of pain progression as a measure of efficacy.  
The BPI-SF assessment should assess pain related to prostate cancer only. Subjects in both 
phases of the study will complete the BPI-SF. 
11.3.6.2. Functional Assessment of Cancer Therapy-Prostate (FACT-P) 
The Functional Assessment of Cancer Therapy-Prostate FACT-P is a multidimensional, self-
report instrument specifically designed for use with prostate cancer patients (Esper, 1997). In 
addition to the 27 items comprising the Functional Assessment of Cancer Therapy-General 
(FACT-G) that assesses 4 areas of well-being (physical well-being, social/family well-being, 
emotional well-being, and functional well-being), the FACT-P also contains a 12-item disease-
specific prostate cancer subscale (PCS) that assesses the additional concerns specific to prostate 
cancer patients. The recall period is 1 week. Each question is assessed on a 5-point Likert scale: 
0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, and 4 = very much. The FACT-G 
scoring guide identifies those items that must be reversed before being added to obtain subscale 
totals. Responses to negatively stated items are reversed by subtracting the response from “4” to 
obtain the item score. After reversing proper items, all subscale items are summed to a total, 
which is the subscale score. For all Functional Assessment of Chronic Illness Therapy (FACIT) 
scales and symptom indices, higher scores represent better QoL. 
Only subjects in the phase 2 portion of the study will complete the FACT-P. 
11.3.6.3. EuroQoL 5-Dimension 5-Level (EQ-5D-5L) 
Participant reports of general health status will be assessed using the EuroQoL Group’s 5-level 
EuroQoL 5-Dimension (EQ-5D-5L) questionnaire. (EuroQol, 1990; Pickard, 2007) The EQ-5D-
5L has 2 components: a descriptive system and a visual analogue scale (VAS). The EQ-5D-5L 

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descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 5 levels, including “no,” “slight,” “moderate,” and 
“severe” problems, and either “extreme” problems or “unable to” to do the activity.  A 
dimension for which there are no problems is said to be at level 1, while a dimension for which 
there are extreme problems is said to be at level 5. Accordingly, the vectors 11111 and 55555 
represent the best health state and the worst health state, respectively, described by the 
EQ-5D-5L. Altogether, the instrument describes 3,125 (=55) different health states. Empirically 
derived weights can be applied to an individual’s responses to the EQ-5D-5L descriptive system 
to generate a utility index (ie, Health Utility Index [HUI]) measuring the value to society of his 
or her current health. In addition, the EQ-5D-5L VAS allows respondents to rate their own 
current health on a 101-point scale ranging from “best imaginable” to “worst imaginable” health. 
Thresholds for meaningful change for the EQ-5D-5L utility index and VAS in cancer patients 
have not been conclusively defined. The EQ-5D-5L is available in more than 130 languages. 
Only subjects in the phase 2 portion of the study will complete the EQ-5D-5L. 
11.4. 
Pharmacokinetic Assessments 
11.4.1. 
Blood Sample Collection 
In the phase 1b part of the study, blood samples for PK analysis were collected in cycle 1 on 
days 1, 2, and 21 at pre-dose (0 hours) and at 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose; and in 
cycle 2 on day 1 pre-dose (0 hours) and at 2 and 6 hours post-dose.  
In the randomized phase 2 part of the study, blood samples for sparse PK blood samples for 
analysis will be collected only from subjects assigned to the combination arm in cycles 2, 3, 5, 
and 10 on day 1 at pre-dose (0 hours) and at 2- and 6-hours post-dose. For PK assessment days, 
subjects will be required to take their study drug/s in the morning at the clinic after the pre-dose 
sample has been collected. The date and time of last dose on PK sampling days will be recorded. 
NOTE: On all days of PK blood draws, the subject must take the first tazemetostat dose at the 
clinic after the pre-dose (0 hour) PK blood draw. 
A laboratory manual detailing the PK sample collection, preparation, storage, and shipping 
process will be provided to investigators. 
11.4.2. 
Urine Pharmacokinetic Sample Collection 
Not applicable. 
11.5. 
Pharmacogenomics, Biomarkers, and Other Assessments  
11.5.1. 
Tumor Biopsy 
Matched biopsies will be performed or available archival biopsies will be requested to evaluate 
the association of genetic or molecular markers of disease, such as loss of PTEN, TP53, and RB1 
and gene expression signatures, including for NEPC, AR and AR splice variants, tumor 
inflammation and immune cell infiltration, in tumor tissue with drug response. The baseline 
ELRSV\ FDQ EH WDNHQ IURP DUFKLYDO WXPRU SURYLGHG WKH VDPSOH ZDV REWDLQHG  \HDU EHIRUH

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enrollment. Epizyme will request archival tumor samples from all subjects (5 to 20 slides per 
subject) who do not provide matched biopsies from Screening (added with Amendment #5). 
Instructions for providing biopsy from bone will be provided in a separate laboratory manual.  
For subjects in phase 1b, optional tumor biopsies are obtained pre-treatment, during drug 
treatment at first response, and at time of disease progression.  
In the phase 2 part of the study, tumor biopsies (primary and metastatic, including from lymph 
node and bone) will be collected when safe and feasible from 12-20 subjects randomized only to 
the combination arm of tazemetostat plus enzalutamide at: 1) pre-treatment, 2) on cycle 2 day 1 
during treatment, and 3) at the time of disease progression only in subjects who responded to 
treatment.  In order to ascertain which treatment group a subject is randomized to in advance of 
organizing a pre-treatment tumor biopsy, randomization of phase 2 subjects who consent to 
provide the biopsy may occur up to 3 days before cycle 1 day 1. Randomization of phase 2 
subjects not providing a pre-treatment biopsy should occur on cycle 1 day 1. Longitudinal 
biopsies should be taken whenever feasible from the same lesions.  
11.5.2. 
Blood Samples for Disease Markers and Pharmacogenomics (PGx) 
Blood samples for disease markers and pharmacogenomics will be processed, and plasma and 
peripheral blood mononuclear cells (PBMCs) will be isolated from whole blood and each 
fraction will be stored separately. Circulating tumor DNA (ctDNA) will be separated from 
plasma. PBMC isolation is done at a central laboratory, and viably frozen and standard frozen 
cell pellets will be collected and stored. A laboratory manual detailing the ctDNA and PBMC 
sample collection, preparation, storage, and shipping process will be provided. 
11.5.2.1. Blood Sample for ctDNA Genotyping 
Whole blood samples for ctDNA genotype analysis will be collected as detailed in Table 8. 
A laboratory manual detailing blood sample collection, preparation, storage, and shipping 
process will be provided. 
11.5.2.2. AR-V7 and NEPC Status in Circulating Tumor Cells 
AR-V7 and NEPC status (morphologically) will be determined in CTCs from liquid biopsies 
taken at baseline. AR-V7 status will be determined by IF detection of the splice variant in nuclei 
of CTCs; NEPC status will be determined morphologically in CTCs by assessing imaging of 
multiple small cell neuroendocrine parameters. Neuroendocrine status will also be determined in 
baseline serum samples by assessing serum biomarker neuron-specific enolase (NSE) collected 
pre-dosing. 
Enumeration of CTC levels are to be done at a central laboratory. A laboratory manual detailing 
sample collection, preparation, storage, and shipping process will be provided. 
11.5.2.3. Blood Biomarkers of Neuroendocrine Prostate Cancer 
A blood sample will be drawn at screening in phase 2 to assess for the NEPC biomarker NSE 
(serum chromogranin A was removed with Amendment #5). 

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11.5.3. 
Future Use of Biosamples 
Not all the tissue and blood components obtained during this study may be required for the tests 
that are part of the clinical trial. Following the conclusion of the study, the samples may be used 
for additional research. These samples will be held for a maximum of 15 years. This research 
will help to understand disease subtypes, drug response, and toxicity, and to possibly identify 
new drug targets or biomarkers that predict subject response to treatment. The use of the samples 
for internal research will be done according to both the FDA guidance for In Vitro Diagnostic 
Device Studies Using Leftover Human Specimens that are Not Individual Identifiable (issued 
25 April 2006) and the European Medicines Agency (EMA) Reflection Paper on 
Pharmacogenetic Samples, Testing and Data Handling (EMA/CHMP/PGxWP/201914/2006). If 
a subject requests destruction of their tissue and blood samples, and the samples have not yet 
been de-identified, the Sponsor will destroy the samples as described in the FDA guidance. The 
Sponsor will notify the Investigator in writing that the samples have been destroyed. The 
Sponsor reserves the right to destroy biosamples for any reason during the storage period without 
further notice. 
11.6. 
Follow-up 
11.6.1. 
Post-treatment Follow-up Visit 
Subjects will have a post-treatment follow-up visit 30 (±3) days after their last dose of 
tazemetostat or prior to initiation of an investigational agent or cytotoxic chemotherapy, 
whichever occurs first.  
11.6.2. 
Long-Term Follow-up 
Beginning after study drug discontinuation:  
x  For subjects who discontinue study treatment for reasons other than confirmed 
radiographic disease progression (such as unequivocal clinical or chemical 
progression), radiographic tumor assessment scans are required every 12 weeks 
(±7 days) during long-term follow-up, and other study assessment will continue as 
scheduled, until the earlier of either: 18 months post last study drug dose; 
radiographic disease progression; the start of a new systemic anticancer therapy for 
prostate cancer; withdrawal of consent/loss to follow-XS GHDWK RU  U3)6 HYHQWV
have been observed in the study (as communicated by the Sponsor).s communicated 
by the Sponsor). 
11.6.3. 
Subsequent Therapy After Discontinuation of Study Treatment 
Once a subject has permanently discontinued study treatment, every effort should be made to 
have the subject complete the post-treatment follow-up visit prior to initiating any subsequent 
anti-cancer therapy (approved or investigational). Post-study anti-cancer therapy will not be 
provided as part of this study. The subject may receive subsequent anti-cancer therapy at the 
discretion of the treating physician. The subsequent anti-cancer therapy should be documented 
on the eCRF. 

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11.6.4. 
Evaluation of Response to Subsequent Anti-Cancer Therapy 
To identify a potential epigenetic priming effect of tazemetostat, subjects who are withdrawn 
from this study due to disease progression and who go on to receive subsequent therapy should 
be followed for response whenever possible. Data to be recorded on the subsequent regimen 
should include agents received, best response, and duration of response. 
Refer to the Schedule of Assessment and Procedures (Table 8) for additional details. 

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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Vital Signs 
Vital signs will be performed after the subject is seated for 5 minutes and will include the 
following: 
x Systolic blood pressure 
x Diastolic blood pressure 
x Heart rate 
x Temperature 
Vital signs will be documented in source documents and captured in the relevant eCRF. Any 
clinically significant changes noted by the investigator should be reported as an AE. 
12.1.2. 
Weight and Height 
Weight is required to be measured at screening, on Day 1 of each cycle, and at the post-treatment 
visit. 
Height measurement is required at screening only. 
12.1.3. 
Physical Examination 
A brief physical examination is required at each visit, with the exception of the screening visit 
during which a complete physical examination will be completed. 
A complete physical examination of all body systems must be performed at screening by a 
qualified licensed individual. A review of body systems will include the following: 
x General appearance 
x Skin 
x Head, Ears, Eyes, Nose, Throat (HEENT) 
x Respiratory 
x Cardiovascular 
x Abdomen (including liver and kidneys) 
x Neurological examination with sensory testing and seizure status, if applicable 
x Musculoskeletal 
Any abnormalities or changes in intensity noted during the review of body systems should be 
documented in the source document and reported appropriately in the eCRF. If a new clinically 
significant finding (eg, not noted at screening) occurs from the initial tazemetostat administration 
until the end of the study, an AE must be documented. In addition, resolution of any abnormal 
findings during the study will be noted in source document and the eCRF if clinically significant. 

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These assessments will be completed as indicated in the Schedule of Assessments and 
Procedures, refer to Table 8. 
A brief or symptom-directed physical examination must be performed when a complete physical 
examination is not required (as indicated in the Schedule of Assessments) by a qualified licensed 
individual. This will consist of a focused review of systems and physical examination addressing 
any new symptoms, AEs, or complaints. 
12.1.4. 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed. ECG collection will occur after a 10-minute rest and 
with the subject in a supine position. ECGs will be collected prior to any blood collection. 
The ECGs will be performed as indicated in the Schedule of Assessments and Procedures 
(Table 8). A single ECG will be recorded unless there is an abnormality, such as prolonged QT 
interval corrected for heart rate using Fridericia’s formuOD 47F)  PVHF QHZ DUUK\WKPLD
or other clinically significant finding. If an abnormality is observed, the ECG is to be performed 
in triplicate at least 2 minutes apart. 
Machine read ECGs should be reviewed by the Investigator at the time of assessment. ECGs will 
be read locally within 72 business hours and data from the Central Reader should be entered in 
the clinical database. 
If cardiotoxicity is suspected, the investigator may conduct additional testing per institutional 
standard of care (eg, cardiac biomarkers, including B-type natriuretic peptide and cardiac 
troponin I or cardiac troponin T). 
12.1.5. 
Laboratory Assessments 
All clinical safety laboratory assays will be performed at local laboratories according to the 
ODERUDWRU\
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assess the laboratory data for clinical significance and out of range pathological changes. 
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condition should be repeated until confirmed, explained, or resolved. Laboratory value changes 
starting from the initial tazemetostat exposure will be recorded in the eCRF as an AE if clinically 
significant. 
Specific laboratory tests for hematology, serum chemistry, urinalysis, and coagulation profile are 
detailed in Appendix 3. 
During Screening and within 30 days following the end of study treatment (before initiation of 
subsequent antineoplastic therapy), a complete blood count (CBC) with differential (manual or 
automated peripheral blood smear) will be performed and assessed per institutional practice to 
rule out myeloid malignancies, including but not limited to MDS/AML/MPN.  
During the study treatment period, the Investigator will monitor subjects for the development of 
myeloid malignancies as medically indicated. 
Any suspected or confirmed AESIs identified during and following the study treatment period 
will be reported as delineated in Section 12.2.  
 

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12.1.6. 
Creatinine Clearance 
&UHDWLQLQH FOHDUDQFH LV UHTXLUHG RQO\ LI VHUXP FUHDWLQLQH LV ! î 8/1 Creatinine clearance 
should be calculated by Cockcroft-Gault formula (Appendix 4) or by institutional standard and 
must be >50 mL/min. 
12.1.7. 
ECOG Performance Status 
See Appendix 1. 
12.1.8. 
Optional Chest Ultrasound 
An optional chest ultrasound may be performed at screening and every 8 weeks at the 
Investigator’s discretion to monitor for early signs of T-LBL/T-ALL, thymus enlargement. 
12.2. 
Adverse Events 
12.2.1. 
Definitions of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IP, whether or not related to the IP. 
Worsening of a pre-treatment event, after initiation of any study drugs, must be recorded as a 
new AE. For example, mild intermittent dyspepsia prior to dosing of study drug, but becoming 
severe or more frequent after the first dose of study drug, requires that a new AE of severe 
worsening dyspepsia (with the appropriate date of onset) be recorded as an AE in the eCRF. 
"Lack of efficacy" or "failure of an expected pharmacological action" per se is not to be reported 
as an AE. However, any signs and symptoms and/or clinical sequelae resulting from "lack of 
efficacy" will be reported as an AE, if they fulfill the definition. 
Events that do not meet the definition of an AE include: 
x Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
x Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
All AEs that occur after any subject has signed informed consent, before treatment, during 
treatment, or within 30 days following the cessation of study treatment or prior to initiation of 
another investigational agent or cytotoxic chemotherapy, whichever occurs first, whether or not 
they are related to the study, must be recorded in the eCRF forms. 

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12.2.1.2. Serious Adverse Event (SAE) 
An SAE is an AE occurring during any study phase (ie, baseline, treatment, or follow-up), and at 
any dose of the investigational product, comparator or placebo, that fulfils one or more of the 
following: 
x Results in death 
x Is life-threatening 
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death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
x Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
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patient setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in 
doubt as to whether "hospitalization" occurred or was necessary, the AE should be 
considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered adverse or as meeting seriousness criteria of hospitalization. 
x Results in disability or incapacity 
NOTE: The term disability means a subsWDQWLDO GLVUXSWLRQ RI D SHUVRQ
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normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
and accidental trauma (eg, sprained ankle) which do not constitute a substantial 
disruption. 
x Is a congenital abnormality or birth defect as a result of intra-uterine exposure.  
x Is an important medical event.  
NOTE: Events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions (in subjects without pre-existing seizure 
disorder) that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
Serious AEs will be collected from the time a subject has signed informed consent until screen 
failure, 30 days following the cessation of treatment, or upon initiation of an investigational 
agent or cytotoxic chemotherapy, whichever occurs first, whether or not the events are related to 
the study.  Any SAEs that occur beyond 30 days following cessation of treatment that are 
considered related to study treatment will also be reported. 

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12.2.1.3. Laboratory Abnormalities 
Any laboratory value that is considered clinically significant by the investigator and/or has 
caused a medical intervention or is accompanied by clinical symptoms should be reported as an 
AE. All laboratory AEs should be repeated until the values return to normal limits, to baseline, or 
until a plausible explanation (ie, concomitant disease) is found for the pathological laboratory 
values. 
Laboratory abnormalities are recorded in the lab eCRF, but those that have not required medical 
intervention should not be recorded as AEs. If a medical intervention occurs, it should be 
recorded as a treatment with the abnormal laboratory finding as the AE (eg, anemia with 
treatment required and blood transfusion recorded as a procedure). 
12.2.1.4. Other Safety Assessment Abnormalities 
Other safety assessments (eg, ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline and events considered to be clinically significant by the 
investigator, are to be recorded as an AE in accordance with the definitions provided in Section 
12.2.1.1 and Section 12.2.1.2, respectively. 
Any other safety assessment that led to an intervention, including permanent discontinuation of 
study treatment, dose reduction, and/or dose interruption/delay is also to be recorded as an AE 
and assessed accordingly. 
12.2.1.5. Disease-Related Events 
Events that meet the criteria for seriousness but are thought to be associated with progression of 
the disease under study should not be reported as SAEs unless they are untoward for that subject 
and/or disease under investigation. 
NOTE: Disease progression should not be reported as an SAE term. 
12.2.1.6. Adverse Events of Special Interest (AESIs) 
The following AESIs have been identified as requiring mitigation steps and monitoring to 
minimize the risk for the occurrence of these events. All potential and identified AESIs must also 
be discussed with the Medical Monitor and reported using an SAE form (Section 12.2.1.2). All 
instances of AESI will undergo review by the tazemetostat safety committees 
(Section 12.2.1.6.3).  
Refer to the most current version of the tazemetostat IB for additional information about AESIs. 
12.2.1.6.1. T-Lymphoblastic Leukemia/T-Acute Lymphoblastic Leukemia 
Lymphoblastic lymphomas are considered thymus derived malignancies that have not yet 
completed T-cell maturations. Approximately 90% of lymphoblastic lymphomas are the T-cell 
phenotype and typically occur in young adults and adolescents, accounting for 29% of pediatric 
and 2% of adult non-Hodgkin lymphoma with a median age at diagnosis of 25 years (Lones, 
2007; Lai, 2013; Cortelazzo, 2017). T-LBL is morphologically and immunophenotypically 
indistinct from T-ALL, with both diseases arising from precursor lymphoid cells of the T-cell 
lineage (Portell, 2012; Patel, 2014). Despite the similarities of the two diseases, significant yet 
unknown characteristics lead to differences in clinical presentations (Burkhardt, 2009). Initial 

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clinical manifestation of both adult and pediatric T-LBL includes a mediastinal mass or 
lymphadenopathy with <25% bone marrow blasts. Adult T-LBL patients tend to have less 
thymic disease and greater lymph node disease and bone marrow involvement (Baleydier, 2008; 
Swerdlow, 2008; Campo, 2011). In contrast, T-ALL cases predominantly present with bone 
marrow and peripheral blood disease, and >25% bone marrow blasts (Swerdlow, 2008; Campo, 
2011). 
On 06 April 2018, an event of T-LBL was observed in a pediatric subject on study EZH-102. 
This event was reported to regulatory authorities as a 7-day suspected unexpected serious 
adverse reaction (SUSAR) on 13 April 2018 (Case number 2018USEPZ64380299). 
Following this report, Epizyme conducted a comprehensive evaluation, including: 
x Review of literature and available preclinical/clinical data to better understand event of 
T-LBL. 
x Review of the literature and available preclinical/clinical data to better understand the 
risk of MDS/AML and myeloid malignancies, and other solid tumor malignancies. 
x Assessment of safety, PK at various doses tested, benefit-risk across tumor types in adults 
and children. 
x Consultation with well recognized external experts in T-cell malignancies and 
pediatric/adult oncology. 
Heightened surveillance will be conducted to monitor and identify early signs and symptoms 
(per local practice/standard of care) of T-LBL/T-ALL so that tazemetostat may be discontinued 
in the subject and treatment can be initiated for these malignancies. Epizyme considers the risk 
IRU 7ဩ/%/7-ALL in tazemetostat clinical trials to be largely concentrated in pediatric subjects. 
Two events of T-LBL have occurred in approximately 160 pediatric subjects. Total exposure to 
tazemetostat includes more than 1105 subjects (adults and pediatrics) in clinical trials and over 
2,280 subjects from both clinical and post-marketing sources. 
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If an adult case of T-LBL/T-ALL occurs in this study, enrollment in this study will be 
suspended. Refer also to Section 12.2.1.6.3 below. 
12.2.1.6.2. MDS/AML/MPN 
As of 2022, less than 1% of cases of myeloid malignancies have been reported in an estimated 
cumulative exposure of >2280 patients from both clinical and post-marketing sources. All 
myeloid malignancy events were reported in adult clinical trial subjects. Brief textual summaries 
of each myeloid malignancy are provided in the IB. 
In the event of suspicion of these malignancies or related concerns, please contact the Medical 
Monitor for evaluation and consideration of dose adjustments. Heightened surveillance will be 
conducted to monitor and identify early signs and symptoms (per local practice/standard of care) 
of any case of MDS/AML and other myeloid malignancies like MPN. For any case of 
MDS/AML or other myeloid malignancies like MPN that occurs in the study, tazemetostat 
treatment will be discontinued in the subject. Refer also to Section 12.2.1.6.3 below. 

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12.2.1.6.3. Tazemetostat Safety Committees  
The QSR and the ESC will review all AESI cases per charter, including T-LBL/T-ALL, 
MDS/AML and other myeloid malignancies like MPN (both related and unrelated), and other 
solid tumor malignancies.  
If a case of T-LBL/T-ALL occurs in the study, the subject will be permanently discontinued 
from the study.  Enrollment of new subjects and dosing of subjects on study will be paused while 
the QSR/ESC assesses the case; new enrollment and continued dosing will resume pending a 
decision by the QSR/ESC and communication with health authorities. 
If a case of MDS/AML or other myeloid malignancies like MPN occurs in the study, 
tazemetostat treatment will be discontinued for the subject.  
Recommendations for next steps in the event of an AESI will be communicated, per charter, by 
the Epizyme Chief Medical Officer.  
The ESC is composed of independent oncology medical consultants, one of whom serves as the 
Chair. The ESC meets quarterly to review new data, or it may meet ad hoc. 
The purpose of the ESC is to provide independent review of clinical data for the purposes of 
identifying and evaluating secondary malignancy safety signals from Epizyme sponsored clinical 
trials. The ESC also monitors the data of those study subjects who have experienced the 
tazemetostat AESIs, namely T-LBL/T-ALL, MDS, AML, and other myeloproliferative 
malignancies such as MPN. 
Outcomes from ESC meetings may include, but are not limited to, the identification of new 
AESI and/or potential risk factors, the need for additional non-clinical studies or data analyses, 
proposals for risk mitigation measures and confirmation or revision of the tazemetostat benefit-
risk. The ESC will make recommendations in the event of an AESI safety concern. Epizyme will 
implement recommendations which may include suspension of enrollment, protocol amendment 
and communication to health authorities. 
12.2.1.7. Safety Signal Under Evaluation: B-cell acute lymphoblastic leukemia (B-ALL) 
A 73-year-old female patient experienced an SAE of B-ALL while enrolled in Study EZH-501. 
The patient was diagnosed with Grade 2 follicular lymphoma (FL) in Oct 2016 following an 
initial diagnosis of diffuse large B-cell lymphoma (DLBCL) on 14 Aug 2006.  
The patient was enrolled in the FL EZH2 mutant-type cohort of the phase 2 E7438-G000-101 
study and began treatment with tazemetostat 800 mg twice daily on 04 Jan 2017.  
Prior to enrollment in the E7438-G000-101 study, the patient had received 2 prior systemic 
therapeutic regimens as follows: rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone (22 Sep 2006 to 21 Mar 2007) with the addition of methotrexate and dexamethasone 
04 Oct 2006 to 18 Jan 2007.  Under an investigational protocol (ROMULUS), the subject 
received treatment with MabThera (rituximab) with pinatuzumab vedotin (11 Jun 2013 to 
17 Sep 2013 and 15 Oct 2013 to 17 Dec 2013).   
On the E7438-G000-101 study, the patient received tazemetostat for 26 cycles and achieved an 
objective PR at week 16 that was maintained through week 104.   

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The subject was subsequently enrolled onto the EZH-501 maintenance study and received the 
first dose on 21 Jan 2019. Molecular characterization of the B-ALL clone found in the bone 
marrow biopsy from November 2020 was conducted for comparison to the primary FL tumor 
sample isolated in the October 2016 lymph node biopsy. The molecular analysis of the B-ALL 
and FL clones indicates that they are not related, and that the B-ALL clone is not derived from 
the FL clone through a clonal evolution mechanism. Based upon medical review of the biology, 
nonclinical data, and literature with regard to this sentinel case of B-ALL, Epizyme believes the 
event is unlikely related to tazemetostat exposure. 
There have been no events of B- ALL or B-cell lymphoblastic lymphoma (B-LBL) observed in 
any nonclinical safety studies performed at Epizyme with EZH2 inhibition. Additionally, no 
events of B-ALL or B-LBL occurred in preclinical efficacy studies using mouse models with an 
intact B cell compartment. On the contrary, EZH2 inhibition with tazemetostat in vitro in adult 
and pediatric B-ALL cell lines did not enhance proliferation and in fact caused modest decreases 
in proliferation in a subset of cell lines. 
Based upon medical review of the biology, nonclinical data and literature of this case of B-ALL, 
Epizyme believes the event is unlikely related to tazemetostat exposure.  Refer to the 
tazemetostat IB for case detail. However, Epizyme will continue to monitor patient safety with 
regard to secondary malignancy and all hematological secondary malignancies will be assessed 
by the tazemetostat QSR and ESC (Section 12.2.1.6.3). 
12.2.2. 
Reporting of Special Situations 
Report the special situation(s) of overdose, misuse, abuse, and/or medication error using one of 
the following sets of instructions according to whether the special situation occurred without any 
associated AEs, with an associated non-serious AE, or with an associated SAE: 
Special situation(s) without associated AE(s): 
x Report to Sponsor or designee using a paper Special Situations Form following the 
procedures for reporting SAE (Section 12.2.8).   
Special situation(s) with an associated non-serious AE: 
x Enter the non-serious event on the AE eCRF and mark the SAE field, “no”. The 
eCRF SAE-related fields should not be completed. 
x Report to Sponsor or designee using a paper Special Situations Form following the 
procedures for reporting SAEs (Section 12.2.8).  
Special situation(s) with an associated SAE: 
x Complete the AE eCRF per protocol for the associated SAE term ONLY (Special 
situations are not adverse event terms in and of themselves); complete eCRF SAE 
fields. 
x Report to Sponsor or designee using both a paper Special Situations Form and a paper 
Serious Adverse Event Form following the procedures for reporting SAEs 
(Section 12.2.8). 

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12.2.3. 
Grading and Severity 
The severity of all AEs and SAEs, including appropriate laboratory values, will be graded 
utilizing the CTCAE v5.0. The link to the CTCAE version 5.0 is: 
https://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/ctcae v5 quick refere
nce 5x7.pdf 
In the event that an AE is not covered by the CTCAE, the assessment of severity will be 
determined by using the CTCAE general guideline, as follows: 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated.  
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.a  
Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b  
Grade 4:  Life-threatening consequences; urgent intervention indicated.  
Grade 5:  Death related to AE  
ADL = activities of daily living; AE = adverse event. 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.  
b Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.  
An AE that is assessed as severe should not be confused with an SAE. Severity is a category 
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12.2.4. 
Relationship to Study Drug 
A qualified Investigator must make the determination of relationship to study drugs for each AE 
or SAE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by one or more of the study drugs. 
The following should be considered when assessing the relationship of an AE to study treatment: 
x Temporal relationship of the onset of the event to the first dose of study drugs 
x The course of the event, considering especially the effect of discontinuation of study 
treatment or the reintroduction of study treatment, as applicable 
x Whether the event is known to be associated with the study treatment or with other 
similar treatments 
x The presence of risk factors in the study subject known to increase the occurrence of 
the event 

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x The presence of non-study treatment-related factors that are known to be associated 
with the occurrence of the event. 
Investigators must also systematically assess the causal relationship of AEs to the study drugs 
using the following definitions (the decisive factor being the temporal relationship between the 
AE and administration of the study drug): 
x Probable:  A causal relationship is clinically/biologically highly plausible, there is a 
plausible time sequence between onset of the AE and administration of the study 
drug, and there is a reasonable response on withdrawal. 
x Possible:  A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the study 
drug. 
x Unlikely:  A causal relationship is improbable and another documented cause of the 
AE is most plausible. 
x Unrelated:  A causal relationship can be definitively excluded and another 
documented cause of the AE is most plausible. 
12.2.5. 
Outcome and Follow-Up  
Outcome of an AE/SAE may be classified as resolved, resolved with sequelae, unresolved, or 
fatal. All AEs/SAEs will be followed by the Investigator to resolution (the subject’s health has 
returned to his/her baseline status or all variables have returned to normal), or until an outcome is 
reached, stabilization occurs (the Investigator does not expect any further improvement or 
worsening of the event), or the event is otherwise explained through the study closure and 
database lock.  All SAEs (including all AESIs) will be followed by Epizyme to resolution or 
other outcome is reached, regardless of study closure/database lock. Where appropriate, medical 
tests and examinations will be performed to document resolution of the event(s).  
12.2.6. 
Timeframe for Collecting AEs and SAEs 
AEs: Adverse events will be collected from the time when the subject signs the informed consent 
form until the earlier of either screen failure, 30 days after the discontinuation of study treatment, 
or until the initiation of subsequent anti-cancer therapy. 
SAEs/AESI: SAEs/AESIs, regardless of seriousness, will be collected over the same time period 
as stated above for AEs. In addition, any SAE assessed as related to study participation (eg, 
protocol-mandated procedures, invasive tests, or change in existing therapy) must be recorded 
from the time a subject provides consent to participate in the study up to and including any 
follow-up contact. All SAEs will be reported to the sponsor within 24 hours. 
Beyond the 30-day follow-up or until the initiation of subsequent anti-cancer therapy, the 
Investigator will report any new SAE that they consider to be possibly related to study treatment. 
Note that any incidence of a primary secondary malignancy, even if occurring more than 30 days 
after the last dose of study drug, will be reported to the Sponsor as an SAE. 

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12.2.7. 
Recording Adverse Events and Pregnancy 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. Clinically significant changes, per Investigator assessment, in laboratory 
values, blood pressure, and pulse should be recorded as AEs.  
The AE term should be reported in standard medical terminology when possible. For each AE, 
the investigator will evaluate and report the onset (date and time), resolution (date and time), 
intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused 
the subject to discontinue the study. 
Should a pregnancy occur in the partner of a subject after starting treatment with tazemetostat, it 
must be recorded on the study pregnancy form and reported to Epizyme using the SAE reporting 
timeframes and contact information on the form. Pregnancy in itself is not regarded as an AE. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented, even if the subject was 
discontinued from the study. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
12.2.8. 
Reporting of SAEs and AESIs 
All SAEs and all potential and identified AESIs (regardless of seriousness or relationship to 
study drug) will be reported within 24 hours of the investigator becoming aware of the event 
using the contact information printed on the SAE form. The investigator must promptly notify 
the sponsor or its designee of all SAEs in order that the legal obligations and ethical 
responsibilities of the sponsor or its designee are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of the IMP under clinical investigation. The sponsor and its 
designee will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/EC/CEC, and investigators. 
An investigator who receives an investigator safety report describing a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR) or other specific safety information from the sponsor will 
file it with the IB and will notify the IRB/EC/CEC, if appropriate according to local 
requirements. 
12.3. 
Safety Review Committee (SRC) 
During the phase 1b (complete) part of the study, an SRC composed of investigators, medical 
monitors, and Epizyme study members  reviewed safety data, available PK data, treatment 
delays, study agent dosing records, treatment reductions, and treatment discontinuations from 
each cohort. The SRC assessed DLTs and endorsed acceptable doses of tazemetostat to be 
considered as the RP2D for the combination with enzalutamide.  Its membership, and procedures 
are outlined in an SRC charter.  

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The SRC reviewed safety data from cycle 1 (days 1 through 28) from each dose escalation 
cohort. The SRC reviewed the following safety data: 
x AEs/SAEs, including DLTs and any actions taken with the study treatment (eg, dose 
reduction, dose interruption, dose withdrawal) 
x Clinical laboratory values 
x ECGs 
x Vital signs 
x Concomitant medications 
Based on the review of data, the Epizyme SRC could have recommended that the study continue 
as planned or may alternatively recommend that the study be placed on hold or terminated. A 
recommendation of study hold, study treatment dose de-escalation, or study termination would 
be made in the event of the discovery of an unexpected, serious, or unacceptable risk to the 
subjects in the study and implemented via QSR and/or ESC review (Section 12.2.1.6.3). 
The Epizyme Medical Monitor along with the Principal Investigator will also review safety data 
on an ongoing basis during the dose expansion (phase 2) part of the study. 
12.4. 
Quarterly Safety Review (QSR) Committee 
The QSR is composed of internal Epizyme subject matter experts. It is a cross-functional 
workgroup whose mission is to provide internal review of aggregate safety data from Epizyme 
global clinical and safety databases. The core committee is composed of the Epizyme Chief 
Medical Officer (CMO), Medical Monitor(s), Head of Nonclinical Safety, Vice President (VP) 
Pharmacovigilance, VP Clinical Operations, and VP Regulatory Affairs. 

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13. 
STATISTICS 
The statistical analysis plan will be developed and finalized before database lock.  
13.1. 
Analysis Sets 
13.1.1. 
Phase 1b Analysis Sets 
Enrolled Population: The enrolled population consists of all subjects in the phase 1b part who 
signed the inform consent form and were not screen failures. The enrolled population will be 
used in summaries of disposition of subjects, protocol deviations, demographics and other 
baseline characteristics, as well as efficacy analyses. 
Safety Population: The Safety population is defined as all subjects who received 1 dose or 
partial dose of any of the study drugs. The safety population will be used for all safety analysis. 
Subjects will be analyzed according to the assigned dose level for the respective dose escalation 
cohort. 
Dose-Limiting Toxicity (DLT) Population (Phase 1b only): The DLT Population set will 
consist of dose escalation cohort subjects in the Safety Population who received at least 80% of 
planned study drug during cycle 1. Subjects will be analyzed according to the assigned dose level 
for the respective dose escalation cohort. 
Pharmacokinetic (PK) Population: The PK population will include all subjects in the Safety 
population who have  post-dose sample collected to allow estimation of the PK parameters. 
The PK population will be used for population-based analysis. 
13.1.2. 
Phase 2 Analysis Sets 
Intent-to-treat (ITT) Population: The ITT population is defined as all subjects who are 
randomized into the trial. The ITT population will be used for summaries of disposition of 
subjects, protocol deviations, demographics and other baseline characteristics as well as efficacy 
analysis. Subjects will be analyzed according to the treatment arm to which they are randomized.  
Safety Population: The safety population is defined as all subjects in the ITT population who 
have received at least one dose or partial dose of study medication. The safety population will be 
used for all safety analysis. Subjects will be analyzed according to the treatment which they 
actually received. 
Pharmacokinetic (PK) Population: The PK population will include all subjects in the ITT 
SRSXODWLRQ ZKR KDYH  SRVW-dose sample collected to allow estimation of the PK parameters. 
The PK population will be used for population-based analysis. 
FACT-P Population: The FACT-P population will include all subjects in the ITT population 
who complete an evaluable FACT-3 TXHVWLRQQDLUH DW EDVHOLQH DQG  SRVW-baseline visit. An 
evaluable questionnaLUH ZLOO KDYH VXIILFLHQW LWHPV FRPSOHWHG WR DOORZ FDOFXODWLRQ RI  )$&7-P 
subscale. 
13.2. 
Sample Size Justification 
For the Phase 2 randomized component of the study: The sample size calculation was 
performed based on the primary endpoint of rPFS. To compare the combination of tazemetostat 

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with enzalutamide to enzalutamide alone, 
 rPFS events from a total of 74 total subjects (37 per 
arm) will provide approximately 
 power for the analysis of rPFS, with a 2-sided total type I 
error of 0.05 to reject the null hypothesis that there is no difference in rPFS between the two 
arms. To account for the approximate 
 dropout, the sample size will increase to 80 (40 per 
arm).  
The sample size assumes that the combination of tazemetostat with enzalutamide will prolong 
rPFS by 
 (hazard ratio [HR] = 
) from
months for enzalutamide to 
 months, with 
 of subjects lost to follow-up over a 
-month enrollment period, a 9-month follow-up 
period (a total follow-up time of 18 months, tmax = 18), and a total phase 2 study duration of 
approximately 
 months. (The critical boundary to achieve statistical significance for the final 
rPFS logrank testing between two arms  is HR=
 or 
 months of improvement in rPFS.) 
13.3. 
Analyses 
13.3.1. 
Disposition, Demographics, Baseline Characteristics, and Prior Cancer 
Treatments 
Subject disposition, including reasons for treatment and study withdrawal, will be summarized 
descriptively for each population described in Section 13.1 and provided in a listing.  
Demographics and other baseline characteristics, including medical history, cancer-related 
history, prior cancer treatments, and performance status, will be listed and summarized 
descriptively. 
Medical history and prior surgical terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary in use at the time of the analysis and 
presented by system organ class (SOC) and preferred term (PT). Surgical history will be 
summarized by the MedDRA high-level group term (HLGT) and PT. 
Reported terms for prior cancer treatments will be coded using the World Health Organization 
(WHO) Drug Dictionary in effect at the of the analysis and will be listed for each subject, and 
the numbers of subjects who received each treatment will summarized according to generic 
name. 
13.3.2. 
Efficacy Analyses  
All efficacy analysis will be performed by dose level using the enrolled population for the 
phase 1b part and by treatment using the ITT population for the phase 2 part. 
13.3.2.1. Primary Efficacy Endpoint Analysis 
x Radiographic progression-free survival (phase 2 randomized treatment groups): The 
rPFS of tazemetostat in combination with enzalutamide will be compared to the rPFS of 
enzalutamide alone. rPFS is defined as the time from the date of randomization to the 
date of the first objective evidence of radiographic progression or death from any cause, 
whichever occurs first. In cases where PD or death has not occurred, censoring rules will 
be applied as provided in the SAP. Radiographic disease progression is defined by the 
criteria in Table 10 and Figure 2. The primary analysis of rPFS for tazemetostat in 
combination with enzalutamide compared with enzalutamide treatment alone will be 
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based upon at least the first 
 rPFS events observed. A log-rank test will be used to 
compare tazemetostat in combination with enzalutamide to enzalutamide treatment alone 
at the significance level of 0.05 (one-sided). Conventionally, HRs with corresponding 
2-sided 95% CI will be estimated using the Cox proportional hazards model. Graphical 
methods will be used to assess the Cox proportional hazards model assumptions. rPFS 
will also be summarized descriptively using the Kaplan-Meier (KM) method. The KM 
estimate along with the corresponding 95% CI will be calculated using the Brookmeyer 
and Crowley method and will be provided for the median. The event-free rate with 
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provided at 4 months, 8 months, 12 months, and 18 months. Median follow-up for rPFS 
will be estimated according to the KM estimate of potential follow-up (Schemper, 1996).  
KM curves will also be provided. 
In the phase 2 portion of the study, comparisons between treatment groups for the 
secondary endpoints will occur only if the primary endpoint (rPFS) achieves statistical 
significance at an alpha level of 0.05.  
13.3.2.2. Analysis of Secondary Efficacy Endpoints 
Secondary efficacy endpoint analyses will include.   
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weeks later required to confirm the PSA response. If a consecutive value meets the 
response criteria but is obtained within 3 weeks and the next assessment also meets 
response criteria and is taken after 3 weeks, then the initial response is considered as 
confirmed response as well. However, a subject with a missing confirmation PSA value 
after 3 weeks is considered as non-responder. PSA50 will be calculated by treatment 
group for subjects with PSA values at the baseline assessment (cycle 1 day 1 predose) 
and at least 1 post baseline assessment. A Cochran-Mantel-Haenszel mean score test will 
be used to compare the response rates between tazemetostat in combination with 
enzalutamide and enzalutamide treatment alone. 
x ORR and Best Overall Soft Tissue Response: ORR is defined per RECIST 1.1 
guidelines. The best overall soft tissue response as assessed by Investigators using 
RECIST 1.1 will be summarized. Only subjects with measurable soft tissue disease at 
screening (ie, at least 1 target lesion per RECIST 1.1; see Appendix 5) will be included in 
this analysis. The Clopper-Pearson exact method will be used to compare the proportion 
of subjects with an objective response (complete response or partial response) per 
RECIST 1.1 between tazemetostat in combination with enzalutamide and enzalutamide 
treatment alone. 
x Disease Control Rate (no radiographic progression per PCWG3, and no unequivocal 
clinical progression or death) at 6 months on study therapy. A Cochran-Mantel-Haenszel 
test will be used to compare DCR between tazemetostat in combination with 
enzalutamide and enzalutamide treatment alone, and the corresponding p-value will be 
CCI

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provided. Also, the 95% CI will be provided for each treatment group and for the 
difference in proportion between the two treatment groups, using Clopper-Pearson exact 
method and Newcombe method, respectively. 
x Time to First SRE: Time to first SRE is defined as the time from randomization to the 
date of first SRE. In cases where a SRE has not occurred at the time of the analysis, the 
subject will be right-censored. Censoring rules will be provided in the SAP. An SRE is 
defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord 
compression, or change of antineoplastic therapy to treat bone pain. A log-rank test will 
be used to compare time to first SREs between tazemetostat in combination with 
enzalutamide and enzalutamide treatment alone. 
x Time to Initiation of the Next Systemic Treatment for Prostate Cancer (TTNT): 
TTNT is defined as the time from the date of randomization to date of first documented 
administration of the next systemic treatment for prostate cancer. The TTNT will be right-
censored at the last study assessment date if the subject did not receive a subsequent 
treatment. A log-rank test will be used to compare time to initiation of subsequent 
treatment between tazemetostat in combination with enzalutamide and enzalutamide 
alone.  
x Time to PSA Progression: Time to PSA progression (TTPP) is defined as the duration 
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value for subjects who did not have a decline in PSA value by week 17). This increase 
must be confirmed by a second consecutive assessment conducted at least 3 weeks later. 
7KH GDWH RI FRQILUPHG 36$ SURJUHVVLRQ LV WKH GDWH RI WKH LQLWLDO  increase. Subjects 
without confirmed PSA progression at the time of analysis will be right-censored. 
Censoring rules will be provided in the SAP. Time from randomization to first 
observation of PSA progression will be assessed. A log-rank test will be used to compare 
TTPP between tazemetostat in combination with enzalutamide and enzalutamide 
treatment alone. 
x CTCs: In subjects who enter the study with a detectable number of CTCs, the rate of 
CTC reduction to zero is the proportion of subjects who convert to an undetectable 
number of CTCs. &7& UHVSRQVH LV GHILQHG DV D  UHGXFtion in CTCs from baseline in 
subjects who enter the study with a detectable number of CTCs, and the CTC response 
rate LV WKH SURSRUWLRQ RI VXEMHFWV ZLWK D  UHGXFWLRQ LQ &7&V IURP EDVHOLQH F\FOH 
day 1 pre-dose). The rate of CTC reduction to zero and CTC response rate for 
tazemetostat in combination with enzalutamide will be compared with those for 
enzalutamide treatment alone using the Clopper-Pearson exact method. 
Refer also to secondary QoL endpoint analysis described in Section 13.3.5. 
13.3.2.3. Subgroup Analysis 
Subgroup analysis will be performed for rPFS by AR-V7 and NEPC (negative and positive) 
status. A swim lane plot (time on treatment) showing AR-V7 and NEPC status will be provide 
for each endpoint. 

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13.3.3. 
Pharmacokinetic and Population Pharmacokinetic Analysis 
In-order to assess the effect of tazemetostat on abiraterone/prednisone and enzalutamide PK and, 
vice-versa, the effect of enzalutamide and abiraterone/prednisone treatment alone on 
tazemetostat PK, the following PK parameters were assessed during the dose-escalation portion 
of the study (phase 1b) on Days 1, 2, and 21 in cycle 1: 
x AUC0-last: area under the plasma concentration-time curve from time 0 to the time of 
the last quantifiable concentration. 
x AUC0-24: area under the plasma concentration-time curve from time 0 to the time of 
24 hours. 
x Cmax: maximum plasma concentration.  
Plasma concentrations will be summarized using descriptive statistics (n, mean, SD, coefficient 
of variation [CV%], standard error [SE] of the mean, median, maximum, and minimum) at each 
scheduled evaluation time point. The mean PK concentrations will be plotted over time since last 
dose and time since first dose.  
Population PK analyses will also be performed. Population PK modeling will be conducted 
combining data from the phase 1b and phase 2 portions of the study to quantitatively describe the 
PK profile of tazemetostat, explore the PK variability, and identify any covariate effects.  
In addition, exposure relationship for efficacy and safety endpoints will be investigated based on 
phase 2 data where appropriate. The objective of exposure-response analysis is to characterize 
the relationships between exposure and efficacy, and exposure and safety. 
x Key efficacy variables include (but are not limited to) the following: 
 Radiographic rPFS 
 Additional efficacy endpoints as appropriate (eg, PSA50, TTPP, DCR, ORR) 
x Key safety variables include (but are not limited to) the following: 
 AE of interest identified based on the data 
Key exposure variables will be based on measured or population PK model predicted 
concentrations and will include peak concentration (Cmax), steady-state concentration at the end 
of a dosing interval (Cmin), and AUC at steady-state for tazemetostat. Effect of clinically relevant 
covariates will be evaluated. 
Exploratory PK analysis is discussed below in Section 13.3.4. 
13.3.4. 
Exploratory Analyses and Endpoints 
As data warrant, exploratory analysis may be performed on each exploratory endpoint listed 
below. 
In addition, exploratory analyses may be performed to examine the relationship between 
exposure to tazemetostat and clinical and safety endpoints (including tumor size or change in 
tumor size from baseline). Also, through aggregate analysis of tumor biomarker data, exploration 
of whether a subset of subjects might benefit from tazemetostat with enzalutamide will be 
performed. 

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Additional details of the analysis of exploratory endpoints will be described in a separate 
PK/pharmacodynamic/biomarker SAP, and the results of these analyses may be reported 
separately from the CSR. Refer also to Section 11.5.3 for future use of tissue samples. 
Exploratory endpoints include: 
x PSA90: Defined and analyzed similarly to PSA50. 
x Changes in ctDNA burden (defined as the proportion of ctDNA in the entire population 
of cell-free DNA [cfDNA]) from longitudinal samples taken throughout the period of 
drug treatment as compared to baseline.  
x Characterization of tazemetostat combination exposure (possible example: Cmin). 
x Pharmacodynamic modulation of EZH2 activity by tazemetostat as assessed by 
measuring H3K27me3 levels in paired pre- and on-treatment tumor biopsies that may be 
obtained from the phase 1b and phase 2 portions of the study. Analyses will include 
change from screening to on-study values plotted at cycle 2 day 1 and at progression 
using a waterfall plot. 
x The mutational landscape of pre-treatment tumor biopsies and baseline ctDNA, such 
as for loss of PTEN, TP53, and RB1, will be determined using bioinformatic analysis of 
whole exome next generation sequencing (NGS) and compared when possible to the 
mutational landscape in biopsies taken on-treatment and at disease progression.  In 
addition, whole transcriptome data will be obtained from tumor biopsies using RNASeq, 
and bioinformatics analysis of NEPC and AR signaling pathways, including AR variant 
AR-V7 gene expression, and other pathways involved in prostate cancer biology will be 
performed in matched biopsies.  Finally, the state of the immune microenvironment in 
pre-treatment, on treatment (at cycle 2 day 1), and at disease progression (only in 
responders) tumor biopsies in subjects receiving tazemetostat in combination with 
enzalutamide will be evaluated by investigating the occurrence of various gene 
expression signatures of tumor inflammation and infiltrating lymphocytes available from 
public sources. 
x Circulating tumor DNA (ctDNA) obtained from liquid biopsies taken minimally at 
baseline prior to the first dose and on the same days as CT/MRI scans to ascertain first 
sign of response and disease progression based on ctDNA burden will also undergo 
targeted whole exome sequencing (WES) to determine the mutational status of genes, 
such as PTEN, TP53, and RB1, associated with clinical outcome.   
x Concordance of genetic characteristics of disease in tumor biopsies and ctDNA 
isolated from baseline liquid biopsies will be evaluated using regression analysis 
methods.   
x Assessment of immunological endpoints in tumor biopsies taken at pre-treatment, 
on-treatment (at cycle 2 day 1), and at disease progression (only in responders) in the 
phase 2 portion of the study will be conducted to determine the level of infiltration of 
various T-cell lymphocyte and other immune cell populations (cell type number and 
activation status) using multiplex IF staining and DNA sequence analysis.  Differences in 
the composition of the immune microenvironment between responders and non-
responders in each treatment cohort will be determined and compared to published tumor 

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immune profiles associated with response or resistance to immunotherapy, such as 
checkpoint inhibitor blockade or enzalutamide therapy. In addition, circulating immune 
cell sub-populations isolated from PBMCs from blood taken pre-treatment, on-treatment 
(cycle 2 day 1), and at disease progression (only in responders) in the phase 2 portion of 
the study will be investigated to determine the impact of drug treatment on immune cell 
numbers, antigen presentation, and activation status.  
Refer also to Section 13.3.5  for information about analysis of exploratory QoL endpoints. 
13.3.5. 
Health-Related Quality of Life Assessment Endpoints and Analysis 
The following are key health-related QoL endpoints for each instrument; other endpoints from 
these instruments may also be assessed.  The algorithms for scoring patient reported outcomes 
(PROs) and plans for the corresponding analyses will be provided in a PRO SAP.  
BPI-SF (phase 1 and phase 2 exploratory objectives): 
In phase 1, the rate of pain progression, defined as the proportion of subjects with an 
LQFUHDVH RI  IURP WKH WLPH RI VFUHHQLQJ LQ WKH DYHUDJH RI %3, SDLQ LQWHQVLW\ LWHP VFRUHV
(items 3, 4, 5, and 6) at 6 months will be used to assess tazemetostat in combination with 
enzalutamide and tazemetostat in combination with abiraterone/prednisone. The BPI scores 
will be summarized descriptively at time of screening, at 3 months, and at 6 months. 
In phase 2, the rate of pain progression, defined as the proportion of subjects with an 
LQFUHDVH RI  IURP EDVHOLQH LQ WKH DYHUDJH RI %3, SDLQ LQWHQVLW\ LWHP VFRUHV LWHPV  
5, and 6) at each post-baseline time point will be used to compare tazemetostat in 
combination with enzalutamide to enzalutamide treatment alone. The BPI scores will be 
summarized descriptively at baseline and each postbaseline time point. 
The BPI mean severity score will be analyzed using mixed-effects model for repeated 
measures (MMRM) and mixed-effects models with baseline score and treatment group as 
covariates, and the differences in mean scores between treatment groups will be presented 
with corresponding 95% CIs at each time point and overall. Changes from baseline will also 
be presented.  The mean change from baseline will be summarized and plotted by treatment 
group. Continuous endpoints will be analyzed similarly as for BPI pain intensity score. 
FACT-P (phase 2 secondary and exploratory objectives): 
For the secondary objective, the percentage of subjects with a decline from baseline in the 
):% VXEVFDOH VFRUH E\  SRLQWV DQG WKH SHUFHQWDJH RI VXEMHFWV ZLWK D GHFOLQH IURP
baseline LQ WKH 3URVWDWH &DQFHU 6XEVFDOH 3&6 VFRUH E\  SRLQWV DW DQ\ SRVWEDVHOLQH YLVLW
will be compared between the treatment groups. 
For the secondary objective, the TDD is a decline from baseline in FACT-P FWB subscale 
VFRUH RI  SRLQWV DQG WKH WLPH IURP baseline to decline in FACT-P PCS subscale score of 
 SRLQWV ZLOO EH FRPSDUHG EHWZHHQ WKH WUHDWPHQW JURXSV 
For exploratory objectives, scores will be summarized descriptively over the course of the 
study by treatment group, with emphasis on the following FACT-P domains: Emotional, 
Social, and Physical Well-being. 

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The analyses will be conducted on the intent to-treat FACT-P population, defined as all 
randomized subjects who have completed an evaluable FACT-P questionnaire at baseline 
DQG  SRVW-baseline visit. An evaluable questionnaire will have sufficient items completed 
WR DOORZ FDOFXODWLRQ RI  )$&7-P subscale. 
In general, to estimate longitudinal changes in FACT-P scores from baseline, the primary 
analysis will be carried out using an MMRM. MMRM analysis uses all available data and 
assumes that any missing observations are missing at random. The differences in mean scores 
between treatment groups will be presented with the corresponding 95% CI at each time 
point and overall. To address the possibility that missing data may not be at random, a second 
analysis will be carried out using a pattern-mixture model (PMM) with placebo-based pattern 
imputation. In both models, the baseline covariates may include: treatment group; time; 
baseline ECOG score (0–1 or 2); average baseline domain score. Due to the exploratory 
nature of the analyses, adjustments for multiple comparisons will not be made.  
The cumulative distribution function will be presented as a continuous plot of the numerical 
change in FACT-P scores from baseline on the horizontal axis, with the cumulative 
percentage of patients experiencing up to that change on the vertical axis. One curve for each 
treatment group will be plotted for each visit. 
EQ-5D-5L (phase 2 exploratory objective): 
For the exploratory objective, scores will be summarized descriptively over the course of 
the study by treatment group, with emphasis on changes from baseline in EQ-5D-5L VAS 
and HUI scores over the course of the study. The analysis method is similar to those for 
FACT-P. 
13.3.6. 
Safety Analyses 
13.3.6.1. General Considerations 
Safety analyses will be based on all subjects who receive 1 dose or partial dose of any of the 
study drugs (ie, the Safety population). Safety data from the phase 1b and phase 2 portions of the 
study will be presented separately. In general, safety data from the phase 1b portion of the study 
will be tabulated by assigned dose levels and overall, and the data from the phase 2 portion of the 
study will be tabulated by assigned treatment group and overall. For all analyses, subjects who 
receive a dose modification will be retained and analyzed in the treatment group originally 
assigned.  
13.3.6.2. Study Drug Exposure and Compliance 
Study drug exposure and compliance (including for example, duration, cycles, total amount, dose 
intensity, dose modifications, and percentage of assigned study drug taken) for each of the study 
drugs will be listed and summarized using descriptive statistics. Exposure will be summarized 
separately by treatment group and overall. 
13.3.6.3. Adverse Events and Deaths 
Summary tables will be provided for all reported TEAEs, defined as AEs that started or 
worsened in severity on or after the date of the first dose of study drug (study day 1) through 

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30 days after the end of treatment. Handling of missing or partially missing start and end dates 
for AEs and SAEs will be provided in the SAP. For cases in which it is not possible to ascertain 
treatment emergence, the event will be classified as treatment emergent. 
Severity of all AEs is to be evaluated by the Investigator based on the CTCAE version 5.0 and 
will be coded to preferred term, higher level term, and system organ class using the Medical 
Dictionary for Regulatory Activities (MedDRA) version in effect at the time of the analysis. . 
Laboratory values also will be classified by toxicity grade based on the CTCAE version 5.0.  
Tabular summaries of the number and percentage of subjects with adverse events will be 
presented by MedDRA system organ class and preferred term by relationship to study treatment 
and by severity as listed below. If a subject experiences repeat episodes of the same AE (as 
defined by the MedDRA system organ class and preferred term), then the event with the highest 
reported severity grade and the strongest causal relationship to study drug will be used for 
purposes of incidence tabulations. 
x All TEAEs 
x 7($(V ZLWK  LQFLGHQFH RYHUDOO EDVHG RQ SUHIHUUHG WHUP 
x TEAEs of Grade 3 or 4 
x Treatment-related TEAEs 
x Treatment-related TEAEs of Grade 3 or 4 
x TEAEs leading to dose interruption 
x TEAEs leading to dose reduction 
x TEAEs leading to discontinuation of study drug 
x Treatment-emergent SAEs 
x Treatment-related treatment-emergent SAEs 
x TEAEs of special interest 
Separate listings of all AEs, SAEs, TEAEs leading to discontinuation of study drug, and TEAEs 
leading to dose modifications (interruption and dose reduction) will be provided. A listing of the 
AESIs described in this protocol will also be provided. 
Deaths will be summarized and listed as follows: 
x Summary and listing of subjects who died during and up to 30 days after last dose of 
study drug. 
x Summary and listing of subjects who died during and up to 30 days after last dose of 
study drug with treatment-related TEAEs. 
x Summary and listing of subjects who died after 30 days after the last dose of study 
drug with treatment-related AEs. 
The summaries and listing of deaths will include the categorical reason for death. 

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13.3.6.4. Clinical Laboratory Values 
All clinical laboratory values will be standardized according to the International System of Units 
prior to summarization. Laboratory values also will be classified by toxicity grade based on the 
CTCAE version 5.0.  
Separate listings and summary tables will be produced for the laboratory test groups (eg, 
hematology, coagulation, chemistry, urinalysis). Laboratory values outside the normal ranges 
will be flagged as “L” (Low) or “H” (High) in the data listing. Laboratory shift tables of the 
changes from baseline values to the worst post-baseline values based on CTCAE toxicity grades 
will be produced for each parameter. 
13.3.6.5. Other Safety Measures 
Vital sign values will be listed and summarized descriptively.  In addition, descriptive summaries 
based on the predefined markedly abnormal criteria shown below will be produced. 
Vital Sign 
Markedly Abnormal Criteria 
Heart rate (bpm) 
<60 bpm 
>100 bpm 
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Systolic blood pressure (mmHg) 
120-139 mmHg, inclusive (CTCAE grade 1) 
140–159 mm Hg, inclusive (CTCAE grade 2) 
 PP+J &7&$( *UDGH  
Diastolic blood pressure (mmHg) 
80–89 mmHg, inclusive (CTCAE grade 1) 
90–99 mm Hg, inclusive (CTCAE grade 2) 
 PP+J &7&$( JUDGH  
 
Electrocardiogram data will be listed.  Categorical analyses of absolute QTcF values and changes 
from baseline in QTcF values by the predefined threshold levels shown below will be produced. 
QTcF Value 
Threshold Levels 
Absolute value 
>450 msec 
>480 msec 
>500 msec 
Increases from baseline 
>30 msec 
>60 msec 
 
Physical examination results will be listed by subject. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Epizyme will 
visit the investigational study site to: 
x Determine the adequacy of the facilities 
x Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Epizyme or its representatives. This will 
be documented in a Clinical Study Agreement between Epizyme and the investigator. 
During the study, a monitor from Epizyme or representative will have regular contacts with the 
investigational site, for the following: 
x Provide information and support to the investigator(s) 
x Confirm that facilities remain acceptable 
x Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
x Perform source data verification. This includes a comparison of the data in the case report 
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relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts). 
x Record and report any protocol deviations not previously sent to Epizyme. 
x Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Epizyme and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of Epizyme, a regulatory authority, an IEC or an IRB may visit the 
site to perform audits or inspections, including source data verification. The purpose of an 
Epizyme audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, ICH Good Clinical 
Practice guidelines , and any applicable regulatory requirements. The investigator should contact 
Epizyme immediately if contacted by a regulatory agency about an inspection. 
 

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14.3. 
Institutional Review Boards/Independent Ethics Committees 
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study including the subject consent 
form and recruitment materials must be maintained by the Investigator and made available for 
inspection. 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Epizyme may conduct a quality assurance audit. Please see Section 14.2 for more details 
regarding the audit process. 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. The 
investigator must submit written approval to Epizyme before he or she can enroll any subject 
into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Epizyme will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements, and Epizyme
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16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
7KH VXEMHFW
V VLJQHG DQG GDWHG LQIRUPHG FRQVHQW PXst be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy 
of the signed Informed Consent Form must be given to the subject. 
No protocol-specific procedures, including screening procedures are to be performed until the 
subject has signed and dated an IRB/IEC-approved ICF. 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Epizyme will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, eg, eCRFs and hospital records), all original signed ICFs, eCRFs, SAE forms, 
source documents, detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, telephone calls reports). The records must 
be retained by the Investigator according to the ICH, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the Sponsor must be prospectively notified. The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor. The Investigator must obtain the Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 

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18. 
PUBLICATION POLICY 
A summary of the study results will be made publicly available within 12 months of reaching the 
end of the study, defined as the date of the last subject’s last visit (LSLV).  
If a manuscript is published in a peer-reviewed journal, then that initial release may be an 
abstract that meets the requirements of the International Committee of Medical Journal Editors. 
All manuscripts, abstracts, or other modes of presentation arising from the results of the study 
must be reviewed and approved in writing by Epizyme, Inc. in advance of submission. The 
UHYLHZ LV DLPHG DW SURWHFWLQJ WKH 6SRQVRU
V SURSULHWDU\ LQIRUPDWLon existing either at the date of 
the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information, generated or created in relation to the study shall be set out in the agreement 
between each Investigator and the Sponsor. 

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19. 
LIST OF REFERENCES 
Abida W, Armenia J, Gopalan A, et al. Prospective Genomic Profiling of Prostate Cancer Across 
Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision 
Making. JCO Precis Oncol. 2017;2017. 
Alimova I, Birks DK, Harris PS, et al. Inhibition of EZH2 suppresses self-renewal and induces 
radiation sensitivity in atypical rhabdoid teratoid tumor cells. Neuro Oncol. 2013;15(2):149-160. 
Antonarakis ES. Predicting treatment response in castration-resistant prostate cancer: could 
androgen receptor variant-7 hold the key? Expert review of anticancer therapy. 2015;15(2):143-
145. 
Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in 
prostate cancer. N Engl J Med. 2014;371(11):1028-1038. 
Armenia J, Wankowicz SAM, Liu D, et al. The long tail of oncogenic drivers in prostate cancer. 
Nat Genet. 2018;50(5):645-651. 
Attard G, Borre M, Gurney H, et al. Abiraterone Alone or in Combination With Enzalutamide in 
Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During 
Enzalutamide Treatment. J Clin Oncol. 2018;36(25):2639-2646. 
Azad AA, Volik SV, Wyatt AW, et al. Androgen Receptor Gene Aberrations in Circulating Cell-
Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer. Clin 
Cancer Res. 2015;21(10):2315-2324. 
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