Clinical trial NCT02799745
Conditions: Prostate Cancer
Keywords: Therapeutic Cancer Progression Pathological Cancer Progression Enzalutamide Prostate Cancer Active surveillance
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2016-06-09; Completion date: 2020-08-28
Enrollment: 227 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study was to compare the time to prostate cancer progression (pathological or therapeutic progression) between patients treated with enzalutamide versus patients undergoing active surveillance.

Detailed description:
This was a multicenter, randomized, open label exploratory study, conducted in the US and Canada, evaluating the efficacy and safety of enzalutamide for extension of time to prostate cancer progression (pathological or therapeutic) in patients with clinically localized, histologically proven prostate cancer that is categorized as low risk or intermediate risk and who were under AS.

Arms: arm 1: Participants received 160-milligrams (mg) enzalutamide administered as four 40-mg capsules, orally once daily for 1 year of treatment period. Following the 1-year treatment period, all participants were followed for 1 additional year. Post the 1-year follow-up period, participants then started the continued follow-up period, in which, participants were followed up every 3 months for these 2 years, after which follow-up was either every 6 months up to 36 months or until the end of study (total duration of follow up in the study was approximately up to 35.9 months). arm 2: Participants did not receive any study treatment in this arm but were on continued active surveillance (AS) for 1 year of treatment period. Following the 1-year treatment period, all participants were followed for 1 additional year. Post the 1-year follow up, participants then started the continued follow-up period, in which, participants were followed up every 3 months for these 2 years, after which follow-up was either every 6 months up to 36 months or until the end of study (total duration of follow up in the study was approximately up to 35.9 months).
Interventions: intervention 1: Enzalutamide intervention 2: Active Surveillance
Intervention descriptions: intervention 1: Oral intervention 2: None

Protocol documents:
Prot_000.pdf: 


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Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························· 9
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················10
IV.
SYNOPSIS··························································································14
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································21
1
INTRODUCTION·················································································24
1.1
Background ····················································································24
1.2
Non-clinical and Clinical Data ······························································25
1.3
Summary of Key Safety Information for Study Drugs ···································29
1.4
Risk-Benefit Assessment·····································································30
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································31
2.1
Study Objectives ··············································································31
2.2
Study Design and Dose Rationale···························································31
2.2.1
Study Design·············································································31
2.2.2
Dose Rationale···········································································33
2.3
Endpoints·······················································································33
2.3.1
Primary Endpoints·······································································33
2.3.2
Secondary Endpoints····································································33
2.3.3
Exploratory Endpoints··································································33
3
STUDY POPULATION··········································································34
3.1
Selection of Study Population ·······························································34
3.2
Inclusion Criteria··············································································34
3.3
Exclusion Criteria·············································································35
4
TREATMENT(S)··················································································36
4.1
Identification of Investigational Product(s) ················································36
4.1.1
Test Drug(s)··············································································36
4.2
Comparative Drug(s) ·········································································36
4.3
Packaging and Labeling······································································36
4.4
Study Drug Handling ·········································································36
4.5
Blinding ························································································37
4.6
Assignment and Allocation ··································································37


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5
TREATMENTS AND EVALUATION························································38
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················38
5.1.1
Dose/Dose Regimen and Administration Period ····································38
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································38
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································38
5.1.4
Treatment Compliance··································································39
5.1.5
Criteria for Continuation of Treatment ···············································40
5.1.6
Restrictions During the Study··························································40
5.2
Demographics and Baseline Characteristics ···············································40
5.2.1
Demographics············································································40
5.2.2
Medical History··········································································40
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············40
5.3
Efficacy Assessment··········································································40
5.3.1
Histopathology···········································································40
5.3.2
Therapeutic progression ································································41
5.3.3
Prostate-Specific Antigen (PSA) ······················································42
5.3.4
Brief Fatigue Inventory (BFI)··························································42
5.3.5
Expanded Prostate Cancer Index Composite (EPIC) ·······························42
5.3.6
Memorial Anxiety Scale for Prostate Cancer (MAX-PC) ··························42
5.3.7
Medical Outcomes Study 12-Item Short Form Survey (SF-12) ···················43
5.4
Safety Assessment ············································································43
5.4.1
Vital Signs················································································43
5.4.2
Adverse Events ··········································································43
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································43
5.4.3
Laboratory Assessments································································44
5.4.4
Physical Examination···································································45
5.4.5
Electrocardiogram (ECG) ······························································45
5.4.6
Imaging ···················································································45
5.5
Adverse Events and Other Safety Aspects ·················································46
5.5.1
Definition of Adverse Events (AEs) ··················································46
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································46
5.5.3
Criteria for Causal Relationship to the Study Drug ·································47
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························47
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································48


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5.5.6
Follow-up of Adverse Events··························································49
5.5.7
Monitoring of Common Serious Adverse Events ···································49
5.5.8
Procedure in Case of Pregnancy·······················································49
5.5.9
Emergency Procedures and Management of Overdose ·····························50
5.5.10
Supply of New Information Affecting the Conduct of the Study··················50
5.6
Test Drug Concentration ·····································································50
5.7
Other Measurements, Assessments or Methods ···········································50
5.7.1
Sample for the Analysis of Genes Related to Efficacy ·····························50
5.7.2
···········································51
5.7.3
·························51
5.8
Total Amount of Blood·······································································51
6
DISCONTINUATION············································································52
6.1
Discontinuation of Individual Subject(s)···················································52
6.2
Discontinuation of the Site···································································53
6.3
Discontinuation of the Study ································································53
7
STATISTICAL METHODOLOGY ···························································53
7.1
Sample Size····················································································53
7.2
Analysis Set····················································································54
7.2.1
Full Analysis Set (FAS) ································································54
7.2.2
Per Protocol Set (PPS)··································································54
7.2.3
Safety Analysis Set (SAF)······························································54
7.2.4
Pharmacokinetic Analysis Set (PKAS) ···············································54
7.3
Demographics and Other Baseline Characteristics········································54
7.4
Analysis of Efficacy ··········································································54
7.4.1
Analysis of Primary Endpoint ·························································54
7.4.1.1
Primary Analysis···································································54
7.4.1.2
Secondary Analysis································································55
7.4.1.3
Subgroup Analysis·································································55
7.4.2
Analysis of Secondary Endpoints ·····················································55
7.4.3
Analysis of Exploratory Endpoints····················································56
7.5
Analysis of Safety·············································································56
7.5.1
Adverse Events ··········································································56
7.5.2
Laboratory Assessments································································56
7.5.3
Vital Signs················································································56
CCI
CCI


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7.6
Analysis of Pharmacokinetics ·······························································56
7.7
Protocol Deviations and Other Analyses···················································57
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················57
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········57
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················57
8.1
Procedure for Clinical Study Quality Control ·············································57
8.1.1
Data Collection ··········································································57
8.1.2
Specification of Source Documents···················································58
8.1.3
Clinical Study Monitoring······························································58
8.1.4
Direct Access to Source Data/Documents············································59
8.1.5
Data Management ·······································································59
8.1.6
Protocol Deviations ·····································································59
8.1.7
End of Trial in All Participating Countries···········································60
8.2
Ethics and Protection of Subject Confidentiality··········································60
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································60
8.2.2
Ethical Conduct of the Study···························································60
8.2.3
Informed Consent of Subjects ·························································61
8.2.3.1
Subject Information and Consent················································61
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information·····························61
8.2.4
Subject Confidentiality ·································································61
8.3
Administrative Matters ·······································································62
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····62
8.3.2
Documents and Records Related to the Clinical Study ·····························62
8.3.3
Protocol Amendment and/or Revision················································62
8.3.4
Signatory Investigator for Clinical Study Report····································63
9
QUALITY ASSURANCE········································································63
10
STUDY ORGANIZATION······································································63
10.1
Other Study Organization ····································································63
11
REFERENCES ····················································································64
12
APPENDICES ·····················································································68
12.1
List of Excluded Concomitant Medications ···············································68
12.2
Liver Safety Monitoring and Assessment··················································69


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12.3
Common Serious Adverse Events···························································72
13
SIGNATURES ·····················································································73


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I.
SIGNATURES
1.  SPONSOR’S SIGNATURE
A Randomized Study of Enzalutamide in Patients with Localized Prostate Cancer 
Undergoing Active Surveillance (ENACT)
ISN/Protocol 9785-MA-1010 / Version 1.0 dated 18 Dec 2015
Required signatures (e.g. Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 13, Signatures; e-signatures (when applicable) are located at the end of 
this document.


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2.  INVESTIGATOR’S SIGNATURE
A Randomized Study of Enzalutamide in Patients with Localized Prostate Cancer 
Undergoing Active Surveillance (ENACT)
ISN/Protocol 9785-MA-1010 / Version 1.0 dated 18 Dec 2015
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that sub-investigator(s) 
and other relevant members of my staff have access to copies of this protocol and the ICH 
GCP guidelines to enable them to work in accordance with the provisions of these 
documents.
Principal Investigator:
Signature:
<Insert name and qualifications of the Investigator>
Printed Name:
Date (DD Mmm YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ADT
Androgen Deprivation Therapy
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APGD
Astellas Pharma Global Development
AR
Androgen Receptor
AS
Active Surveillance
AST
Aspartate Aminotransferase
AT
Aminotransferases
BCRP
Breast Cancer Resistance Protein
BFI
Brief Fatigue Index
BMI
Body Mass Index
CA
Competent Authorities
CBC
Complete Blood  Count
CLCR
Creatinine Clearance
CRO
Contract Research Organization
CRPC
Castration Resistant Prostate Cancer
CSR
Clinical Study Report
CT
Computerized Tomography
CTL
Cytotoxic T Lymphocyte
DDI
Drug-Drug Interaction
DHEA
Dehydroepiandrosterone 
DHT
Dihydrotestosterone
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EPIC
Expanded Prostate Cancer Index Composite
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GS
Gleason Score
HIPAA
Health Insurance Portability and Accountability Act
HRQoL
Health-Related Quality of Life
ICF
Informed Consent Form
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use


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Abbreviations
Description of abbreviations
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISN
International Study Number
LA-CRF
Liver Abnormality Case Report Form
LBD
Ligand Binding Domain
LFT
Liver Function Testing
LS
Least Square
LSO
Last Subject Out
LVEF
Left Ventricular Ejection Fraction
MAX-PC
Memorial Anxiety Scale for Prostate Cancer
mCRPC
Metastatic Castration Resistant Prostate Cancer
MedDRA
Medical Dictionary for Regulatory Authorities
mpMRI
Multiparametric Magnetic Resonance Imaging
MRI
Magnetic Resonance Imaging
MUGA
Multi Gated Acquisition Scan
NASH
Non-Alcoholic Steatohepatitis
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDA
New Drug Application
NYHA
New York Heart Association
PD
Protocol Deviation
PHI
Protected Health Information
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set
PRO
Patient Reported Outcomes
PSA
Prostate Specific Antigen
QOL
Quality of Life
rPFS
Radiographic Progression Free Survival
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SEER
Surveillance, Epidemiology and End Results
SF-12
Medical Outcomes Study 12-Item Short Form Survey
SOP
Standard Operating Procedures
TBL
Total Bilirubin
TEAE
Treatment-Emergent Adverse Event
TLFs
Tables, Listings and Figures


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Abbreviations
Description of abbreviations
TMF
Trial Master File
TREC
T-Cell Receptor Excision Circles
TRUS
Transrectal Ultrasonography
ULN
Upper Limit of Normal
WHO
World Health Organization


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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison. 
Enroll
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject. 
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Investigational 
period
Period of time where major interests of protocol objectives  are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Post investigational 
period
Period of time after the last assessment of the protocol. Follow-up observations 
for sustained adverse events and/or survival are done in this period.
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet one or more criteria required for 
participation in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Therapeutic 
progression
The institution of definite therapy (prostatectomy, radiation therapy or 
systemic therapy) for prostate cancer.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.




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targeting) is required. Low risk is defined as T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if 
CT/bone scan not done due to low risk of metastases), Gleason score (GS) ≤6 and ECOG status ≤2
with a life expectancy >5 years. Intermediate risk is defined as T2b-T2c, PSA<20, N0, M0 (or 
presumed N0, M0 if computerized tomography [CT]/bone scan not done), GS ≤7 (3+4 pattern only),
ECOG status ≤2 and estimated life expectancy > 5 years. Prostate cancer progression is defined as 
either therapeutic progression or pathological progression. Pathological progression is defined as 
increase in primary or secondary Gleason pattern by ≥1 or higher proportion of cancer positive cores 
(≥15% increase).Therapeutic progression is defined as the earliest occurrence of primary therapy for 
prostate cancer (prostatectomy/radiation/focal therapy/systemic therapy). Patients will be stratified by 
low versus intermediate risk and type of biopsy performed (mpMRI targeted versus non mpMRI
targeted). With regards to the use of mpMRI targeting, each site must be consistent with their method 
of biopsy throughout the study, for all subjects they enroll.
Subjects will be randomized to receive treatment with enzalutamide (160 mg), administered as four 
40 mg capsules, by mouth, once daily, or to AS during the one year study treatment period. Following 
the one year treatment period, all subjects will be followed for one additional year (without any 
treatment). Subjects will be followed up every 3 months for these 2 years. Serum PSA will be 
measured at baseline and every 3 months during subsequent follow-up visits. Digital rectal 
examination will be done at baseline and every 6 months during subsequent follow-up visits. All 
subjects will have transrectal ultrasound-guided prostate biopsy (with or without mpMRI targeting) at 
12 months and 24 months with a standard of 12 cores required. Systematic biopsies (12 core 
transrectal ultrasonography [TRUS] guided systematic biopsies including six lateral and six mid lobar 
cores from the base, middle and apex of the gland) are required even if mpMRI targeted technique is 
performed; mpMRI targeting should consist of two cores from any targeted lesion. All sites will be 
consistent with their method of biopsy (with regards to the use of mpMRI targeting) throughout the 
study for all patients enrolled at that site. If there is a significant clinical reason such as adverse 
changes on digital rectal examination or increase in PSA, biopsy is allowed based on investigator’s 
decision. If at any time during the study the patient considers intervention for prostate cancer, biopsy 
is allowed and recommended. Treatment decisions based on pathological progression are at the 
discretion of the individual investigator. Hormonal levels (testosterone, DHT, 
dihydroepiandrosterone, androstenedione and estradiol) will also be collected at baseline, 12 months 
and 24 months. Quality of life/sexual function questionnaires (EPIC), anxiety measures (MAX-PC), 
BFI and SF-12 assessments will also be done at baseline, 6 months, 12 months, 18 months and 24 
months. An additional BFI assessment will be done at 3 months. Subjects who withdraw from the 
study before the 24 Month Visit will be asked to complete the EPIC, MAX-PC, BFI and SF-12
assessments at their final study visit.   
Subjects will be followed beyond the two year study period until the last patient has completed the 
24 Month Visit. This additional follow up will entail biannual visits (every 6 months) that include 
measurement of serum PSA and digital rectal examination.
All biopsy samples will be centrally read by a designated pathologist blinded to treatment allocation. 
CT, magnetic resonance imaging (MRI) and bone scan will be performed at the discretion of the 
investigator based on clinical need and will be read locally.
Throughout the study, safety and tolerability will be assessed by the recording of adverse events
(AEs), monitoring of vital signs, physical examinations and safety laboratory evaluations. 


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Inclusion/Exclusion Criteria:  
Inclusion:  
Subject is eligible for the study if all of the following apply:
1.
Age 18 years or older and willing and able to provide informed consent
2.
Histologically proven adenocarcinoma of the prostate diagnosed (with ≥10 core biopsy) 
within 6 months of screening. The biopsy that was used for this diagnosis must be submitted
for central pathology review.
3.
Prostate cancer categorized (as determined by central pathology review) as low risk is defined 
as T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if CT/bone scan not done due to low 
risk of metastases), GS ≤6, ECOG status ≤2 and estimated life expectancy >5 years OR
intermediate risk is defined as T2b-T2c, PSA<20, N0, M0 (or presumed N0, M0 if CT/bone 
scan not done), GS ≤7 (3+4 pattern only), ECOG status ≤2 and estimated life expectancy > 5 
years. Prostate cancer categorized (as determined by central pathology review) to the very 
low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3 prostate biopsy cores positive, 
≤50% cancer in any core, PSA density <0.15 ng/mL/g) is not  included. 
4.
Ability to swallow study drugs and to comply with study requirements throughout the study
5.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulations (e.g., HIPAA 
Authorization for U.S. sites) must be obtained from the subject or legally authorized 
representative prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable) 
6.
Throughout study, male subject and a female partner who is of childbearing potential must 
use two acceptable methods of birth control (one of which must include a condom barrier 
method of contraception) starting at screening and continuing throughout the study period and 
for three months after the final study drug administration. Two acceptable methods of birth 
control thus include the following:
a.
Condom (barrier method of contraception)
AND
b.
One of the following is required:
i.
Established use of oral, injected or implanted hormonal methods of 
contraception by the female partner;
ii.
Placement of an intrauterine device or intrauterine system by the female 
partner;
iii.
Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam / gel / film / cream / suppository by the female 
partner;
iv.
Tubal ligation in the female partner. 
7.
Must not donate sperm starting at screening throughout the study period and for 
90 days after the final study drug administration
8.
Subject agrees not to participate in another interventional study while on 
treatment
Waivers to the inclusion criteria will NOT be allowed
Exclusion:  
Patients will be excluded from participation if any of the following apply:
1.
Prior radiotherapy, surgery, chemotherapy, or hormonal therapy for prostate cancer
2.
Very low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3 prostate biopsy cores 
positive, ≤50% cancer in any core, PSA density <0.15 ng/mL/g)
3.
Prior transurethral resection of the prostate or prior transurethral microwave thermotherapy of 
the prostate
4.
Use of oral glucocorticoids within 1 month of screening
5.
Use of 5 alpha reductase inhibitor within 1 month of screening or total use, within the last two 


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years prior to screening, of >3 months
6.
Presence of metastatic disease 
7. History of seizure or any condition that may predispose to seizures (e.g., prior cortical stroke 
or significant brain trauma) at any time in the past. History of loss of consciousness or 
transient ischemic attack within 12 months of screening
8. Absolute neutrophil count < 1,500/µL, platelet count < 100,000/µL, or hemoglobin < 6.2 
mmol/L (10 g/dL) at screening
9. Total bilirubin >1.5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) 
or aspartate aminotransferase (AST) ≥ 2.5 X ULN at screening
10. Creatinine > 177 μmol/L (> 2 mg/dL) at screening
11. Albumin < 30 g/L (3.0 g/dL) at screening
12. Major surgery within 4 weeks prior to Randomization Visit
13. Clinically significant cardiovascular disease including:  
a.
Myocardial infarction or uncontrolled angina within 6 months
b.
Congestive heart failure New York Heart Association (NYHA) class 3 or 4
c.
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, torsades de pointes)
d.
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place
e.
Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury 
(mm Hg) at screening
f.
Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram (ECG) and on physical examination
g.
Uncontrolled hypertension as indicated by at least 2 consecutive measurements of a 
resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg 
at the Screening Visit
14. Known hypersensitivity to enzalutamide or any of its components.
15. Subject has received investigational therapy within 28 days or 5 half lives, whichever is 
longer, prior to screening. 
16. Any condition (e.g., non-prostate malignancy or other active non-malignant disease) which, in 
the investigator’s opinion, makes the subject unsuitable for study participation. 
Waivers to the exclusion criteria will NOT be allowed. 
Investigational Product(s):
Enzalutamide 40 mg soft gelatin capsules
Dose(s):  
Enzalutamide 160 mg/day.
Mode of Administration:
Enzalutamide capsules are administered orally with or without food.
Comparative Drug(s): NA
Dose(s): NA
Mode of Administration: NA


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Concomitant Medication Restrictions or Requirements:   
Prohibited Medications
The following medications are prohibited in the absence of disease progression:

5α-reductase inhibitors (finasteride, dutasteride)

Estrogens

Cyproterone acetate

Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)

Antiestrogens or other medications to manage gynecomastia / breast complications

Any other investigational agent
Restricted Medications
Usage of the following medications is restricted for subjects receiving enzalutamide:
●
Co-administration of strong CYP2C8 inhibitors should be avoided if possible. If subjects 
must be co-administered a strong CYP2C8 inhibitor, reduce the enzalutamide dose to 80 mg 
once daily. If co-administration of the strong inhibitor is discontinued, the enzalutamide dose 
should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor
●
Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, rifapentine) should be avoided if possible. St John’s Wort may 
decrease enzalutamide exposure and should be avoided. If subjects must be co-administered a 
strong CYP3A4 inducer, increase the enzalutamide dose from 160 mg to 240 mg once daily. 
If co-administration of the strong CYP3A4 inducer is discontinued, the enzalutamide dose 
should be returned to the dose used prior to initiation of the strong CYP3A4 inducer. 
●
Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized 
by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and 
CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their 
exposure. If co-administration with warfarin cannot be avoided, conduct additional 
international normalized ratio (INR) monitoring.
Restrictions on Concomitant Treatment
At initiation of the study, the options to manage gynecomastia/breast complications of enzalutamide 
treatment, which may occur in subjects randomized to the enzalutamide treatment arm, should be 
discussed with the study subjects and a strategy should be decided between each individual 
investigator and subject. Options to be offered are prophylactic breast irradiation (to be performed 
locally according to local standard of care), breast irradiation as needed for symptoms or dose 
reduction / interruption of medication as needed for symptoms. Antiestrogens or other medications 
are prohibited to manage these conditions.
Duration of Treatment:  
Treatment on study drug will be 1 year or until disease progression or unacceptable toxicity, 
whichever occurs first.




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Fixed effects for the model will include the treatment groups, stratification factors, race, and time 
since prostate cancer diagnosis.  Complete details of the model and all covariates will be included in 
the statistical analysis plan.
The proportional hazards assumption will be investigated graphically by the log on the negative log of 
the estimated survival versus the log on time to progression.
The secondary endpoints of treatment-emergent adverse events, negative biopsy for cancer, percent of 
positive cores, secondary rise in serum PSA, BFI, SF-12, EPIC and MAX-PC questionnaire scoring 
will be summarized with descriptive statistics or frequencies and percentages, as appropriate.  
Appropriate statistical analyses of treatment group differences will be included for all secondary 
endpoints.
Time to PSA progression will be analyzed using methods analogous to those detailed above for the 
primary endpoint. 
Pharmacokinetics:  
NA
Pharmacodynamics:  
NA
Safety:  
All AEs will be collected and the severity the AEs will be evaluated by the investigator based on the 
latest version of National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-
CTCAE). All AEs will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) to preferred term, high level term and system organ class. AEs will be 
presented by the number and percentage of subjects by MedDRA system organ class and preferred 
term, relationship to study treatment and severity. The latest version of NCI-CTCAE will be used to 
classify laboratory values by toxicity grade. Descriptive statistics will be used for AEs.
Interim analyses: 
NA


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart




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3. Medical history will include capturing information about any first degree relatives with prostate cancer. Any updates to the subject’s medical history will be recorded at the 
Randomization Visit (Study Day 1) prior to randomization.
4. A complete physical examination will be completed at the Screening Visit. For all visits after the Randomization visit, only a brief physical examination is required.
5. This procedure (if required)  must be done within 28 days prior to randomization.
6. A multi-gated acquisition (MUGA) scan or echocardiogram is only required if the patient has a history of anthracycline or anthracenedione (mitoxantrone) treatment.
7. Clinical labs, which will be assessed by the study’s central laboratory, include serum chemistries (comprehensive metabolic panel) and hematology (CBC with differential).
8. Serum hormonal levels to be measured are testosterone, DHT, dihydroepiandrosterone, androstenedione and estradiol.
9. Serum PSA will be measured by the study’s central laboratory. 
10. If warranted per Investigator’s clinical opinion or per standard of care.
11. 
 
12. Biopsies may be done with or without mpMRI targeting. Sites must use a consistent method (either with or without mpMRI targeting) for all of their study patients. Any biopsy 
performed during the patient’s study participation will be analyzed centrally (for histological reading, 
).
13. Biopsy must be done within 6 months prior to the Screening Visit, and submitted for central analysis (histological reading, 
). For this 
biopsy, a minimum of 10 cores is required. 
14. Subjects who withdraw from the study prior to the 24m Visit will be asked to complete all patient reported outcomes questionnaires (BFI, SF-12, EPIC, MAX-PC) at their final 
study visit. 
15. Only the urinary, sexual and hormonal domains will be used. 
16. Adverse events (serious and non-serious) will be collected from the time the patient signs the consent form until the patient completes the study.
17. Study drug is only applicable to subjects randomized to the enzalutamide arm; subjects randomized to AS will not be dispensed any study drug. 
18. Subjects will have the option of having an additional sample collected at each phlebotomy session for storage and analysis in future trials of future trials of biomarker discovery for 
localized prostate cancer.
CCI
CCI
CCI


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1
INTRODUCTION
1.1
Background
Prostate cancer is the most commonly diagnosed cancer (other than skin cancer) among men. 
In 2015 the American Cancer Society estimates that 220,800 men will develop prostate 
cancer in the United States and about 27,540 will die of prostate cancer (American Cancer 
Society, 2015). Of those diagnosed, 80% will be diagnosed with localized disease according 
to Surveillance, Epidemiology and End Results (SEER) data (SEER 18 2005-2011).  For 
localized disease, there are multiple options – active surveillance (AS), radical prostatectomy 
and external beam radiotherapy / brachytherapy (NCCN, 2015). Interventional options, 
however, carry risks. Radical prostatectomy (open or robotic) has long term risks of erectile
dysfunction and urinary incontinence. External beam radiation therapy and brachytherapy 
also carry risks, such as erectile dysfunction, urinary incontinence and bowel complications.  
AS has emerged as one of the recommended options for localized prostate cancer (Mohler et 
al, 2010; Thompson et al, 2007). AS use is increasing for low risk disease over the years 
2010-2013 compared to the years before then (Cooperberg & Carroll, 2015; Ritch et al, 2015; 
Weiner et al, 2015). Ritch et al (2015) also noted increasing use of observation for low risk 
prostate cancer in an analysis of the SEER-Medicare database. This increase in AS is mostly 
due to concern that clinically low risk prostate cancer is over-treated, and AS may reduce 
unnecessary treatment in these patients. (Lane et al, 2014; Wilt, 2014; Wilt et al, 2012; 
Bill-Axelson et al, 2011; ). AS studies have also included men with higher risk features 
including Gleason pattern 4 (Klotz et al, 2015; Cooperberg et al, 2011). 
There are major differences, however, in the criteria for entering AS and the routines that are 
followed. There are still significant numbers of men whose cancer is upgraded on subsequent 
biopsies (pathological progression) and who are thus considered for an interventional 
treatment due to this.  In a low risk population, one recent study demonstrated upgrading of 
the initial Gleason score (GS) in 42% of patients with a median time to initial upgrade of 
23 months (Hussein et al, 2015) and 76% of those eventually received treatment for this 
upgrade or progression. Another study that included 20% intermediate risk patients in 
addition to the low risk patients demonstrated upgrading in 31% of the patients with a median 
time to upgrading of 1.8 years. Of those who were upgraded, 62% had active interventional 
treatment (Jain et al, 2015). Another study with low risk patients undergoing AS 
demonstrated upgrading in 32.7% of patients with a median follow-up of 2.3 years (Tseng et 
al, 2010). A further study of long-term follow up also concurs with this general range of 
reclassification or upgrading during the course of AS follow up (Klotz et al, 2010). Higher 
upgrading rates are found when radical prostatectomy specimens are used as the reference 
(Shaw et al, 2014). Pathological upgrading may occur due to a variety of reasons—biological 
progression/cancer dedifferentiation, sampling error at diagnosis, changes in pathological 
classification over time and /or inter observer variability (Jain et al, 2015). Whether this 
upgrading represents true progression or tumor missed at diagnosis is not definitively known 
and may be influenced by the type of biopsy performed (multiparametric magnetic resonance 
imaging [mpMRI] targeted versus non-mpMRI targeted systematic biopsy) and some studies 
show that significant numbers of men are excluded from AS protocols after undergoing 


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targeted biopsy (Hu et al, 2014). To date, there have been few studies with pharmacologic 
interventions for AS. The REDEEM study investigated the effect of dutasteride (5 alpha 
reductase inhibitor) on low risk prostate cancer patients who chose an AS protocol (Fleshner 
et al, 2012).  Dutasteride delayed the progression of prostate cancer; by 3 years, 54 (38%) of 
144 men in the dutasteride group and 70 (48%) of 145 controls had prostate cancer 
progression (pathological or therapeutic; hazard ratio 0.62, 95% CI 0.43–0.89; p=0.009).
Most other ongoing AS studies offer only behavioral interventions or interventions with 
dietary or herbal supplements (http://clinicaltrials.gov).
1.2
Non-clinical and Clinical Data
Enzalutamide (formerly known as MDV3100) competitively binds to the ligand binding 
domain (LBD) of the androgen receptor (AR) and inhibits AR translocation to the cell 
nucleus, recruitment of cofactors and binding to DNA (Tran et al, 2009). Enzalutamide has 
been shown in two phase 3 randomized trials to have significant activity in metastatic 
castration resistant prostate cancer (mCRPC). In the phase 3 AFFIRM trial (Scher et al, 
2012), 1199 men with prior chemotherapy exposure who were randomly assigned to receive 
enzalutamide versus placebo, a statistically significant improvement in overall survival of 
18.4 versus 13.6 months was detected with enzalutamide (HR, 0.63; 95% CI, 0.53 to 0.75; 
P < 0.001).  Radiographic progression free survival (rPFS) was 8.3 versus 2.9 months (HR, 
0.40; P < 0.001), prostate specific antigen (PSA) response was 54% versus 2% (P< 0.001), 
time to PSA progression was 8.3 versus 3.0 months (HR, 0.25; P < 0.001) and time to first 
skeletal-related event was 16.7 versus 13.3 months (HR, 0.69; P < 0.001), all in favor of 
enzalutamide. Overall quality of life (QOL) benefit was observed in 43% versus 18% 
(P < 0.001) of patients receiving enzalutamide compared with placebo, whereas fatigue, 
diarrhea and hot flushes were more common with enzalutamide. Five patients (0.6%) 
experienced seizures in the enzalutamide group.  In the phase 3 PREVAIL trial (Beer et al, 
2014), 1717 men without prior chemotherapy exposure were randomized to receive 
enzalutamide or placebo. Compared to placebo, enzalutamide improved rPFS (rPFS rate at 
12-month: 65% versus 12%; HR= 0.19; 95% CI, 0.15 to 0.23; P<0.001) and overall survival 
(HR=0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with 
respect to all secondary endpoints, including the time until the initiation of cytotoxic 
chemotherapy (HR= 0.35), the time until the first skeletal-related event (HR= 0.72), a 
complete or partial soft-tissue response (59% versus 5%), the time until PSA progression 
(HR, 0.17) and a rate of decline of at least 50% in PSA (78% versus 3%) (P<0.001 for all 
comparisons). Fatigue and hypertension were the most common clinically relevant adverse 
events (AEs) associated with enzalutamide treatment. 
Enzalutamide was studied in the neoadjuvant setting before radical prostatectomy 
(Montgomery et al, 2015). However, these were patients with features of high risk localized 
disease (Gleason 8, etc) who would not be candidates for AS.
An open-label, single-arm, phase 2 study was conducted in the European Union to assess the 
efficacy and safety of enzalutamide monotherapy in male patients with localized, locally 
advanced, or metastatic prostate cancer who had never received hormone therapy (Tombal et 


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al, 2015). The study enrolled 67 patients who presented with hormone-naïve prostate cancer 
requiring hormonal therapy and presented with non-castrate testosterone levels (≥230 ng/dL). 
The primary endpoint was PSA response, defined as a decline in baseline PSA of ≥ 80% at 
Week 25. Pre-specified secondary and exploratory endpoints included change from baseline 
in hormone levels, safety, objective disease response and change from baseline in lipids, 
insulin sensitivity, bone mineral density, body composition and health related quality of life 
(HRQoL). Sixty-two patients (92.5%; 95% CI, 86.2-98.8) achieved the primary endpoint of 
PSA response at Week 25 with a median maximum decline in PSA of -99.6% (IQR: -100.0%
to -97.8%), with a tolerable risk/benefit profile and minimal effects on total body bone 
mineral density.
Pharmacokinetics
The pharmacokinetics and metabolism of enzalutamide have been evaluated in patients with 
castration resistant prostate cancer (CRPC), hormone-naïve prostate cancer patients, healthy 
male volunteers and subjects with mild or moderate hepatic impairment. Individual doses 
have ranged from 30 to 600 mg. Pharmacokinetic studies of enzalutamide in women have not 
been completed.
After oral administration to patients with CRPC, the median time to reach maximum 
enzalutamide plasma concentrations was 1 hour, and the mean terminal half-life was 5.8 days. 
Enzalutamide steady state was achieved by day 28, and the accumulation ratio was 8.3-fold. 
At steady state, enzalutamide showed approximately dose proportional pharmacokinetics 
over the range of 30 to 360 mg/day. Enzalutamide is primarily eliminated by hepatic 
metabolism. Food does not have a clinically relevant effect on the AUC of enzalutamide and 
its active metabolite so it can be taken with or without food.  Composite AUC of 
enzalutamide plus its active metabolite after single-dose enzalutamide was similar in subjects 
with impaired baseline hepatic function (i.e. Child-Pugh Class A, B, or C) relative to subjects 
with normal hepatic function, and no starting dose adjustment is needed. 
Based on population pharmacokinetics modeling, age, weight and renal function (creatinine 
clearance [CLCR] ≥ 30 mL/min) do not have clinically meaningful effects on enzalutamide 
exposures; therefore, no dose adjustments are indicated for these covariates. Clinical data are 
insufficient to assess the potential effect of severe renal impairment (CLCR < 30 mL/min) 
and end-stage renal disease on enzalutamide pharmacokinetics.
Drug-Drug Interaction (DDI) studies in prostate cancer patients showed that enzalutamide 
can affect exposures to other co-medications. At steady state, enzalutamide is a strong 
CYP3A4 inducer and moderate CYP2C9 and CYP2C19 inhibitor, and was shown to have 
reduced the AUC of oral midazolam (CYP3A4 substrate), S-warfarin (CYP2C9 substrate) 
and omeprazole (CYP2C19 substrate) by 86%, 56% and 70%, respectively. Enzalutamide 
(160 mg/day) did not have a clinically relevant effect on exposure to intravenous docetaxel 
(CYP3A4 substrate) or oral pioglitazone (CYP2C8 substrate). 
In vivo data shows that, at steady state, enzalutamide did not cause clinically meaningful 
changes in exposure to the CYP1A2 or CYP2D6 substrates.


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In vitro data shows that enzalutamide caused direct inhibition of multiple CYP enzymes 
including CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP3A4/5; however, subsequent 
clinical data showed that enzalutamide is an inducer of CYP2C9, CYP2C19 and CYP3A4 
and had no clinically meaningful effect on CYP2C8. In vitro, enzalutamide caused time-
dependent inhibition of CYP1A2.
In vitro studies showed that enzalutamide induces CYP2B6 and CYP3A4 and does not 
induce CYP1A2 at therapeutically relevant concentrations.
DDI studies in healthy subjects showed that concomitant medications can affect exposure to 
enzalutamide. Coadministration of gemfibrozil (a strong CYP2C8 inhibitor) increased the 
composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. 
Coadministration of itraconazole (strong CYP3A4 inhibitor) increased the composite AUC of 
enzalutamide plus N-desmethyl enzalutamide by 1.3-fold.
Coadminstration of rifampin (moderate CYP2C8 inducer and strong CYP3A4 inducer) 
decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
In vitro data indicate that enzalutamide and its major metabolites are not substrates for 
human P-glycoprotein (P-gp); enzalutamide and N-desmethyl enzalutamide are inhibitors for 
P-gp.  
In vitro data also show that enzalutamide and N-desmethyl enazlutamide do not appear to be 
substrates for human breast cancer resistance protein (BCRP), however, enzalutamide and 
N-desmethyl enzalutamide are inhibitors of BCRP at clinically relevant concentrations.
Rationale for study
Patients who progress on AS are at risk for sequelae of their prostate cancer and often receive 
interventions which carry significant risks and side effects. To date, no studies have been 
published with an intervention of a known anti-cancer agent in an AS population. Because of 
this, novel approaches are needed to both stratify and offer options for those on AS as well as 
to offer an intervention that might affect progression. Also, current AS groups encompass 
different patient populations. Some populations with certain characteristics (related to 
medical or family history 
) might progress more often on 
AS than other populations. This study will allow us to examine these issues, as well as to 
examine any effect of enzalutamide on these different subsets of patients. The use of 
enzalutamide monotherapy will potentially allow for optimal tumor treatment without the 
side effects and effects on quality of life inherent to androgen deprivation therapy (ADT).
Treatment duration that would be applicable to this study group has also not been directly 
studied. One study using enzalutamide in the neoadjuvant setting before radical 
prostatectomy utilized 6 months of enzalutamide in prostate cancer patients considered for 
radical prostatectomy with PSA >10 and Gleason ≥7. This demonstrated 0/25 patients with 
pathologic complete response (as assessed by radical prostatectomy specimen). Because of 
this limited response in relatively higher risk patients than our current study, 12 months of 
enzalutamide was felt to be more appropriate in this group with lower risk disease 
characteristics in order to demonstrate a significant treatment difference.
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Rationale for mpMRI targeted biopsies
Newer tools and techniques such as multiparametric magnetic resonance imaging (mpMRI)
and biopsy based biomarker assessments are being reported in localized prostate cancer 
patients on AS (Lin et al, 2013; Stamatakis et al, 2013). These not only help to predict 
progression but also can assist in the accurate initial and ongoing assessment of the tumor, as 
there is evidence that early tumor progression (in the first few years after diagnosis) is due to 
inadequate initial assessment of the tumor (Cooperberg et al, 2011), with one study 
estimating this rate of inaccurate initial assessment at 30% (Conti et al, 2009) while another 
study estimated a 10% reclassification of patients (from those eligible for AS to those not 
eligible) based on mpMRI targeted biopsy (Ouzzane et al, 2015). Having a mix of patients 
being followed with and without mpMRI will also help predict the utility of this test in our 
dataset. mpMRI profiling can also possibly help identify aggressive versus indolent tumors 
and aid the clinician in deciding on possible therapy in patients who progress on AS (Hussein 
et al, 2015). While the detection rate for higher grade tumors has been found with the use of 
mpMRI, clinically significant tumors have also been found with systematic biopsy which 
justifies our use of both techniques in this study (de Gorski et al, 2015). While mpMRI use is 
increasing in prostate cancer detection and management of those with recently diagnosed
prostate cancer, the question as to how to apply this in clinical practice remains unanswered 
at this time. There is variability in the use of mpMRI targeted biopsies and the utility and 
yield of mpMRI targeted biopsies versus standard systematic biopsies depends largely on the 
biopsy history of the included men (Taneja, 2015) and the relative benefit of an mpMRI
targeted approach is not fully defined at this time.  
 
 
 
 
 
 
 
 
 
  
CCI
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1.3
Summary of Key Safety Information for Study Drugs
Please reference the current Investigator Brochure (IB) for the safety profile of enzalutamide. 
The following information is summarized from the IB (Edition 8 dated 09 June 2015) unless 
otherwise noted. 
Briefly, the safety profile of enzalutamide in patients with CRPC is primarily derived from 
two randomized, placebo-controlled phase 3 studies (MDV3100-03 [PREVAIL] and CRPC2 
[AFFIRM]). Additional studies of enzalutamide in patients with prostate cancer, as well as 
studies of enzalutamide in patients with breast cancer and in healthy volunteers, contribute to 
the available enzalutamide safety data. Generally, the emerging data from open-label breast 
cancer studies and from the other individual studies is consistent with what was observed in 
patients with CRPC via the combined controlled population, which consists of both 
PREVAIL and AFFIRM. 
Summary of safety information from the combined controlled population (CRPC)
In the combined controlled population, the enzalutamide group included patients with more 
advanced disease at study entry compared with the placebo group due to the differing 
randomization allocation ratios of PREVAIL and AFFIRM. In this population, AEs more 
common in the enzalutamide treatment group with at least a 2% higher absolute incidence 
over placebo are the following: constipation (23.9% versus 20.7%), diarrhea (19.2% versus 
15.4%), fatigue (35.1% versus 27.0%), asthenia (15.8% versus 10.9%), edema peripheral 
(12.8% versus 9.3%), fall (8.8% versus 4.0%), weight decreased (12.3% versus 9.2%), 
decreased appetite (23.8% versus 20.8%), back pain (27.5% versus 23.0%), arthralgia (20.9% 
versus 16.5%), musculoskeletal pain (12.7% versus 9.6%), muscular weakness (6.9% versus 
4.4%), headache (11.5% versus 6.5%), dysgeusia (6.1% versus 3.6%), spinal cord 
compression (5.9% versus 3.9%), insomnia (8.4% versus 5.8%), anxiety (5.2% versus 3.1%), 
hematuria (7.9% versus 5.4%), hot flush (19.1% versus 8.6%) and hypertension (10.5% 
versus 3.7%). Overall, in this population, study drug-related SAEs were reported infrequently 
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with no meaningful difference between treatment groups. SAEs with at least a 0.5% higher 
absolute incidence in the enzalutamide group compared with the placebo group included 
anemia, general physical health deterioration, pathological fracture, spinal cord compression 
and cauda equine syndrome. Expected adverse drug reactions (ADR) identified in this 
population include: seizure, hypertension, fatigue, hot flush, falls, mental impairment 
disorders, neutropenia, headache, anxiety, hallucination, dry skin and gynecomastia.  
Summary of safety information in patients with hormone naïve prostate cancer
In a study of enzalutamide monotherapy in hormone naïve prostate cancer (9785-CL-0321), 
sixty-seven patients enrolled and received ≥1 dose of enzalutamide. Fifty-four patients (81%) 
completed the study through Week 49, and 45 (67%) remained on treatment at and after 
Week 97 (Tombal et al, 2015). Sixty-two (92.5%) patients experienced treatment-emergent 
adverse events (TEAEs) assessed as related to the study drug regimen. The most frequently 
reported TEAEs were gynecomastia, fatigue, nipple pain, hot flush, diarrhea, hypertension, 
nausea, back pain, pain in extremity and constipation. The majority of these TEAEs were 
NCI-CTCAE Grade 1 or 2. 
Thirty-one SAEs were reported; five of these SAEs were deemed to be related to the study 
drug regimen: worsening of arrhythmia (Grade 3), atrial fibrillation (two patients, Grade 3),  
tachycardia (Grade 2) and chronic fatigue syndrome (Grade 3). Anoxic seizure was reported 
in one patient following a cardiac arrest. 
Summary of safety information in patients with localized intermediate or high-risk 
prostate cancer 
In a study of single-agent enzalutamide therapy versus triple therapy (enzalutamide, 
leuprolide, dutasteride) in patients with localized intermediate or high-risk prostate cancer 
who had not received prior ADT, chemotherapy, surgery, or radiation for prostate cancer 
(MDV3100-07), fifty-two patients enrolled and received at least one dose of enzalutamide 
(twenty-five patients received triple therapy and twenty-seven received single-agent 
enzalutamide). All of these patients experienced at least one TEAE; the most common (≥24% 
in either treatment group) were fatigue (60.0% triple therapy and 70.4% enzalutamide), hot 
flush (96.0% and 25.9%), gynecomastia (12.0% and 63.0%), insomnia (36.0% and 22.2%), 
libido decreased (32.0% and 14.8%), breast tenderness (8.0% and 33.3%), diarrhea (24.0% 
and 18.5%) and pollakiuria (24.0% and 14.8%). Grade 3 or higher AEs occurred in nine 
patients (diarrhea, medical device pain, clostridial infection, pelvic abscess [Grade 4], 
procedural pain, hyperglycemia, hyponatremia, hot flush, lymphocele [more than one 
patient]). All SAEs (lymphocele [two patients], postoperative ileus, pelvic abscess, clostridial 
infection) occurred after the radical prostatectomy procedure that was done following six 
months of study treatment.
1.4
Risk-Benefit Assessment
Cumulatively through the data lock point of 30 Aug 2015, 343 healthy volunteers and over 
7800 patients had been enrolled in enzalutamide clinical studies, of whom approximately 
6290 received enzalutamide. The safety and tolerability of enzalutamide continues to be 




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AS. A minimum of ten cores from transrectal ultrasound-guided prostate biopsy (mpMRI
targeted versus non mpMRI targeted) are required; confirmatory biopsy before entering the 
study is not required and is done at the discretion of the investigator. Low risk is defined as 
T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if computerized tomography [CT]/bone 
scan not done due to low risk of metastases), GS ≤6, ECOG status ≤2 and estimated life 
expectancy >5 years. Intermediate risk is defined as T2b-T2c, PSA<20, N0, M0 (or 
presumed N0, M0 if CT/bone scan not done), GS ≤7 (3+4 pattern only), ECOG status ≤2 and 
estimated life expectancy > 5 years. Prostate cancer progression is defined as either 
therapeutic progression or pathological progression. Therapeutic progression is defined as the 
earliest occurrence of primary therapy for prostate cancer (prostatectomy / radiation / focal 
therapy / systemic therapy). Pathological progression is defined as increase in primary or 
secondary Gleason pattern by > 1 or higher proportion of cancer positive cores (>15% 
increase). Patients will be stratified by low versus intermediate risk and type of biopsy 
performed (mpMRI targeted versus non mpMRI targeted).
Subjects will be randomized (1:1) either to receive treatment with enzalutamide (160 mg), 
administered as four 40 mg capsules, by mouth, once daily or to AS during the one year 
study treatment period. Following the one year treatment period, all subjects will be followed 
for one additional year. Subjects will be followed up every 3 months for these 2 years. Serum 
PSA will be measured at baseline and every 3 months during subsequent follow-up visits. 
Digital rectal examination will be done at baseline and every 6 months during subsequent 
follow-up visits. All subjects will have transrectal ultrasound-guided prostate biopsy (with or 
without mpMRI targeting) at 12 months and 24 months with a standard of 12 cores required; 
two biopsies are required from each target site (if mpMRI is used) as well as 12 systematic 
biopsies (12 core transrectal ultrasonography [TRUS] guided systematic biopsies including 
six lateral and six mid lobar cores from the base, middle and apex of the gland) at the same 
time. All sites will be consistent with their method of biopsy (with regards to the use of 
mpMRI targeting) throughout the study for all patients enrolled at that site. If there is a 
significant clinical reason such as adverse changes on digital rectal examination or increase 
in PSA, biopsy is allowed based on investigator’s decision. If at any time during the study the 
patient considers intervention for prostate cancer, biopsy is allowed and recommended. 
Treatment decisions based on pathological progression are at the discretion of the individual 
investigator. Hormonal levels (testosterone, DHT, dihydroepiandrosterone, androstenedione 
and estradiol) will be collected at baseline, 12 months and 24 months. Quality of life/sexual 
function questionnaires (EPIC), anxiety measures (MAX-PC), BFI, SF-12 assessments will 
also be done at baseline, 6 months, 12 months, 18 months and 24 months. An additional BFI 
assessment will be done at 3 months. Subjects who withdraw from the study before the 24 
Month visit will be asked to complete the EPIC, MAX-PC, BFI and SF-12 assessments at 
their final study visit. 
Subjects will be followed beyond the two year study period until the last patient has 
completed the 24 month visit. This additional follow up will entail biannual visits (every 
6 months) that include measurement of serum PSA and digital rectal exam. 




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3
STUDY POPULATION
3.1
Selection of Study Population 
This study will enroll 222 patients with clinically localized, histologically proven prostate 
cancer who are considered National Comprehensive Cancer Network (NCCN) low risk or 
intermediate risk (as described in inclusion criteria) AND undergoing AS. 
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Age 18 years or older and willing and able to provide informed consent
2.
Histologically proven adenocarcinoma of the prostate diagnosed (with ≥10 core biopsy)
within 6 months of screening. The biopsy that was used for this diagnosis must be 
submitted for central pathology review.  
3.
Prostate cancer categorized (as determined by central pathology review) as low risk is 
defined as T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if CT/bone scan not done 
due to low risk of metastases), GS < 6, ECOG status <2, and estimated life expectancy 
> 5 years OR intermediate risk is defined as T2b-T2c, PSA<20, N0, M0 (or presumed 
N0, M0 if CT/bone scan not done), GS <7 (3+4 pattern only), ECOG status ≤2 and
estimated life expectancy > 5 years. Prostate cancer categorized (as determined by 
central pathology review) to the very low risk category (T1c, GS ≤6, PSA <10 ng/mL, 
fewer than 3 prostate biopsy cores positive, ≤50% cancer in any core, PSA density 
<0.15 ng/mL/g) is not included. 
4.
Ability to swallow study drugs and to comply with study requirements throughout the 
study
5.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written Informed Consent and privacy language as per national regulations (e.g., HIPAA 
Authorization for U.S. sites) must be obtained from the subject or legally authorized 
representative prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable).
6.
Throughout study, male subject and a female partner who is of childbearing potential 
must use two acceptable methods of birth control (one of which must include a condom 
barrier method of contraception) starting at screening and continuing throughout the 
study period and for three months after the final study drug administration. Two 
acceptable methods of birth control thus include the following: 
a.
Condom (barrier method of contraception)
AND
b.
One of the following is required:
i.
Established use of oral, injected or implanted hormonal methods of 
contraception by the female partner;
ii.
Placement of an intrauterine device or intrauterine system by the female 
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iii.
Additional barrier method: Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam / gel / film / cream / suppository by the 
female partner;
iv.
Tubal ligation in the female partner.
7.
Must not donate sperm starting at screening and throughout the study period and for
90 days after the final study drug administration
8.
Subject agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Prior radiotherapy, surgery, chemotherapy, or hormonal therapy for prostate cancer
2.
Very low risk category (T1c, GS ≤6, PSA <10 ng/mL, fewer than 3 prostate biopsy cores 
positive, ≤50% cancer in any core, PSA density <0.15 ng/mL/g)
3.
Prior transurethral resection of the prostate or prior transurethral microwave 
thermotherapy of the prostate 
4.
Use of oral glucocorticoids within 1 month of screening
5.
Use of 5 alpha reductase inhibitor within 1 month of screening or total use, within the 
last two years prior to screening, of >3 months
6.
Presence of metastatic disease 
7.
History of seizure or any condition that may predispose to seizures (e.g., prior cortical 
stroke or significant brain trauma) at any time in the past. History of loss of 
consciousness or transient ischemic attack within 12 months of screening
8.
Absolute neutrophil count < 1,500/µL, platelet count < 100,000/µL, or hemoglobin 
< 6.2 mmol/L (10  g/dL) at screening
9.
Total bilirubin >1.5 times the upper limit of normal (ULN) or alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) ≥ 2.5 X ULN at screening
10. Creatinine > 177 μmol/L (> 2 mg/dL) at screening
11. Albumin < 30 g/L (3.0 g/dL) at screening
12. Major surgery within 4 weeks prior to Randomization Visit
13. Clinically significant cardiovascular disease including:  
a.
Myocardial infarction or uncontrolled angina within 6 months
b. Congestive heart failure New York Heart Association (NYHA) class 3 or 4
c.
History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsades de pointes)
d. History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place
e.
Hypotension as indicated by systolic blood pressure < 86 millimeters of 
mercury (mm Hg) at screening
f.
Bradycardia as indicated by a heart rate of < 45 beats per minute on the 
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g. Uncontrolled hypertension as indicated by at least 2 consecutive 
measurements of a resting systolic blood pressure > 170 mmHg or diastolic 
blood pressure > 105 mmHg at the Screening Visit
14. Known hypersensitivity to enzalutamide or any of its components.
15. Subject has received investigational therapy within 28 days or 5 half lives, whichever is 
longer, prior to screening. 
16. Any condition (e.g., non-prostate malignancy or other active non-malignant disease)
which, in the investigator’s opinion, makes the subject unsuitable for study participation.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
Enzalutamide capsules are opaque white to off-white oblong liquid filled soft gelatin capsules
for oral administration. Each capsule contains 40 mg enzalutamide.
4.2
Comparative Drug(s) 
Not applicable. 
4.3
Packaging and Labeling
Enzalutamide is supplied by Astellas Pharma Global Development (APGD), Medical Affairs, 
Americas. Enzalutamide capsules will be packaged in high-density polyethylene bottles with 
child-resistant induction seal closure.
Enzalutamide used in this study will be prepared, packaged and labeled under the 
responsibility of qualified staff at Astellas or Sponsor’s designee in accordance with Astellas
or Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, ICH GCP guidelines and applicable local laws/regulations.
Each bottle will have a label conforming to regulatory guidelines, Good Manufacturing 
Practice and local laws and regulations which identifies the contents as investigational drug.
4.4
Study Drug Handling 
Enzalutamide will be stored in a secure, dry location with limited access at 20°C to 25°C 
(68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F). Subjects will be 
instructed to store study drug at room temperature and out of the reach of children.
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the Sponsor are received by the investigator/or designee and
●
that such deliveries are recorded,
●
that study drug is handled and stored according to labeled storage conditions,
●
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and


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●
that any unused study drug is returned to the Sponsor.
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/or designee. Study drug accountability throughout the study must be documented 
and reconciled. The following guidelines are therefore pertinent:
●
The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.
●
The investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these test drugs.
●
A study drug inventory will be maintained by the investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.
●
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.
●
The site must return study drugs to the Sponsor or designee at the end of the study or
upon expiration.
●
Study drugs provided by Astellas will not be destroyed on-site, unless considered 
hazardous materials or drugs for which the clinical unit SOP dictates destruction must be 
handled by the institution. Destruction must not occur until final study drug 
accountability reconciliation has been performed and Sponsor has approved destruction 
in writing.
4.5
Blinding
This section is not applicable as this is an open label study.
4.6
Assignment and Allocation
Randomization will be performed on Study Day 1 via Interactive Response Technology 
(IRT). Prior to the initiation of the study treatment, the site staff will contact the IRT in order 
to determine the randomly assigned treatment. Specific procedures for randomization through 
the IRT are contained in the study procedures manual.
The randomization allocation will consist of 1:1 ratio for once daily enzalutamide or AS. The 
randomization will be stratified according to the following two factors:
●
Low versus intermediate risk 
●
Type of biopsy performed (mpMRI targeted versus non mpMRI targeted)
Additionally, enrollment of subjects with low risk prostate cancer will be capped to not 
exceed 80% of the study population.


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5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other 
Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Subjects randomized to the enzalutamide treatment arm will receive treatment with 
enzalutamide (160 mg daily), administered as four 40 mg capsules, by mouth, once daily for 
one year. Subjects in the enzalutamide treatment arm will be instructed to swallow the 
enzalutamide capsules whole, either with or without food and to take the drug as close to the 
same time each day as possible. 
Subjects randomized to the AS arm will not receive any study drug. 
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
If a subject in the enzalutamide treatment arm experiences a Grade 3 or greater toxicity or 
intolerable adverse side effect, withhold dosing for one week or until symptoms improve to 
Grade 2 or lower severity or become tolerable, then resume at the same or reduced dose 
(120 mg or 80 mg per day) if warranted.
Enzalutamide dosing may be reduced to 120 mg or 80 mg per day if needed to manage 
gynecomastia / breast complications. Enzalutamide dosing may also be reduced or held, if 
warranted per Investigator’s discretion, to manage adverse side effects. 
Dose reductions will be captured in the eCRF. 
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication
Therapy)
Concomitant treatments will be captured on the eCRF at every study visit, beginning with the 
Screening Visit. At the Screening Visit, treatments taken within four weeks prior to the visit
will also be captured in the eCRF.
Treatments captured in the eCRF will include both drug and non-drug therapies, prescribed 
and over-the-counter and all alternative medicines. 
Subjects must be instructed not to start any new medication, prescribed or over-the-counter, 
without consulting the Investigator, unless the new medication is required for emergency use. 
Subjects must be instructed to notify the Investigator immediately if medications were 
required for emergency use. 
Prohibited Medications
The following medications are prohibited in the absence of disease progression:
●
5α-reductase inhibitors (finasteride, dutasteride)
●
Estrogens
●
Cyproterone acetate
●
Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)
●
Antiestrogens or other medications to manage gynecomastia / breast complications


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●
Any other investigational agent
Restricted Medications
Usage of the following medications is restricted for subjects receiving enzalutamide:
●
Co-administration of strong CYP2C8 inhibitors should be avoided if possible. If 
subjects must be co-administered a strong CYP2C8 inhibitor, reduce the enzalutamide 
dose to 80 mg once daily. If co-administration of the strong inhibitor is discontinued, 
the enzalutamide dose should be returned to the dose used prior to initiation of the 
strong CYP2C8 inhibitor.
●
Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, rifapentine) should be avoided if possible. St John’s 
Wort may decrease enzalutamide exposure and should be avoided. If subjects must be 
co-administered a strong CYP3A4 inducer, increase the enzalutamide dose from 
160 mg to 240 mg once daily. If co-administration of the strong CYP3A4 inducer is 
discontinued, the enzalutamide dose should be returned to the dose used prior to 
initiation of the strong CYP3A4 inducer. 
●
Concomitant use of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., 
phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as 
enzalutamide may decrease their exposure. If co-administration with warfarin cannot 
be avoided, conduct additional international normalized ratio (INR) monitoring.
Restrictions on Concomitant Treatment
At initiation of the study, the options to manage gynecomastia/breast complications of 
enzalutamide treatment, which may occur in subjects randomized to the enzalutamide 
treatment arm, should be discussed with the study subjects and a strategy should be decided 
between each individual investigator and subject. Options to be offered are prophylactic 
breast irradiation (to be performed locally according to local standard of care), breast 
irradiation as needed for symptoms or dose reduction/interruption of medication as needed 
for symptoms. Antiestrogens or other medications are prohibited to manage these conditions.
5.1.4
Treatment Compliance
Study subjects randomized to enzalutamide treatment should be counseled on the need to 
meet 100% compliance with study drug. Investigator or designee should ensure that study 
subjects meet this goal throughout the study. 
The dose and schedule of enzalutamide administered to each subject will be recorded on the 
appropriate form at each study visit. At each study visit after Randomization, the subject will 
be required to bring all unused study medication and empty study medication bottles to each 
visit. The quantity of study medication returned by the subject will be counted and recorded 
in the eCRF. 


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Treatment compliance will be verified by the accounting of study drug at each study visit 
during the one year treatment period. Reasons for dose delay, reduction or omission will be 
recorded. This information about enzalutamide will be used to assess subject compliance 
with the treatment. 
Treatment compliance should be monitored closely and deviation in compliance should be 
reported to the Sponsor.
Compliance of the study drug will be monitored by the accounting of unused medication
returned by the subject at the 3 Month, 6 Month, 9 Month and 12 Month Visits. Compliance 
will be documented.
5.1.5
Criteria for Continuation of Treatment 
Not applicable
5.1.6
Restrictions During the Study 
From the Screening Visit until the subject’s completion or discontinuation of the study, 
genomic tests on prostate biopsy specimens –
 
– are prohibited. 
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
The subject’s date of birth, sex, race, ethnicity, height and weight will be recorded at the 
Screening Visit. 
5.2.2
Medical History
Medical history will be obtained at the Screening Visit from each subject. All relevant past 
and present conditions, as well as prior surgical procedures and information about first 
degree relatives with prostate cancer, will be recorded. Any updates to the subject’s medical 
history will be recorded at the Randomization Visit (Study Day 1) prior to randomization.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
A detailed prostate cancer history for each subject will be obtained at the Screening Visit. 
This will include documenting the subject’s initial diagnosis of histologically proven 
adenocarcinoma of the prostate, GS at time of diagnosis, any prostate cancer-related 
biomarker testing done (as per standard of care) on biopsy samples or other samples from the 
time of diagnosis until the Screening Visit and other disease specific information as 
designated in the eCRF.
5.3
Efficacy Assessment
5.3.1
Histopathology
Transrectal ultrasound-guided prostate biopsies (with or without mpMRI targeting) are 
required for the Screening, 12 Month and 24 Month Visits. Additional transrectal ultrasound-
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guided prostate biopsies may be obtained based on investigator’s decision or local standard 
of care. 
All prostate biopsy samples obtained during a subject’s participation in the study will be 
submitted to the designated pathologist for central review. The central pathologist will be 
blinded to treatment allocation.
After 20 patients (total from both treatment arms) have had the one year biopsy completed, a 
feasibility assessment of the biopsy specimens will be performed. This will be done to assess 
for any possible treatment related effects on the histopathology of the biopsy specimens and 
implications this may have on the completion of the study.
With regards to the use of mpMRI targeting, each site must be consistent with their method 
of biopsy throughout the study, for all subjects they enroll. If mpMRI targeted biopsies are 
utilized, two biopsies are required from each target site as well as 12 systematic biopsies 
(12 core TRUS guided systematic biopsies including six lateral and six mid lobar cores from 
the base, middle and apex of the gland) at the same time. Before the start of the study, sample 
preparation and shipment procedures will be provided in a histopathology manual. 
The biopsy utilized for the Screening Visit must have been done within 6 months prior to the 
visit. A minimum of ten cores is required for this biopsy. A confirmatory biopsy before 
entering the study is not required, but may be done at the discretion of the investigator. The 
biopsy utilized for the Screening Visit must be submitted for central reading by the 
designated pathologist. Should there be disagreement between the local and central pathology 
reports regarding the subject’s eligibility per Inclusion Criteria 3 and Exclusion Criteria 2, 
the subject’s eligibility will be defined using categorization from the central pathologist.
If there is a significant clinical reason such as adverse changes on digital rectal examination 
or increase in PSA, biopsy is allowed based on investigator’s decision. If at any time during 
the study the patient considers intervention for prostate cancer, biopsy is allowed and 
recommended. Treatment decisions based on pathological progression are at the discretion of 
the individual investigator. 
Genomic tests on prostate biopsy specimens –
 
 – are prohibited during the subject’s participation in this study. 
For all biopsies obtained during the study, published criteria will be used to centrally 
diagnose pathological progression as defined above. Treatment decisions based on the biopsy 
results will be at the discretion of the investigator.
5.3.2
Therapeutic progression
At each study visit from the Randomization visit through the subject’s discontinuation, 
therapy for prostate cancer will be assessed. The subject will be considered as having 
therapeutic progression at the earliest occurrence of primary therapy for prostate cancer 
(prostatectomy / radiation / focal therapy / systemic therapy). 
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5.3.3
Prostate-Specific Antigen (PSA)
Serum samples for assessment of PSA levels will be collected at all study visits and analyzed 
by the designated central laboratory. Additional assessments of PSA levels during the 
subject’s participation in the study, either done for-cause or per standard of care, should be 
done through the designated central laboratory as well. 
Before the start of the study, sampling and shipment procedures will be provided in a 
laboratory manual. 
5.3.4
Brief Fatigue Inventory (BFI)
BFI consists of 5 questions to rapidly assess the severity and impact of cancer-related fatigue.
BFI will be completed by study subjects on paper during the Randomization (Day 1), 3 
Month, 6 Month, 12 Month, 18 Month and 24 Month Visits. Subjects who withdraw from the 
study before the 24 Month Visit will be asked to complete BFI at their final study visit.
Subjects should complete the BFI during the study visit instead of taking it home for 
completion. Before the start of the study, patient reported outcomes (PRO) instructions will 
be provided in a study PRO guidelines document. Site personnel should ensure subjects 
complete BFI in accordance with the BFI instructions and study PRO guidelines, and are 
responsible for entering the subjects’ responses into the eCRF.
5.3.5
Expanded Prostate Cancer Index Composite (EPIC)
EPIC is a multi-domain instrument that measures patient function and concerns following 
prostate cancer treatment. 
The urinary, sexual and hormonal domains of EPIC will be completed by study subjects on 
paper at the Randomization (Day 1), 6 Month, 12 Month, 18 Month and 24 Month Visits. 
Subjects who withdraw from the study before the 24 Month Visit will be asked to complete 
the EPIC assessments at their final study visit. Subjects should complete these components of 
EPIC during the study visit instead of taking them home for completion. Before the start of 
the study, PRO instructions will be provided in a study PRO guidelines document. Site 
personnel should ensure subjects complete these components of EPIC in accordance with the 
EPIC instructions and study PRO guidelines, and are responsible for entering the subjects’ 
responses into the eCRF.
5.3.6
Memorial Anxiety Scale for Prostate Cancer (MAX-PC)
MAX-PC is an instrument that measures anxiety in men with prostate cancer. 
MAX-PC will be completed by study subjects at the Randomization (Day 1), 6 Month, 
12 Month, 18 Month and 24 Month Visits. Subjects who withdraw from the study before the 
24 Month Visit will be asked to complete the MAX-PC assessments at their final study visit. 
Subjects should complete the MAX-PC during the study visit instead of taking them home 
for completion. Before the start of the study, PRO instructions will be provided in a study 
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of MAX-PC in accordance with the MAX-PC instructions and study PRO guidelines, and are 
responsible for entering the subjects’ responses into the eCRF.
5.3.7
Medical Outcomes Study 12-Item Short Form Survey (SF-12)
SF-12 is a 12 item instrument that measures overall health related quality of life.
SF-12 will be completed by study subjects at the Randomization (Day 1), 6 Month, 
12 Month, 18 Month and 24 Month Visits. Subjects who withdraw from the study before the 
24 Month Visit will be asked to complete the SF-12 at their final study visit. Subjects should 
complete the SF-12during the study visit instead of taking them home for completion. Before 
the start of the study, PRO instructions will be provided in a study PRO guidelines document. 
Site personnel should ensure subjects complete the SF-12 in accordance with the SF-12
instructions and study PRO guidelines, and are responsible for entering the subjects’ 
responses into the eCRF.
5.4
Safety Assessment
The safety evaluations including vital signs, adverse event recording, clinical laboratory 
assessments and physical examination will be performed according to Table 1: Study 
Schedule of Assessments. Measurements obtained during the Screening and Randomization 
Visits will be considered baseline values. 
5.4.1
Vital Signs
Vital signs including blood pressure, heart rate and temperature will be assessed at the 
Screening Visit, at each 3 monthly visit (between the Randomization and 24 Month Visits, 
inclusive), at each 6 monthly visit (after the 24 Month Visit, until the last subject has 
completed the 24 Month Visit), and at any unscheduled study visits (see Table 1  Study 
Schedule of Assessments). 
For each blood pressure measurement, the subject should be seated comfortably for at least 
5 minutes with the back supported, feet on the floor, arm supported in a horizontal position 
and the blood pressure cuff at heart level. The Investigator will use the same device model 
and cuff size throughout the study. The same arm should be used throughout the study. 
5.4.2
Adverse Events
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding 
adverse event collection and data handling.
5.4.2.1 Adverse Events of Possible Hepatic Origin
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study 
and receiving study drug is accompanied by increases in liver function testing (LFT, e.g.: 
AST, ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction.
Subjects with AE’s of hepatic origin accompanied by Liver Function Test (LFT)
abnormalities should be carefully monitored.


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5.4.3
Laboratory Assessments
Clinical laboratory assessments will be done at every scheduled visit, as well as at any 
unscheduled visits. Assessments of serum hormonal levels will be done at the 
Randomization, 6 Month and 12 Month Visits, at each 6 monthly visit (after the 24 Month 
Visit, until the last subject has completed the 24 Month Visit) and at any unscheduled study 
visits. 
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
See Table 1: Schedule of Assessments for study visit collection dates. 
Serum chemistries
Glucose
Calcium
Total protein 
Albumin
Sodium
Potassium
CO2
Chloride
BUN
Creatinine
ALP
ALT
AST
Bilirubin
Hematology
WBC count
WBC differential
RBC count
RDW
HCT
HgB
MCV
MCH
MCHC
Platelet count
MPV
PDW
Hormonal levels
Testosterone
DHT
Dihydroepiandrosterone
Androstenedione
Estradiol
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician. Any changes in laboratory 
values are to be evaluated by the Investigator. Clinically relevant changes must be recorded 
as AEs in the eCRF (see Section 5.5: Adverse Events and Other Safety Aspects).
Before the start of the study, sampling and shipment procedures will be provided in a 
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The Investigator may decide to repeat a laboratory assessment, should the results be outside 
normal ranges and considered clinically relevant, or if the original sample could not be 
analyzed.
If the blood sample at the Screening Visit cannot be analyzed, the test results are considered a 
lab error or the test results are increased related to a temporary condition unrelated to prostate 
cancer and likely to resolve at short notice, it is acceptable to repeat the laboratory tests to 
check eligibility criteria. The subject should be requested to come for an unscheduled visit 
between the Screening and Randomization Visits. If the repeat test results are still 
exclusionary, the subject should not be randomized. Repeat test to check eligibility criteria 
can only be repeated once before Randomization.
5.4.4
Physical Examination 
Each subject will have a physical examination performed at the Screening Visit and at all 
study visits except the Randomization Visit. A brief physical examination is required at each 
study visit except the Randomization Visit according to Table 1  Study Schedule of 
Activities, with the exception of the Screening Visit during which a complete physical 
examination will be completed. Date of physical examination and any clinically relevant 
adverse changes will be recorded as an AE in the eCRF. Weight will be recorded at each 
study visit. 
Digital rectal examination will be done at the Screening, 6 Month, 12 Month, 18 Month and 
24 Month Visits, as well as at the biannual (every 6 months) visits following the 24 Month 
Visit.
5.4.5
Electrocardiogram (ECG) 
A 12-lead ECG will be recorded as part of the Screening Visit procedures. The ECG must be 
done within 28 days prior to Randomization, and will be taken with the subject in the supine
position.
All tracings will be read locally by the Investigator or referral physician or Investigator’s 
designee to ensure patient safety and care management.  Any abnormalities must be 
evaluated in clinical context (based on subject’s medical history and concomitant medication) 
and the Investigator must determine if it is clinically significant. A copy of the original ECG 
traces should be maintained in the study file with the subject’s source records. Pertinent 
results from the locally read ECG report will be captured on the eCRF. 
5.4.6
Imaging
A multi gated acquisition (MUGA) scan or echocardiogram showing left ventricular ejection 
fraction (LVEF) ≥ 45% is required as part of the Screening Visit procedures only for subjects
with a history of anthracycline or anthracenedione (mitoxantrone) treatment. For these 
subjects, a MUGA scan or echocardiogram must be done by the Investigator or referral 
physician or Investigator’s designee within 28 days prior to Randomization. A copy of the 
original MUGA scan or echocardiogram should be maintained in the study file with the 


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subject’s source records. Pertinent results from the locally read MUGA scan or 
echocardiogram will be captured on the eCRF.
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or who has undergone study procedures and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event is considered “serious” if, in the view of either the investigator or Sponsor, 
it results in any of the following outcomes:
●
Results in death
●
Is life threatening (an adverse event is considered “life-threatening” if, in the view of 
either the investigator or Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more severe form, 
might have caused death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 


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an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
Special Situations occurring on the medicinal products administered to the subject as part of 
the study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)
All of the special situations noted above should be recorded on the (e)CRF. Any situation 
involving these special situations that also meet the criteria for an SAE should be recorded on 
the AE page of the (e)CRF and marked ‘serious’ and the SAE worksheet.
The Sponsor has a list of events that they classify as “always serious” events.  If an adverse 
event is reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.  
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse 
events whose relationship to the study drugs could not be ruled out".
Causal relationship
to the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and/or in  which other drugs, chemicals or 
underlying disease provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear.
Probable
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or  other drugs or chemicals, and 
which follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
AEs, including abnormal clinical laboratory values, will be graded using the National Cancer 
Institute (NCI)-Common Terminology Criteria for Adverse Event (CTCAE) guidelines 


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(Version 4.03). The items that are not stipulated in the NCI-CTCAE Version 4.03 will be 
assessed according to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations 
noted; intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization.
4-Life Threatening
Life threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the investigator must contact the Sponsor by 
telephone or fax immediately (within 24 hours of awareness).
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor immediately (within 24 hours of 
awareness). If submitting an SAE Worksheet is not possible or is not possible within 
24 hours, the local drug safety contact should be informed by phone.
For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please fax the 
SAE Worksheet to:
Astellas Pharma Global Development – United States
Product Safety & Pharmacovigilance, 
Fax number 888-396-3750 (alternate fax: 847-317-1241)
Email: Safety-US@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification.
Full details of the SAE should be recorded on the medical records and on the (e)CRF.
The following minimum information is required:
●
ISN/Study number,
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e. IND Safety 
Reports) to the regulatory agencies (i.e. FDA) as necessary, and will inform the investigators 
of such regulatory reports. Investigators must submit safety reports as required by their 


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Institutional Review Board (IRB)/Independent Ethics Committee (IEC) within timelines set 
by regional regulations (i.e. EU, (e)CTD, FDA). Documentation of the submission to and 
receipt by the IRB/IEC of expedited safety reports should be retained by the site.
The Sponsor or Sponsor’s designee will notify all investigators responsible for ongoing 
clinical studies with the study drug of all SAEs which require submission per local 
requirements /IRB/IEC / head of the study site.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the adverse event progresses to an "SAE", or if a subject experiences 
a new SAE, the investigator must immediately report the information to the Sponsor. 
Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed 
instructions on Drug Induced Liver Injury (DILI).
5.5.7
Monitoring of Common Serious Adverse Events
Common serious adverse events are SAEs commonly anticipated to occur in the study 
population independent of drug exposure. SAEs classified as “common” are provided in 
Appendix 12.3 Common Serious Adverse Events for your reference. The list does NOT 
change your reporting obligations or prevent the need to report an AE meeting the definition 
of an SAE as detailed above. The purpose of this list is to alert you that some events reported 
as SAEs may not require expedited reporting to the regulatory authorities based on the 
classification of “common serious adverse events” as specified in Appendix 12.3 Common 
Serious Adverse Events. The Sponsor will monitor these events throughout the course of 
the study for any change in frequency. Any changes to this list will be communicated to the 
participating investigational sites. Investigators must report individual occurrences of these 
events as stated in Section 5.5.5 Reporting of Serious Adverse Events. 
5.5.8
Procedure in Case of Pregnancy
If a partner of a male subject becomes pregnant during the study dosing period or within 
90 days from the discontinuation of dosing, the investigator should report the information to 
the Sponsor as if it is an SAE. The expected date of delivery or expected date of the end of 
the pregnancy, last menstruation, estimated conception date, pregnancy result and neonatal 
data etc., should be included in this information.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.


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When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the investigator. The investigator will report the pregnancy to 
the Sponsor as an SAE.
5.5.9
Emergency Procedures and Management of Overdose
There is no antidote for enzalutamide. In the event of an overdose, stop treatment with
enzalutamide and initiate general supportive measures based on the clinical presentation of 
the patient. Subjects may be at increased risk of seizures following an overdose.
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed. 
5.6
Test Drug Concentration
Not applicable
5.7
Other Measurements, Assessments or Methods
 
 
 
 
 
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5.7.3
Banking of Blood Samples for Future Studies (Optional)
Patients participating in ENACT will be provided, through the informed consent process, the 
option of having an additional sample (5 ml) collected at each phlebotomy session for storage 
and future analyses related to biomarker discovery for localized prostate cancer.  In the event 
additional investigations beyond these are contemplated, patients will be re-consented for this 
additional use of their biological material.  Samples will be stored for a maximum of 5 years 
and then destroyed thereafter.  Samples will be stored at -80◦C at a facility designated by the 
Sponsor.
5.8
Total Amount of Blood
Blood samples will be taken for the purposes of assessing serum hormone levels at the 
Randomization, 12 Month and 24 Month Visits, as well as at any unscheduled visits. Blood 
samples will be taken for the purpose of assessing PSA as well as hematology and chemistry
levels at all scheduled study visits as well as at any unscheduled visits.
The total amount of blood taken per subject solely for scheduled visits up to the 24 Month 
Visit is anticipated to be 150-165 ml. An additional 50 ml (5 ml per scheduled visit) will be 
collected if the subject chooses to provide blood samples for future analyses.
During the 6 monthly visits after the 24 Month Visit (which continue until the last subject has 
completed the 24 Month Visit), an anticipated 15 ml will be collected per visit, with an 
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additional 5 ml per visit collected if the subject chooses to provide blood samples for future 
analyses.
Furthermore, if any laboratory abnormalities are found for a subject, additional blood may be 
drawn for monitoring. 
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it. The medical monitor must be notified when an 
investigator terminates a subject’s involvement in the study due to the subject’s clinical 
condition. 
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
Study Discontinuation Criteria for Individual Subjects (during any study period):
●
Subject starts new anti-cancer therapy
●
Subject develops radiological progressive disease
●
Subject is lost to follow up despite reasonable efforts by the investigator to locate the
subject
●
Subject withdraws consent
●
Gross noncompliance with protocol: The medical monitor or investigator may request 
permanent treatment discontinuation in the event of a major protocol deviation such as 
administration of prohibited concomitant medication, lack of cooperation, or 
noncompliance.
●
Death
Subjects who are discontinued from enzalutamide treatment due to the below criteria should 
remain in the study and continue with the scheduled study visits for follow-up of their 
outcomes.
Criteria for Discontinuation of Enzalutamide Treatment for Individual Subjects:
●
Subject develops unacceptable toxicity
●
Subject withdraws consent for enzalutamide treatment but consents to continued study 
follow-up
Reasonable effort should be made to contact any subject lost to follow-up during the course 
of the study in order to complete study related assessments and retrieve any outstanding data 


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and study drug. Following unsuccessful telephone contact, an effort to contact the subject by 
mail using a method that provides proof of receipt should be attempted. Such efforts should 
be documented in the source documents.
6.2
Discontinuation of the Site
If an investigator intends to discontinue participation in the study, the investigator must
immediately inform the Sponsor. 
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD-US. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the Clinical Study Report (CSR).
Prior to Database Lock, a Final Review of Data and tables, listings and figures (TLFs)
Meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented.  A meeting to determine analysis set classifications may 
also be held prior to database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints and 
frequency and percentage for categorical endpoints.  
Unless otherwise specified, all statistical testing will be conducted using two-sided tests with 
a significance level of 0.05.
7.1
Sample Size
This study is designed to evaluate time to prostate cancer progression (pathological or 
therapeutic progression) as the primary end point. The overall two-sided type I error for this 
study is set at 0.05 level. The characteristics of time to prostate cancer progression 
(pathological or therapeutic progression) are used to determine the total sample size and 
overall duration.
A sample size of 222 subjects randomized in a 1 to 1 manner accrued over one year, a study 
duration of 3 years, loss-to follow-up of 16%, an assumed underlying hazard ratio of 0.52
and a three year median time-to-progression for the Control group (0.2310 rate) will result in 


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72 events (Fleshner et al., 2012). This sample size is sufficient to power this study at 80% 
with a two-sided type I error rate of 5%.
The assumed hazard ratio of 0.52 is consistent with Fleshner et al. (2012). Specifically, the 
Fleshner study is powered to detect a 39% failure rate reduction in the treated group with 
respect to a three year 45% failure rate in the control group. We used a more conservative 
30% failure rate reduction for the treated group and a 50% three year failure rate for the 
control group. This resulted in parameter estimates of 0.2310 for the Control group and 
0.1189 for the Treatment group, and thus, resulted in the hazard rate of 0.52.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in data specifications and the allocation of 
subjects to analysis sets will be determined prior to database hard-lock.
7.2.1
Full Analysis Set (FAS)
The full analysis set will consist of all subjects who are randomized.  This will be the primary 
analysis set for efficacy analyses.
7.2.2
Per Protocol Set (PPS)
The per protocol set will consist of patients who adhere to the protocol.  The criteria defining 
adherence to the protocol will be defined in the SAP. 
7.2.3
Safety Analysis Set (SAF)
For the statistical summary and analysis of safety data, the safety analysis set (SAF) will be 
used. The SAF consists of all subjects who enrolled into the study and were randomized.  
Therefore, the SAF is equivalent to the FAS.
7.2.4
Pharmacokinetic Analysis Set (PKAS)
Not applicable
7.3
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group for 
the SAF. Descriptive statistics will be included for continuous endpoints and frequency and 
percentage for categorical endpoints.
7.4
Analysis of Efficacy 
Efficacy analysis will be conducted on the FAS and PPS. The interpretation of results from
statistical tests will be based on the FAS. The PPS will be used to assess the robustness of the 
results from the statistical tests based on the FAS.
7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
The primary efficacy endpoint is time to prostate cancer progression (pathological or 
therapeutic), and the hypothesis for analysis is:


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H0: The times to progression for enzalutamide and AS are the same
H1: The times to progression for enzalutamide and AS are not the same
Median and 95% confidence intervals for time to prostate cancer progression (pathological or 
therapeutic) will be calculated with the Kaplan-Meier (KM) method for each treatment 
group.  Subjects with no cancer progression at the time of trial completion, discontinuation or 
death will be censored at the last assessment date. Additionally, subjects switching therapy
during the study will be censored at the time of the initial therapy switch, but subjects 
discontinuing therapy will not be censored until the time of study discontinuation. If less 
than 50% of subjects progress by study cut-off time, the 25th percentile and its two-sided 95% 
confidence interval will be reported.
Treatment group differences between enzalutamide versus AS will be based on a Cox 
regression model.  The resulting Hazard ratio (enzalutamide/AS) and 95% confidence 
interval will be included in the summary. Censoring assumptions will follow the same rules 
as applied for the KM estimates.  Fixed effects for the model will include the treatment 
groups, stratification factors, race, and time since prostate cancer diagnosis.  Complete details 
of the model and all covariates will be included in the SAP.
The proportional hazards assumption will be investigated graphically by the log on the 
negative log of the estimated survival versus the log on time to progression.
7.4.1.2 Secondary Analysis
The incidence of subjects with prostate cancer progression (pathological or therapeutic) will 
be summarized with frequencies and percentages.  Treatment group differences will be 
assessed using logistic regression and include two-sided 95% confidence interval estimates of 
the odds ratio.
7.4.1.3 Subgroup Analysis
Subgroup analyses of time to progression will be performed to evaluate the treatment effect 
based on the following subgroups: age, and race.  Further subgroups may be defined in the 
SAP. 
7.4.2
Analysis of Secondary Endpoints 
The incidence of negative biopsy for cancer and secondary rise in serum PSA will be 
summarized with frequencies and percentages at one and two years by treatment group, 
subgroup and overall.
Inferences will include 95% confidence intervals of the odds ratio for the primary endpoint 
between treatment groups. Comparison between enzalutamide and AS will be evaluated by 
logistic regression using the randomization stratification factors as fixed effects. 
Time to PSA progression will be analyzed with the same methods as detailed for the primary 
endpoint analysis in Section 7.4.1.1.  
BFI scores and change from baseline will be summarized with descriptive statistics by 
treatment group, stratification factors, subgroups and overall. Analyses of treatment group 


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differences will be analyzed with repeated measures linear models using subject as a random 
factor.  Fixed effects will include the stratification factors as appropriate (for the overall 
analysis), time, time-by-treatment interaction and baseline scores.  If the normality 
assumption is not valid, rank-based scoring will be used for inferences. Estimates will 
include 95% confidence intervals of least square means (LS Means) for each treatment group
with and without stratification factors as appropriate. If the normal assumption is rejected, 
estimates will include the 25th and 75th percentiles. 
Percent positive cores, SF-12 subdomain and the physical and mental component scores,
QOL/sexual function EPIC domains (urinary, sexual and hormonal), and MAX-PC total and 
subscale scores, and the respective change from baseline assessments for all will be analyzed 
by time point in the same manner as the BFI scores.  
7.4.3
Analysis of Exploratory Endpoints 
The SAP will detail exploratory endpoint analyses.
7.5
Analysis of Safety
7.5.1
Adverse Events 
All AEs will be collected and the severity of the AEs will be evaluated by the investigator 
based on the latest version of NCI-CTCAE. All AEs will be coded using the latest version of 
Medical Dictionary for Regulatory Activities (MedDRA) to preferred term, high level term 
and system organ class. AEs, SAEs, AEs leading to discontinuation and AEs related to study 
drug will be presented by the number and percentage of subjects by MedDRA system organ 
class and preferred term, relationship to study treatment and severity. The latest version of 
NCI-CTCAE will be used to classify laboratory values by toxicity grade. Descriptive 
statistics will be used for AEs.
7.5.2
Laboratory Assessments 
Laboratory data in this study consist of hematology, serum chemistry, PSA levels and 
hormonal levels.
 
 
Normal ranges will be applied to identify values that are outside the normal ranges and create 
NCI toxicity grade using the latest NCI-CTCAE. Parameters that have criteria available for 
both low and high values will be summarized for both criteria (low and high).
7.5.3
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time.  Vital signs data will be displayed in listings.
7.6
Analysis of Pharmacokinetics
Not applicable
CCI


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7.7
Protocol Deviations and Other Analyses  
Protocol deviations as defined in Section 8.1.6 will be summarized for all randomized 
subjects by treatment group and total as well as by site. A data listing will be provided by site 
and subject.   
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
No formal interim analysis is planned.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication and visit windows that will be detailed in the 
SAP.
Subjects who do not receive the study drug to which they have been randomized will be 
analyzed as treated.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the investigator 
or site designee should record data (including laboratory values, if applicable) in the eCRF 
within 7 days after the subject visit.
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies.
Laboratory tests on serum samples will be analyzed at the designated central laboratory. The 
central laboratory will compile the results and electronically transfer the data to Astellas or 
designee for inclusion in the clinical study database. 


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All transrectal prostate biopsy samples will be submitted, in accordance with the guidelines 
in the histopathology manual, for central pathology review and 
 
 by designated central laboratories. The designated centers performing 
these assessments will compile the results and electronically transfer the data to Astellas or 
designee for inclusion in the clinical study database.
For all central assessments of biopsy and serum samples, the results for each subject will be 
shared with the corresponding Investigator. 
Subject questionnaires (BFI; SF-12; EPIC urinary, sexual and hormonal domains; MAX-PC) 
will be completed by the subject on paper during the study visit. The investigator or site 
designee should review the questionnaires for completion while the subject is at the site. The 
investigator or site designee will enter the responses from the completed subject 
questionnaire into the EDC system. The monitor will collect the paper questionnaires, and 
submit them to the Sponsor or designee, ensuring a copy remains at site. For screen failures,
the demographic data, reason for failing, informed consent, inclusion and exclusion criteria 
and AEs will be collected in the eCRF.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated informed consent forms (ICFs)
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
Adverse events and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts 
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable)
8.1.3
Clinical Study Monitoring
The Sponsor or delegated Contract Research Organization (CRO) is responsible for 
monitoring the clinical study to ensure that subject's human rights, safety and well-being are 
protected, that the study is properly conducted in adherence to the current protocol and Good 
Clinical Practice (GCP), and study data reported by the investigator/sub-investigator are 
accurate and complete and that they are verifiable with study-related records such as source 
CCI


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documents. The Sponsor is responsible for assigning study monitor(s) to this study for proper 
monitoring. They will monitor the study in accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 "Specification of Source Documents") when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Sponsor or designated CRO of Sponsor in 
accordance with their standard operating procedures (SOPs) for data management. All study 
specific processes and definitions will be documented by Data Management. (e)CRF 
completion will be described in the (e)CRF instructions. Coding of medical terms and 
medications will be performed using MedDRA and World Health Organization (WHO) Drug 
Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who: 
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed withdrawal criteria during the study and not withdrawn.
●
Received wrong treatment or incorrect dose. 
●
Received excluded concomitant treatment.
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the Sponsor 
immediately.


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The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File (TMF).  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable. 
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.
8.2
Ethics and Protection of Subject Confidentiality 
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted.  IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet reporting criteria, as dictated by local regulations, will 
be reported to both responsible Ethics Committees and Regulatory Agencies, as required.
During the conduct of the study, the investigator should promptly provide written reports 
(e.g., ICH Expedited Reports, and any additional reports required by local regulations) to the 
IEC/IRB of any changes that affect the conduct of the study and/or increase the risk to 
subjects. Written documentation of the submission to the IEC/IRB should also be provided to 
Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days
after the close-out visit for APGD-sponsored studies, or for APEB/APEL-sponsored studies 
within one year after last subject out (LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 


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8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative and answer all questions regarding this study.  Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or  
legal representative, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed informed consent form will 
be given to the subject and the original will be placed in the subject’s medical record. An 
entry must also be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a 
signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
2.
The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must reconsent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the informed consent 
form. A copy of the signed informed consent form will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must be made in the 
subject’s records documenting the re-consent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.


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The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e. HIPAA).
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The investigator may use this information for the purpose 
of the study only. It is understood by the investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs and Investigator's File) and relevant correspondence.  These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, two years 
after approval of the NDA or discontinuation of the IND). The Sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued.  The investigator agrees to obtain the Sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records. The Sponsor will archive and 
retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the eCRFs supplied 
for each subject. 
The investigator and sponsor will mutually agree upon the storage format for the retention of 
electronic data.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments/substantial amendments and/or/non-substantial amendments. 


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Depending on the nature of the amendment, IRB/IEC, Competent Authority approval or 
notification may be required. The changes will become effective only after the approval of 
the Sponsor, the investigator, the regulatory authority and the IRB/IEC (if applicable).
Amendments to this protocol must be signed by the Sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor.  An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring Board 
(DSMB) | Monitoring Committee | Other Evaluation Committee(s)
Not applicable 
10.1
Other Study Organization
Not applicable


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11
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Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, et al. Dutasteride in localised prostate 
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Lancet 2012;379:1103-1111
Hu JC, Chang E, Natarajan S, Margolis DJ, Macairan M, Lieu P, et al. Targeted Prostate Biopsy to 
Select Men for Active Surveillance: Do the Epstein Criteria Still Apply? Journal of Urology 
2014;192:385-390.
Hussein AA, Welty CJ, Ameli N, Cowan JE, Leapman M, Porten SP, et al. Untreated Gleason grade 
progression on serial biopsies during prostate cancer active surveillance: clinical course and 
pathological outcomes. Journal of Urology 2015;194:85-90.
Jain S, Lowblaw A, Vesprini D, Zhang L, Kattan MW, Mamedov A, et al. Gleason upgrading with 
time in a large prostate cancer active surveillance cohort. Journal of Urology 2015;194:79-84.
Klotz L, Vesprini D, Sethukavalan P, Jethava V, Zhang L, Jain S, et al. Long-term follow-up of a 
large active surveillance cohort of patients with prostate cancer. Journal of Clinical Oncology 
2015;33:272-277. doi:10.1200/JCO.2014.55.1192. 
Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of 
a large, active surveillance cohort with localized prostate cancer. Journal of Clinical Oncology 
2010;28:126-131. 
Lane JA, Donova JL, Davis M, Walsh E, Dedman D, Down L, et al. Active monitoring, radical 
prostatectomy, or radiotherapy for localized prostate cancer: study design and diagnostic and 
baseline results of the ProtecT randomized phase 3 trial. The Lancet Oncology 2014;15:1109-
1118.
Lin DW, Newcomb LF, Brown EC, Brookes JD, Carroll PR, Feng Z, et al. Urinary TMPRSS2: ERG 
and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary 
Prostate Active Surveillance Study. Clinical Cancer Research 2013;19:2442-2450. 
Mercader M, Bodner BK, Moser MT, Kwon PS, Park ESY, Manecke RG, et al. T cell infiltration of 
the prostate induced by androgen withdrawal in patients with prostate cancer. Proceedings of 
the National Academy of Sciences 2001;98:14565-14570.
Mohler J, Bahnson RR, Boston B, Busby E, D'Amico A, Eastham JA, et al. NCCN clinical practice 
guidelines in oncology: Prostate cancer. Journal of the National Comprehensive Cancer 
Network 2010;8:162–200. 
Montgomery B, Joshua A, Gleave M, Fleshner N, Bubley G, True L, et al. A randomized, open-label, 
phase 2 study of enzalutamide as neoadjuvant therapy for patients undergoing prostatectomy 
for localized prostate cancer. Abstract at European Cancer Congress; 2015 Sep 25-29; Vienna, 
Austria.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate Cancer Version 
1.2015. 20th Annual Edition. Copyrighted 24-Oct-2014
Ouzzane A, Renard-Penna R, Marliere F, Mozer P, Olivier J, Barkatz J, et al. Magnetic Resonance 
Imaging Targeted Biopsy Improves Selection of Patients Considered for Active Surveillance 
for Clinically Low Risk Prostate Cancer Based on Systematic Biopsies. Journal of Urology 
2015;194:350-356.


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Ritch CR, Graves AJ, Keegan KA, Ni S, Bassett JC, Chang, SS, et al. Increasing use of observation 
among men at low risk for prostate cancer mortality. Journal of Urology 2015;193:801-806.
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg C, Miller K, et al. Increased survival with 
enzalutamide in prostate cancer after chemotherapy. New England Journal of Medicine. 
2012;367:1187-1197.
Shaw GL, Thomas BC, Dawson SN, Srivastava G, Vowler SL, Gnanapragasam VJ, et al. 
Identification of pathologically insignificant prostate cancer is not accurate in unscreened men. 
British Journal of Cancer 2014;110:2405-2411.
SEER 18 2005-2011, All Races, Males by SEER Summary Stage 2000.
Shore ND, Abbott B, Concepcion RS, Saltzstein D, Kaldate RR, Moyes K, et al. Stratification of risk 
for patients with prostate cancer at biopsy using CCP score. Meeting Abstract in Journal of 
Clinical Oncology 2013;31(February 20 Supplement):127. 
Stamatakis L, Siddiqui MM, Nix JW, Logan J, Rais‐Bahrami S, Walton‐Diaz A, et al. Accuracy of 
multiparametric magnetic resonance imaging in confirming eligibility for active surveillance 
for men with prostate cancer. Cancer 2013;119:3359-3366.
Strasner A and Karin M. Immune infiltration and prostate cancer. Frontiers in Oncology 2015;5:128.
Sundi D, Ross AE, Humphreys EB, Han M, Partin AW, Carter HB, et al. African American men with 
very low–risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: 
should active surveillance still be an option for them? Journal of Clinical Oncology 
2013;31:2991-2997.
Taneja SS. Re: Comparison of MR/Ultrasound Fusion-Guided Biopsy with Ultrasound-Guided 
Biopsy for the Diagnosis of Prostate Cancer [Urological Survey / Editorial Comment]. Journal 
of Urology 2015;194:112-115. doi:10.1016/j.juro.2015.04.062.
Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, Cookson MS, et al. Guideline for 
the management of clinicall localized prostate cancer: 2007 update. Journal of Urology 
2007;177:2106-2131.
Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, et al. Long-term 
Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1-and 
2-Year Open-label Follow-up Results. European Urology 2015. DOI: 
10.1016/j.eururo.2015.01.027 
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation 
antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-790.
Tseng KS, Landis P, Epstein JI, Trock BJ, Carter HB. Risk stratification of men choosing surveillance 
for low risk prostate cancer. Journal of Urology 2010;183:1779-1785.
Weiner AB, Patel SG, Etzioni R, Eggener SE. National trends in the management of low and 
intermediate risk prostate cancer in the United States. Journal of Urology 2015;193:95-102.


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Wilt TJ. Management of Low Risk and Low PSA Prostate Cancer: Long Term Results from the 
Prostate Cancer Intervention Versus Observation Trial. In: Cuzick J, Thorat MA. Prostate 
Cancer Prevention. Berlin: Springer Berlin Heidelberg; 2014. p.149-169.
Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, et al. Radical prostatectomy versus 
observation for localized prostate cancer. New England Journal of Medicine 2012;367:203-
213.


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
Prohibited Medications
The following medications are prohibited in the absence of disease progression:
●
5α-reductase inhibitors (finasteride, dutasteride)
●
Estrogens
●
Cyproterone acetate
●
Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)
●
Antiestrogens or other medications to manage gynecomastia / breast complications
●
Any other investigational agent
Restricted Medications
The following medications are restricted for subjects receiving enzalutamide; please 
reference Section 5.1.3 for more details regarding these restrictions:
●
Strong CYP2C8 inhibitors
●
Strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, 
rifampin, rifapentine), St. John’s Wort
●
Narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus)
●
Narrow therapeutic index drugs that are metabolized by CYP2C9 (e.g., phenytoin, 
warfarin) 
●
Narrow therapeutic index drugs that are metabolized by CYP2C19 (e.g., 
S-mephenytoin)
Restrictions on Concomitant Treatment
Antiestrogens or other medications to manage gynecomastia/breast complications of 
enzalutamide treatment are prohibited; please reference Section 5.1.3 for more details on 
management of gynecomastia/breast complications.


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at least 
ALT, AST, ALP and TBL). Testing should be repeated within 48-72 hours of notification of the 
test results. For studies for which a central laboratory is used, alerts will be generated by the 
central lab regarding moderate and severe liver abnormality to inform the investigator, study 
monitor and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 x ULN (in patients without liver 
metastases), > 5 x ULN (in patients with liver 
metastases)
or
> 2 x ULN
Severe*
> 3 x ULN
and
> 2 x ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 × ULN.
●
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metasteses).
●
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated).
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF) that has been developed globally and can be activated for any study or 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology
may be considered an important medical event and may be reported as a Serious Adverse 


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Event (SAE). The Sponsor should be contacted and informed of all subjects for whom severe 
hepatic liver function abnormalities possibly attributable to study drug are observed.
To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
Symptoms and new onset-diseases should be recorded as ‘adverse events’ on the AE 
page of (e)CRF. Illnesses and conditions such as hypotensive events and 
decompensated cardiac disease that may lead to secondary liver abnormalities should 
be noted. Non-alcoholic steatohepatitis (NASH) is seen in obese 
hyperlipoproteinemic and/or diabetic patients and may be associated with fluctuating 
aminotransferase levels. The investigator should ensure that the medical history form 
captures any illness that pre-dates study enrollment that may be relevant in assessing 
hepatic function.    
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the (e)CRF. Information on alcohol, other substance use and diet 
should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.
●
Based on the subject’s history, other testing may be appropriate including: 
○
acute viral hepatitis (A,B, C, D, E or other infectious agents) 
○
ultrasound or other imaging to assess biliary tract disease
○
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:
●
ALT or AST > 8 × ULN
●
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metasteses
●
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated)
●
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metasteses)
●
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia ( > 5%). 
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.


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*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 
(or transplant).” The two “requirements” for Hy’s Law are: 1. Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated patients to be discriminating”). 2. Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3 x ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple 
R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3.]
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.3
Common Serious Adverse Events
For this protocol, there is no list of common serious adverse events anticipated for the study 
population for the purposes of IND safety reporting. 


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13
SIGNATURES 
(GPF 4.00)

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Final Version 2.0, dated 16-OCT-2020 
A Randomized Study of Enzalutamide in Subjects with Localized 
Prostate Cancer Undergoing Active Surveillance (ENACT) 
ISN: 9785-MA-1010 
IND number: 74,563 
Astellas Pharma Global Development, Inc. (APGD)/ 1 
Astellas Way, Northbrook, IL 60062 
This confidential document is the property of the sponsor. No unpublished information contained 
in this document may be disclosed without prior written approval of the sponsor. 
NCT02799745


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
ADT 
Androgen Deprivation Therapy 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AR 
Androgen Receptor 
AS 
Active Surveillance 
AST 
Aspartate Aminotransferase 
BFI 
Brief Fatigue Index 
BMI 
Body Mass Index 
CBC 
Complete Blood Count 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
DHT 
Dihydrotestosterone 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EPIC 
Expanded Prostate Cancer Index Composite 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GS 
Gleason Score 
IRT 
Integrated Response Technology 
ISN 
International Study Number 
LS 
Least Square 
MAX-PC 
Memorial Anxiety Scale for Prostate Cancer 
MedDRA 
Medical Dictionary for Regulatory Authorities 
MiPS 
Michigan Prostate Score 
MMRM 
Mixed Model Repeated Measures 
mpMRI 
Multiparametric Magnetic Resonance Imaging 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multi Gated Acquisition Scan 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
PD 
Protocol Deviation 
PPS 
Per Protocol Set 
PSA 
Prostate Specific Antigen 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SEER 
Surveillance, Epidemiology and End Results 
SF-12 
Medical Outcomes Study 12-Item Short Form Survey 
TEAE 
Treatment-Emergent Adverse Event 


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Abbreviations 
Description of abbreviations 
TLFs 
Tables, Listings and Figures 
TRUS 
Transrectal Ultrasonography 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, interim analysis, or accumulation of a substantial amount of data to ensure lack of 
bias. If needed, revisions to the approved SAP may be made prior to database hard lock. 
Revisions will be version controlled. 
This statistical analysis is coordinated by the responsible biostatistician of Astellas Pharma 
US, Medical Affairs, Americas. Any changes from the analyses planned in the SAP will be 
justified in the Clinical Study Report (CSR). 
Prior to database hard lock, a final review meeting of data and tables, listings, and figures 
(TLFs) will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented. A meeting to determine analysis set classifications may 
also be held prior to database hard lock. 
1.1 
Background 
Prostate cancer is the most commonly diagnosed cancer (other than skin cancer) among men. 
In 2015 the American Cancer Society estimates that 220,800 men will develop prostate 
cancer in the United States and about 27,540 will die of prostate cancer (American Cancer 
Society, 2015). Of those diagnosed, 80% will be diagnosed with localized disease according 
to Surveillance, Epidemiology and End Results (SEER) data (SEER 18 2005-2011). For 
localized disease, there are multiple options – active surveillance (AS), radical prostatectomy 
and external beam radiotherapy / brachytherapy (NCCN, 2015). Interventional options, 
however, carry risks. Radical prostatectomy (open or robotic) has long term risks of erectile 
dysfunction and urinary incontinence. External beam radiation therapy and brachytherapy 
also carry risks, such as erectile dysfunction, urinary incontinence and bowel complications. 
AS has emerged as one of the recommended options for localized prostate cancer (Mohler et 
al, 2010; Thompson et al, 2007). AS use is increasing for low risk disease over the years 
2010-2013 compared to the years before then (Cooperberg & Carroll, 2015; Ritch et al, 2015; 
Weiner et al, 2015). Ritch et al (2015) also noted increasing use of observation for low risk 
prostate cancer in an analysis of the SEER-Medicare database. This increase in AS is mostly 
due to concern that clinically low risk prostate cancer is over-treated, and AS may reduce 
unnecessary treatment in these subjects. (Lane et al, 2014; Wilt, 2014; Wilt et al, 2012; Bill- 
Axelson et al, 2011). AS studies have also included men with higher risk features including 
Gleason pattern 4 (Klotz et al, 2015; Cooperberg et al, 2011). 
Subjects who progress on AS are at risk for sequelae of their prostate cancer and often 
receive interventions which carry significant risks and side effects. To date, no studies have 
been published with an intervention of a known anti-cancer agent in an AS population. 
Because of this, novel approaches are needed to both stratify and offer options for those on 
AS as well as to offer an intervention that might affect progression. Also, current AS groups 


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encompass different subject populations. Some populations with certain characteristics 
(related to medical or family history or 
 might progress more 
often on AS than other populations. This study will allow us to examine these issues, as well 
as to examine any effect of enzalutamide on these different subsets of subjects. The use of 
enzalutamide monotherapy will potentially allow for optimal tumor treatment without the side 
effects and effects on quality of life inherent to androgen deprivation therapy (ADT). 
CCI


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2 
FLOW CHART AND VISIT SCHEDULE 
 
Figure 1 
Flow Chart 




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1. 
Subjects will be followed every 6 months until the last subject (study-wide) has completed the 24m Visit. 
2. 
Unscheduled visits may be performed at any time during the study whenever necessary to assess for or follow-up on adverse events (AEs), at the subject’s 
request or if deemed necessary by the investigator. 
3. 
Medical history will include capturing information about any first degree relatives with prostate cancer. Any updates to the subject’s medical history will be 
recorded at the Randomization Visit (Study Day 1) prior to randomization. 
4. 
A complete physical examination will be completed at the Screening Visit. For all visits after the Randomization visit, only a brief physical examination is 
required. 
5. 
This procedure (if required) must be done within 28 days prior to randomization. 
6. 
A multi-gated acquisition (MUGA) scan or echocardiogram is only required if the subject has a history of anthracycline or anthracenedione (mitoxantrone) 
treatment. 
7. 
Clinical labs, which will be assessed by the study’s central laboratory, include serum chemistries (comprehensive metabolic panel) and hematology (CBC 
with differential). 
8. 
Serum hormonal levels to be measured are testosterone, DHT, dihydroepiandrosterone, androstenedione and estradiol. 
9. 
Serum PSA will be measured by the study’s central laboratory. 
10. If warranted per Investigator’s clinical opinion or per standard of care. 
11. 
. 
12. Biopsies may be done with or without mpMRI targeting. Sites must use a consistent method (either with or without mpMRI targeting) for all of their study 
subjects. Any biopsy performed during the subject’s study participation will be analyzed centrally (for histological reading, 
 
. 
13. Biopsy must be done within 6 months prior to the Screening Visit, and submitted for central analysis (histological reading, 
 
. For this biopsy, a minimum of 10 cores is required. 
14. Subjects who withdraw from the study prior to the 24m Visit will be asked to complete all subject reported outcomes questionnaires (BFI, SF-12, EPIC, 
MAX-PC) at their final study visit. 
15. Only the urinary, sexual and hormonal domains will be used. 
16. Adverse events (serious and non-serious) will be collected from the time the subject signs the consent form until the subject completes the study. 
17. Study drug is only applicable to subjects randomized to the enzalutamide arm; subjects randomized to AS will not be dispensed any study drug. 
18. Subjects will have the option of having an additional sample collected at each phlebotomy session for storage and analysis in future trials of future trials of 
biomarker discovery for localized prostate cancer 
CCI
CCI
CCI


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3 
STUDY OBJECTIVE(S) AND DESIGN 
3.1 
Study Objective(s) 
The primary objective is to compare the time to prostate cancer progression (pathological or 
therapeutic progression) between subjects treated with enzalutamide versus subjects 
undergoing active surveillance. 
The secondary objectives are to evaluate: 
● 
Safety 
● 
Proportion of subjects with negative biopsy for cancer at 1 year and 2 years 
● 
Percent of cancer positive cores at 1 year and 2 years 
● 
Time to PSA progression (secondary rise in serum PSA≥25% above baseline or ≥25% 
above nadir or absolute increase ≥ 2 ng/mL) 
● 
Proportion of subjects with secondary rise in serum PSA≥25% above baseline or ≥25% 
above nadir or absolute increase ≥ 2 ng/mL at 1 year and 2 years 
● 
Brief fatigue index (BFI) 
● 
Medical outcomes study 12-item short form survey (SF-12) 
● 
Expanded Prostate Cancer Index Composite (EPIC) questionnaire- urinary, sexual and 
hormonal domains 
● 
Memorial Anxiety Scale for Prostate Cancer (MAX-PC) questionnaire 
 
 
 
 
 
 
 
3.2 
Study Design 
This is a multicenter, randomized, open label exploratory study, conducted in the US and 
Canada, evaluating the efficacy and safety of enzalutamide for extension of time to prostate 
cancer progression (pathological or therapeutic) in subjects with clinically localized, 
histologically proven prostate cancer that is categorized as low risk or intermediate risk and 
who are under AS. A total of 222 subjects from approximately 50 centers will be enrolled. 
Subjects are eligible if they were diagnosed within 6 months of screening and have been on AS. 
A minimum of ten cores from transrectal ultrasound-guided prostate biopsy (mpMRI targeted 
versus non-mpMRI targeted) are required; confirmatory biopsy before entering the study is not 
required and is done at the discretion of the investigator. 
Low risk is defined as T1c-T2a, PSA<10, N0, M0 (or presumed N0, M0 if computerized 
tomography [CT]/bone scan not done due to low risk of metastases), GS ≤ 6, ECOG status ≤2 
and estimated life expectancy >5 years. Intermediate risk is defined as T2b-T2c, PSA<20, N0, 
M0 (or presumed N0, M0 if CT/bone scan not done), GS ≤7 (3+4 pattern only), ECOG status 
≤2 and estimated life expectancy > 5 years. 
Prostate cancer progression is defined as either therapeutic progression or pathological 
progression. Therapeutic progression is defined as the earliest occurrence of primary therapy 
for prostate cancer (prostatectomy / radiation / focal therapy / systemic therapy). Pathological 
progression is defined as increase in primary or secondary Gleason pattern by > 1 or higher 
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proportion of cancer positive cores (>15% increase). Subjects will be stratified by low versus 
intermediate risk and type of biopsy performed (mpMRI targeted versus non-mpMRI targeted). 
Subjects will be randomized (1:1) either to receive treatment with enzalutamide (160 mg), 
administered as four 40 mg capsules, by mouth, once daily or to AS during the one year study 
treatment period. Following the one year treatment period, all subjects will be followed for one 
additional year. Subjects will be followed up every 3 months for these 2 years, after which 
follow-up will either be every 6 months or unscheduled until the last subject finished their 2 
year follow-up. Serum PSA will be measured at baseline and every 3 months during subsequent 
follow-up visits. 
Digital rectal examination will be done at baseline and every 6 months during subsequent 
follow-up visits. All subjects will have transrectal ultrasound-guided prostate biopsy (with or 
without mpMRI targeting) at 12 months and 24 months with a standard of 12 cores required; 
two biopsies are required from each target site (if mpMRI is used) as well as 12 systematic 
biopsies (12 core transrectal ultrasonography [TRUS] guided systematic biopsies including six 
lateral and six mid lobar cores from the base, middle and apex of the gland) at the same time. 
All sites will be consistent with their method of biopsy (with regards to the use of mpMRI 
targeting) throughout the study for all subjects enrolled at that site. If there is a significant 
clinical reason such as adverse changes on digital rectal examination or increase in PSA, biopsy 
is allowed based on investigator’s decision. If at any time during the study the subject considers 
intervention for prostate cancer, biopsy is allowed and recommended. 
Treatment decisions based on pathological progression are at the discretion of the individual 
investigator. Hormonal levels (testosterone, DHT, dihydroepiandrosterone, androstenedione 
and estradiol) will be collected at baseline, 12 months and 24 months. Quality of life/sexual 
function questionnaires (EPIC), anxiety measures (MAX-PC), BFI, SF-12 assessments will also 
be done at baseline, 6 months, 12 months, 18 months and 24 months. An additional BFI 
assessment will be done at 3 months. Subjects who withdraw from the study before the 24 
Month visit will be asked to complete the EPIC, MAX-PC, BFI and SF-12 assessments at their 
final study visit. 
Subjects will be followed beyond the two year study period until the last subject has completed 
the 24 month visit. This additional follow up will entail biannual visits (every 6 months and/or 
unscheduled visits) that include measurement of serum PSA and digital rectal exam. 
All biopsy samples, including those collected for-cause or per standard of care, will be centrally 
read by a designated pathologist blinded to treatment allocation. CT, magnetic resonance 
imaging (MRI) and bone scan will be performed at the discretion of the investigator based on 
clinical need; when performed, these assessments will be read locally and recorded in the 
electronic case report form (eCRF). 
Throughout the study, safety and tolerability will be assessed by the recording of AEs, 
monitoring of vital signs, physical examinations and safety laboratory evaluations. 
A dose of 160 mg enzalutamide (four 40 mg capsules) once daily, administered orally, is the 
FDA approved daily dose for the indications in the approved labeling. 


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3.3 
Randomization 
Randomization will be performed on Study Day 1 via Interactive Response Technology (IRT). 
Prior to the initiation of the study treatment, the site staff will contact the IRT in order to 
determine the randomly assigned treatment. Specific procedures for randomization through 
the IRT are contained in the study procedures manual. 
The randomization allocation will consist of 1:1 ratio for once daily enzalutamide or AS. The 
randomization will be stratified according to the following two factors: 
● 
Low versus intermediate risk 
● 
Type of biopsy performed (mpMRI targeted versus non-mpMRI targeted) 
Additionally, enrollment of subjects with low risk prostate cancer will be capped to not 
exceed 80% of the study population. 
 
 
 


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4 
SAMPLE SIZE 
This study is designed to evaluate time to prostate cancer progression (pathological or 
therapeutic progression) as the primary endpoint. The overall two-sided type I error for this 
study is set at 0.05 level. The characteristics of time to prostate cancer progression 
(pathological or therapeutic progression) are used to determine the total sample size and 
overall duration. 
A sample size of 222 subjects randomized in a 1 to 1 manner accrued over one year, a study 
duration of 3 years, loss-to follow-up of 16%, an assumed underlying hazard ratio of 0.52 and 
a three year median time-to-progression for the Control group (0.2310 rate) will result in 72 
events (Fleshner et al., 2012). This sample size is sufficient to power this study at 80% with a 
two-sided type I error rate of 5%. 
The assumed hazard ratio of 0.52 is consistent with Fleshner et al. (2012). Specifically, the 
Fleshner study is powered to detect a 39% failure rate reduction in the treated group with 
respect to a three year 45% failure rate in the control group. We used a more conservative 
30% failure rate reduction for the treated group and a 50% three year failure rate for the 
control group. This resulted in parameter estimates of 0.2310 for the Control group and 
0.1189 for the Treatment group, and thus, resulted in the hazard rate of 0.52. 


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5 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. 
5.1 
Full Analysis Set (FAS) 
Full Analysis Set (FAS): This population includes all subjects who are randomized. This will 
be the primary analysis set for efficacy analyses. 
5.2 
Per Protocol Set (PPS) 
Per Protocol Set (PPS): This population includes all subjects who adhere to the protocol, i.e. 
all subjects who were randomized and who did not have any protocol deviations. 
The criteria used to define protocol deviations adheres to the International Conference of 
Harmonizations (ICH) definitions of protocol deviations and are defined in section 5.2.1. 
Final judgments on exclusion of subjects from PPS are to be made by the Astellas study team. 
The PPS will be a secondary analysis set for efficacy. Selected baseline demographic and 
baseline characteristics may also be summarized for the PPS. 
5.2.1 
Reasons for Exclusion From PPS 
All documented protocol deviations will be reviewed in the data review meeting prior to 
database lock. The following criteria listed in Table 3 may lead to subject’s exclusion from 
PPS 
Table 3 
ICH Category 
ICH Definition 
ENACT Interpretation 
PD [1] 
Subjects who entered the 
study even though they did 
not satisfy the entry criteria 
 Subject randomized 
without meeting the 
inclusion/exclusion criteria 
 Subject missed 
assessment(s)/procedure(s) 
impacting eligibility for 
study participation 
PD [2] 
Subjects who developed 
withdrawal criteria 
during the study but 
were not withdrawn 
 Subject developed 
withdrawal criteria 
during the study and was 
not withdrawn 
 


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PD [3] 
Subjects who received the 
wrong or incorrect 
treatment dose 
 Subject received wrong 
treatment or incorrect 
dose, or patient taking 
commercial Xtandi 
instead of study-labeled 
enzalutamide, also 
consuming drug that 
should have been 
quarantined 
PD [4] 
Subjects who received 
excluded concomitant 
treatment 
 Subject took medication 
prohibited by the protocol 
5.3 
Safety Analysis Set (SAF) 
Safety Analysis Set (SAF): This population includes all subjects who enrolled in the study are 
randomized to receive study drug. Therefore, the SAF is equivalent to the FAS.  This 
population will be used for analysis of safety data. 
5.4 
Pharmacokinetics Analysis Set (PKAS) 
Not Applicable 
5.5 
Pharmacodynamic Analysis Set (PDAS) 
Not Applicable 


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6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoint(s) 
The primary endpoint is time to prostate cancer progression (pathological or therapeutic 
progression). 
6.1.2 
Secondary Efficacy Endpoints 
The secondary endpoints are: 
● 
Safety 
○ Adverse events / treatment-emergent adverse events 
○ Clinical laboratory variables (hematology, biochemistry including liver 
enzymes and total bilirubin) 
○ Vital signs (systolic and diastolic blood pressure and pulse rate) 
○ 12-lead electrocardiogram (ECG) 
○ Physical examination assessments 
● 
Incidence of negative biopsies for cancer at 1 year and 2 years 
● 
Percent of cancer positive cores at 1 year and 2 years 
● 
Time to PSA progression (secondary rise in serum PSA≥25% of baseline or≥25% above 
nadir or absolute increase ≥ 2ng/mL) 
● 
Incidence of secondary rise in serum PSA≥25% baseline or ≥25% above nadir or 
absolute increase ≥ 2ng/mL at 1 year and 2 years 
● 
BFI 
● 
SF-12 assessments 
● 
EPIC questionnaire (urinary, sexual and hormonal domains) 
● 
MAX-PC questionnaire 
6.1.3 
 
 
 
 
 
 
 
 
6.2 
Pharmacokinetic Variables 
Not Applicable 
6.3 
Pharmacodynamic Variables 
Not Applicable 
CCI


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6.4 
Other Variables 
To clearly state, the following variables are defined: 
 
 Month = 30.4375 days. Year = 365.25 days. 
 BMI(kg/m2) = Weight(kg) / Height(m2) 
 Age at randomization= floor((intck(‘month’, birth date, randomization date) 
– (day(randomization date) < day(birth date)))/12 
 Time since initial/histological diagnosis (years) = [(date informed consent signed - date 
of initial/histological diagnosis) + 1]/365.25. 
 Time since initial diagnosis to Randomization (years) = [(date of Randomization – date 
of initial diagnosis) +1]/365.25. 
 The duration of treatment was calculated as the (last dose date – first dose date) + 1. 
 Number of pills taken from one visit to the next = number of pills dispensed – number 
of pills returned. 
 Study drug compliance at each visit is calculated as = [(number of pills dispensed 
– number of pills returned) / (4 * number of days in the visit period)] * 100. 
 Baseline results are defined as the last assessment prior to first dose of study drug, 
for subjects randomized to once daily enzalutamide. For subjects randomized to 
active surveillance, baseline is defined as the last assessment prior to or on the date 
of randomization. 
 Treatment Emergent Adverse Events (TEAEs) are any AEs occurring on or after 
date of first study drug dose date (or randomization for AS) until 30 days post-
treatment end date (or 1-year plus 30 days for AS). 
 Treatment Phase is defined as date of first study drug dose (or randomization for 
AS) until either 30 days post treatment end date or (if earlier) study discontinuation 
date. 
 1-Year Follow-Up Phase is defined as 31 days post treatment end date until either 
completing 1-Year Follow-Up or (if earlier) study discontinuation date. 
 Continued Follow-Up Phase is defined as the day after completing 1-Year Follow-
Up phase until study discontinuation date. 
Study Day is defined using the following step-wise function: 
 If date of interest is on or following randomization, Study Day = Date of Interest 
– Randomization Date + 1; 
 Else, Study Day = Date of Interest – Randomization Date. 
Change from baseline is the difference between the result on a post baseline visit and 
baseline assessment. 
Rise in serum PSA is defined as PSA ≥ 25% of baseline or ≥ 25% above nadir or 
absolute increase > 2ng/mL. 


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Progression-free survival is defined as the time (in months) from the date of randomization 
until the date of the cancer progression (pathological or therapeutic). Pathological 
progression is defined as increase in primary or secondary Gleason pattern by ≥ 1 or higher 
proportion of cancer positive cores (≥15% increase). Therapeutic progression is defined as 
the earliest occurrence of primary therapy for prostate cancer 
(prostatectomy/radiation/focal therapy/systemic therapy). 
Subjects with no cancer progression at the time of trial completion (the last study-wide 
subject completes a 24 month follow-up visit), discontinuation or death will be censored at 
the last assessment date. Subjects discontinuing therapy will not be censored until the time 
of study discontinuation. Additionally, subjects switching therapy during the study will be 
censored at the time of the initial therapy switch. 
For subjects on enzalutamide, TEAEs, defined as an adverse event observed after starting 
administration of the study drug and until 30 days after treatment end date, are categorized as 
AEs. If the adverse event occurs on Day 1 and the onset check box is marked “Onset after 
first dose of study drug” or the onset check box is left blank, then the adverse event will be 
considered treatment emergent. If the adverse event occurs on Day 1 and the onset check box 
is marked “Onset before first dose of study drug”, then the adverse event will be categorized 
as medical history. If a subject experiences an event both during the pre-investigational 
period and during the investigational period, the event will be considered as an AE only if it 
has worsened in severity (i.e. it is reported with a new start date). All adverse events collected 
that begin within 30 days following study discontinuation will also be counted. 
Percent positive cores are calculated using the number of systemically-sampled prostate 
regions and any targeted regions with at least one positive core divided by the total number of 
systematically-sampled regions and targeted regions. This implies that despite the number of 
samples within a given systematic or targeted region, any positive core will indicate that 
region as positive. 


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7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
In general, descriptive statistics are defined for continuous variables as number of subjects 
(n), mean, standard deviation, minimum, median and maximum, and as frequency and 
percentage for categorical variables. 
In summary and analysis tables of continuous variables, the minimum and maximum statistics 
will be presented to the same number of decimal places as the original data. The mean, 
median, quartile, and 2-sided 95% confidence interval (CI) will be presented to 1 more 
decimal place than the original data. The standard deviation and standard error will be 
presented to 2 more decimal places than the original data. 
In summary tables of categorical variables, the number of non-missing observations and 
percentages will be presented. Unless specified otherwise, percentages by categories will be 
based on the number of subjects with no missing data. For categorical variables with missing 
values, an additional level of the variable will be added to the summary as “Missing” and the 
frequency will be displayed but no percentage. 
Efficacy analysis will be conducted on the FAS and PPS. The primary analysis set for efficacy 
analyses will be the FAS. The PPS will be used to assess the robustness of the results from the 
statistical tests based on the FAS. Summaries based on FAS and PPS will be presented by 
planned treatment group, unless specifically stated otherwise. Safety analysis and other 
summaries based on SAF will be presented by actual treatment received. 
Unless otherwise specified, all statistical testing will be conducted using two-sided tests with 
a significance level of 0.05. 
All statistical analyses will be performed using SAS® v9.3 or higher. Specifications for table, 
figures, and data listing formats can be found in the TLF specifications for this study. 
For the definition of subgroups of interest please refer to section 7.8. 


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7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be presented: 
● 
Number of subjects with informed consent, discontinued before randomization, 
randomized (overall only); 
● 
Number of subjects randomized in each analysis set, by treatment group and overall; 
● 
Number and percentage of subjects that received study drug, by treatment group and 
overall; 
● 
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation for randomized subjects, by treatment group; 
● 
Number and percentage of subjects completed and discontinued the 1 year follow-up 
period, by primary reason for discontinuation, by treatment group and overall; 
● 
Number and percentage of subjects completed and discontinued the continued follow-up 
period, by primary reason for discontinuation, by treatment group and overall; 
● 
Number and percentage of subjects excluded from PPS by reason for exclusion defined 
in section 5.2.1, by treatment group and overall. 
7.2.2 
Protocol Deviations 
 
Protocol deviations will be reported in data listing(s) by site, treatment group and subject. And 
will be presented by Syneos Health no later than the data review meeting (DRM) in order to 
adjudicate deviations prior to database lock. All protocol deviations will be reviewed and 
categorized prior to the database lock. A major deviation has an impact on subject safety, may 
substantially alter risks to subjects, may have an effect on the integrity of the study data, or may 
affect the subject's willingness to participate in the study. A minor deviation is a minor or 
administrative departure from the protocol without prior consent and does not have an impact 
on subject safety, nor an effect on the integrity of the study data. 
7.2.3 
Demographic and Other Baseline Characteristics 
Demographic data (age, sex, race, and ethnicity) will be summarized by treatment group and 
overall for the FAS. Descriptive statistics will be included for continuous endpoints and 
frequency and percentage for categorical endpoints. 
Subject characteristics of height (in cm), weight (in kg), BMI at screening, substance 
use/tobacco history, 12-lead electrocardiogram interpretations, biopsy targeting method 
(mpMRI vs non-mpMRI), prostate cancer risk group (low vs. intermediate) and the incidence 
of relatives with prostate cancer and their age at diagnosis will be summarized with 
descriptive statistics by treatment group and overall for the FAS. 
Data listings will be presented for the demographic and baseline characteristic data. 


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7.2.4 
Previous and Concomitant Medications 
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) DDE version March 2016. Prior medications are non-study medications that are 
recorded and stopped prior to the screening visit date. Prior medications will be exclusively 
reported in data listings. Concomitant medications are those that start on or after the 
screening visit date. Non-medication therapies will not be coded and summaries will be 
limited to overall use, reason for use, and radiation details. 
Concomitant medications will be summarized descriptively for each treatment group and 
overall by therapeutic subgroup (ATC 2nd level), chemical subgroup (ATC 4th level) and 
preferred name by treatment group for the FAS and displayed in data listings. Subjects taking 
the same medication multiple times will be counted once per medication and investigational 
period. A medication that can be classified into several chemical and/or therapeutic subgroups 
is presented in all chemical and therapeutic subgroups. 
7.2.5 
Medical and Disease Histories 
Medical history including cancer (disease history), non-cancer history, and prior surgical 
procedures will be summarized by treatment group and overall for the FAS and coded using 
the Version 23.0 of the Medical Dictionary for Regulatory Activities (MedDRA) to system 
organ class and preferred term. The dictionary will up version once every two years pending 
sponsor decision. If a subject experienced more than one medical condition within a system 
organ class, the subject will be counted once under that system organ class. If a subject had 
more than one count for a particular preferred term, the subject will be counted once under 
that preferred term. 
Disease history data of time since initial diagnosis, time since histological diagnosis and 
incidence of Primary Gleason Pattern (at initial diagnosis), Secondary Gleason Pattern (at 
initial diagnosis), Total Gleason Score (at initial diagnosis), Clinical Tumor Stage (at initial 
diagnosis), Clinical Lymph Node Stage (at initial diagnosis), distant metastasis, prostate 
cancer-related biomarker testing done (from time of diagnosis until screening) will be 
summarized by descriptive statistics by treatment group and overall for the FAS. 
Data listings will be presented for the medical and surgical histories and disease history. 


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7.3 
Study Drugs 
7.3.1 
Exposure 
Active treatment for prostate cancer and type of therapies will be assessed at Randomization 
and every study visit thereafter until month 24 and unscheduled. The following information 
will be presented by treatment group for the FAS: 
● 
Descriptive statistics for cumulative amount of drug that a subject was exposed, and 
● 
Number and percent of subjects with dose decreases, increases or interruptions by 
treatment group. 
Duration of exposure will be summarized in two ways by treatment group. 
● 
Descriptive statistics for days on therapy. 
● 
Frequencies and percentages of exposure time (in days) as follows: 
○ less than 7 days 
○ at least 7 days, less than 14 days 
○ at least 14 days, less than 28 days 
○ at least 28 days, less than 42 days 
○ 42 days or more 
○ Unknown. 
7.3.2 
Treatment Compliance 
The study treatment administration and compliance profile will be summarized descriptively 
for each visit and overall for the SAF and displayed in data listings. Summaries for number 
of pills dispensed during a visit and number of pills taken (number of pills dispensed – 
returned) will be displayed. Compliance (%) for a particular visit will be calculated as: 
[(number of pills dispensed – number of pills returned) / (4 * number of days in the visit 
period)] * 100. 
Percent overall compliance will be summarized in two ways for the SAF: 
● 
Descriptive statistics will be presented by treatment group. 
● 
Percent compliance will be categorized according to the following categories by 
treatment group: 
○ less than 50% 
○ at least 50%, less or equal to 75% 
○ greater than 75% 
○ Unknown. 


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7.4 
Analysis of Efficacy 
All efficacy analyses will be performed on the FAS and PPS. 
7.4.1 
Analysis of Primary Endpoint(s) 
The primary efficacy endpoint is time to prostate cancer progression (pathological or 
therapeutic), and the hypothesis for analysis is: 
H0: The time to progression for Enzalutamide and Active Surveillance (AS) are the 
same H1: The time to progression for Enzalutamide and AS are not the same 
Median and 95% confidence intervals for time to prostate cancer progression (pathological or 
therapeutic) will be calculated with the Kaplan-Meier (KM) method for each treatment group. 
Subjects with no cancer progression at the time of trial completion, discontinuation or death 
will be censored at the last assessment date. Additionally, subjects switching therapy during the 
study will be censored at the time of the initial therapy switch, but subjects discontinuing 
therapy will not be censored until the time of study discontinuation.  If less than 50% of 
subjects progress by study cut-off time, the 25th percentile and its two-sided 95% confidence 
interval will be reported. KM plots will be generated. 
Treatment group differences between enzalutamide versus AS will be based on a Cox 
regression model.  The resulting Hazard ratio (enzalutamide/AS) and 95% confidence 
interval will be included in the summary. Censoring assumptions will follow the same rules 
as applied for the KM estimates. Fixed effects for the model will include the treatment 
groups, randomization stratification factors [prostate cancer risk (low/intermediate), type of 
biopsy performed (mpMRI targeted/non mpMRI targeted)], age, race, and time since prostate 
cancer diagnosis. Additionally, a random effect of site will be included in the model. 
The association between the survival time, log of time to disease progression, and 
survival probability, log negative log, will be investigated graphically by Cox 
proportional-hazards models. If the proportional hazards assumption is violated, 
appropriate remedial methods will be investigated and applied.  
Data listings will be provided. 
In addition to an overall analysis, the primary and secondary analyses will be repeated for 
pathological progression and therapeutic progression, individually. 
Secondary Analyses 
The incidence of subjects with prostate cancer progression (pathological or therapeutic) will 
be summarized with frequencies and percentages at one year, two years, and study 
completion. Treatment group differences will be assessed using a logistic regression with the 
same covariates and random effect used in the primary analysis and include two-sided 95% 
confidence interval estimates of the odds ratio. 
In addition to an overall analysis, the primary and secondary analyses will be repeated for 
pathological progression and therapeutic progression, individually. 
Subgroup Analysis 
Subgroup analyses of time to progression will be performed to evaluate the treatment effect 
based on the following subgroups: age (<65, 65 to <75, and >=75), race, and BMI at screening 


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(<25; 25-30; and >30). Kaplan-Meier methods, Cox regression models and censoring rules 
described in section 7.4.1 will be used for each analysis. Summary tables will be presented. 
Stratification Factors 
Analyses of time to progression will include randomization stratification factors to evaluate 
their effects. These factors are prostate cancer risk (low and intermediate) and type of biopsy 
performed (mpMRI targeted and non-mpMRI targeted). 
7.4.2 
Analysis of Secondary Endpoints 
Cancer Biopsy Incidence and Secondary Rise in PSA 
The incidence of negative biopsy for cancer and secondary rise in serum PSA will be 
summarized with frequencies and percentages at one and two years by treatment group, 
subgroups and overall. 
Treatment comparisons will be performed using the exact binomial distribution as well as the 
normal approximation to the binomial distribution. Inferences will include 95% confidence 
intervals of the odds ratio for each endpoint between treatment groups at both Year 1 and 
Year 2 for biopsies and for each of Years 1 and 2 and end of study for PSA. Comparison 
between enzalutamide and AS will be evaluated by logistic regression using the treatment 
groups, randomization stratification factors [prostate cancer risk (low/intermediate), type of 
biopsy performed (mpMRI targeted/non mpMRI targeted)], age, race, and time since prostate 
cancer diagnosis as fixed effects and site and subject as random effects. 
Time to PSA progression will be analyzed with the same methods as detailed for the primary 
endpoint analysis in Section 7.4.1. 
Brief Fatigue Inventory 
The Brief Fatigue Inventory (BFI) is a questionnaire that assesses tiredness, fatigue, ability to 
perform general activities, mood, walking ability, interaction with others, etc. using 9 
questions, assessed at Randomization, 3, 6, 12, 18, and 24 months. The answers range from 
“0 – minimal/does not interfere” to “10 – severe/completely interferes.” Standard composite 
scores and change from baseline at each time point will be summarized with descriptive 
statistics by treatment group, stratification factors [prostate cancer risk (low/intermediate) 
and type of biopsy performed (mpMRI targeted/non-mpMRI targeted)], subgroups (age, race, 
and BMI at Screening) and overall. Composite scores for all licensed instruments will be 
calculated per the licensing agreements. 
When there are missing data, if half or more questions within scale are answered then a score 
will be calculated for that scale. Otherwise the patient score for that scale will be missing. 
For single-item measures, a missing score will not be imputed. 
BFI compliance and completion rates at each visit will be calculated using the following 
definitions: 
 BFI compliance rate: will be defined as the proportion of patients who completed the 
PRO instrument among those who were expected to complete at each visit, excluding 
those missing by design (e.g. death, discontinuation of treatment, or no visit 
scheduled). 


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 BFI completion rate: defined as the proportion of patients who completed the PRO 
instrument at baseline and >=1 assessment subsequently among those who completed 
PRO baseline and are remaining in study at each follow up timepoint. 
SF-12 
The Medical Outcomes Study 12-Item Short Form Survey (SF-12) is a questionnaire that 
measures overall health related quality of life using 12 questions, assessed at Randomization, 
6, 12, 18, and 24 months. Summation of standardized questions’ scores are used to calculate 
the PCS and MCS Composite Scores. Scores and change from baseline will be analyzed at 
each time point and overall in the same manner as the BFI scores. To distinguish clinically 
meaningful differences from statistically significant differences, the minimum clinically 
important difference (MCID) will be calculated using a distribution-based approach as 0.5 
baseline score standard deviation pooled over treatment groups for each domain. Equivalence 
will be demonstrated when the entire 95% confidence interval for the adjusted mean 
difference or change is within the range from −MCID to + MCID. 
Similar to BFI, SF-12 compliance and completion rates will be calculated at each visit. 
Expanded Prostate Cancer Index Composite (EPIC) 
The EPIC Hormonal Assessment is a questionnaire used to measure quality of life issues in 
patients with prostate cancer. There are a total of 11 questions assessed at Randomization, 6, 
12, 18 and 24 months related to hormonal function such as hot flashes, breast tenderness, 
depression, lack of energy, weight fluctuation, etc. The answers range from “more than once 
a day” to “rarely or never” and “no problem” to “big problem.” 
The EPIC Sexual Assessment is a questionnaire used to measure quality of life issues in 
patients with prostate cancer. There are a total of 13 questions assessed at Randomization, 6, 
12, 18 and 24 months related to sexual function such as level of sexual desire, ability to have 
an erection, ability to reach orgasm, quality and frequency of erections, frequency of sexual 
intercourse, etc. The answers range from “very poor” to “very good,” “never” to “daily,” and 
“no problem” to “big problem.” 
The EPIC Urinary Assessment is a questionnaire used to measure quality of life issues in 
patients with prostate cancer. There are a total of 12 questions assessed at Randomization, 6, 
12, 18 and 24 months related to urinary function such as leaking urine, blood in urine, pain or 
burning with urination, urinary control and frequency, etc. The answers range from “more 
than once a day” to “rarely or never” and “no problem” to “big problem.” 
Total composite and each domain score (hormonal, sexual, and urinary) and their 
corresponding change from baseline assessments will be analyzed by time point and overall 
in the same manner as the BFI scores. 
If >20% of the items that comprise a domain summary score or subscale score are missing a 
response, the corresponding domain summary or subscale score can not be calculated). 
To distinguish clinically meaningful differences from statistically significant differences, the 
minimum clinically important difference (MCID) will be calculated using a distribution-
based approach as 0.5 baseline score standard deviation pooled over treatment groups for 
each domain score and the total composite score. Equivalence will be demonstrated when the 


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entire 95% confidence interval for the adjusted mean difference or change is within the range 
from −MCID to + MCID. 
Similar to BFI, EPIC compliance and completion rates will be calculated at each visit for 
each of the EPIC assessments. 
Memorial Anxiety Scale for Prostate Cancer 
The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) is a questionnaire used to assess 
patients’ feelings about prostate cancer and PSA tests. There are a total of 18 questions 
assessed at Randomization, 6, 12, 18 and 24 months related to understanding how patients 
cope with aspects of their treatment and medical tests frequently involved in their care; 
questions such as strong feelings about prostate cancer, scared of PSA tests, trouble sleeping 
due to thoughts of prostate cancer, unable to plan for the future due to prostate cancer, fear of 
cancer getting worse, etc. The answers range from “not at all” to “often” and “strongly 
disagree” to “strongly agree.” 
When there are missing data, if 66% or more questions within scale are answered then a score 
will be calculated for that scale. Otherwise the patient score for that scale will be missing. For 
single-item measures, a missing score will not be imputed. 
Total composite scores and change from baseline will be analyzed by time point and overall in 
the same manner as the BFI scores. Composite scores for all licensed instruments will be 
calculated per the licensing agreements. 
Data listings including individual scores, subscale scores and total scores will be provided by 
treatment group and visit for all patient reported outcomes. 
To distinguish clinically meaningful differences from statistically significant differences, the 
minimum clinically important difference (MCID) will be calculated using a distribution-based 
approach as 0.5 baseline score standard deviation pooled over treatment groups for each 
domain score and the total composite score. Equivalence will be demonstrated when the entire 
95% confidence interval for the adjusted mean difference or change is within the range from 
−MCID to + MCID. 
Similar to BFI, MAX-PC compliance and completion rates will be calculated at each visit for 
each of the EPIC assessments. 
Cancer Positive Cores 
Percent of cancer positive cores, assessed using the number of systemically-sampled prostate 
regions and any targeted regions with at least one positive core (see Section 6.4 for details), 
will be analyzed at Screening, 12, and 24 months.  
Analyses of treatment group differences for the change from baseline composite score will be 
analyzed with a Mixed Model Repeated Measures (MMRM) model using subject and site as a 
random factors. For the variance- covariance matrix, compound symmetry (CS), 
autoregressive (AR1) and unstructured (UN) will be assessed and the best fit will be chosen 
based on Akaike Information Criteria (AIC) or AICC (correction for finite sample sizes). 
Degrees of freedom will be approximated using the Kenward-Roger method. Fixed effects 
will include treatment group, the stratification factors [prostate cancer risk (low/intermediate) 
and type of biopsy performed (mpMRI targeted/non- mpMRI targeted)], time, time-by-
treatment interaction and baseline composite score. Estimates will include 95% confidence 


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intervals of least square means (LS Means) for each treatment group by nominal time point 
and overall. P-values will be adjusted using the bonferroni-holm method to adjust for 
multiplicity. Additionally, assessments of treatment group differences will be made at 3, 6, 12, 
and 24 months, as well as for the overall model. 
7.4.3 
 
 
 
 
 
 
 
 
 
 
 
 
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7.5 
Analysis of Safety 
The following summary tables and listings will be displayed for the SAF. 
7.5.1 
Adverse Events 
All AEs will be collected and the severity of the AEs will be evaluated by the investigator 
based on Version 4.03 of the NCI-CTCAE criteria, updating to the latest version per 
sponsor decision. All AEs will be coded using the Version 23.0 of the Medical Dictionary 
for Regulatory Activities (MedDRA) to preferred term, high-level term and system organ 
class, up versioning every two years per sponsor decision. 
Adverse events occurring before randomization will be recorded as medical history events. 
To maintain naming consistency with subjects on Active Surveillance (AS), Treatment- 
Emergent Adverse Events (TEAEs) for subjects on Enzalutamide will be reported as 
Adverse Events (AEs). 
An overall summary table will be included that has the following information by treatment 
group and overall by analysis phase (Treatment, 1-Year Follow-Up and Continued 
Follow-Up): 
● 
Number and percentage of subjects with AEs 
● 
Number and percentage of subjects with causally drug-related AEs 
● 
Number and percentage of subjects with serious AEs 
● 
Number and percentage of subjects with serious drug-related AEs 
● 
Number and percentage of subjects with AEs leading to permanent discontinuation of 
study drug, 
● 
Number and percentage of subjects with drug-related AEs leading to permanent 
discontinuation of study drug 
● 
Number of deaths. 
Furthermore, the number of events and number (%) of subjects with AEs, drug-related AEs, 
serious AEs, drug-related serious AEs, AEs leading to permanent discontinuation of study 
drug, drug-related AEs leading to permanent discontinuation of study drug, and common 
AEs occurring in at least 3.5% of any treatment group will be summarized by MedDRA 
system organ class and preferred term by treatment group and overall. Additional summary 
tables will be provided for AEs by relationship to study treatment and by CTCAE maximum 
severity grade. For subjects with missing relationship, the most conservative (related) will be 
assumed for table summaries. 
If a subject reports the same event multiple times, the event will only be displayed once in 
the summary tables at the highest grade and relationship to study drug. 
Version 4.03 of the NCI-CTCAE criteria, updating to the latest version per sponsor decision, 
will be used to classify laboratory values by toxicity grade. 
Listings of AEs, SAEs, Deaths and AEs leading to study drug discontinuation will be 
displayed by treatment group and site. 
7.5.2 
Clinical Laboratory Evaluation 
Clinical laboratory assessments will be done at every scheduled visit, as well as at any 
unscheduled visits. Assessments of serum hormonal levels will be done at the 


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Randomization, 12 Month Visits, 24 month and at any unscheduled study visits. Summary 
tables will be presented for all scheduled visits. Unscheduled visits will be displayed in 
listings only. Values outside the normal range will be flagged. 
Laboratory data in this study consist of hematology (WBC count, WBC differential, RBC 
count, RDW, HCT, HgB, MCV, MCH, MCHC, Platelet count, MPV), serum chemistry 
(Glucose, Calcium, Total protein, Albumin, Sodium, Potassium, CO2, Chloride, BUN, 
Creatinine, ALP, ALT, AST, Bilirubin), PSA levels and hormonal levels (Testosterone, DHT, 
Dihydroepiandrosterone, Androstenedione, Estradiol). 
The results will be summarized by treatment group for actual values and change from 
baseline. Normal ranges will be applied to identify values that are outside the normal ranges. 
Shift analysis tables will be provided for each parameter to present shift from baseline to 
each visit for low, normal and high values. 
Laboratory results will be graded using the Version 5.0 of the NCI-CTCAE criteria, updating 
to the latest version per sponsor decision. Shift tables will be produced and will report the 
baseline NCI-CTCAE grade vs. the worst grade recorded at any post-baseline visit. 
7.5.2.1 Liver Enzymes and Total Bilirubin 
Detailed testing for liver enzymes, specifically ALT, AST, and Total Bilirubin, are done at 
every study visit starting with Randomization and up to month 24 and unscheduled. 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
Moderate: AST or ALT [ >3 x ULN (in patients without liver metastases); >5 x ULN (in 
patients with liver metastases)] or (Total Bilirubin >2 x ULN). 
Severe: AST or ALT >3 x ULN and Total Bilirubin >2 x ULN. 
In addition, the subject will be considered to have severe hepatic abnormalities for any of the 
following: 
● 
ALT or AST > 8 × ULN. 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases). 
● 
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
7.5.3 
Vital Signs 
Vital signs [temperature (in Celsius), blood pressure (mmHg), pulse rate (beats/min), and 
respiratory rate (breaths/min)] will be summarized by treatment group at the Screening Visit 
and at all study visits for actual values and change from baseline. All data will be displayed 
in listings by treatment group and visit. 
7.5.4 
Electrocardiograms (ECGs) 
12–Lead ECG will be performed at the Screening visit only and summarized with the 
baseline characteristics summary by treatment group. 
7.5.5 
Transrectal Ultrasound-guided Prostate Biopsy and Lesion Details 
Results from the Transrectal ultrasound-guided prostate biopsy at Screening, 12 and 24 
months will be summarized in tables and displayed in data listings. Descriptive statistics will 


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be included for continuous endpoints and frequency and percentage for categorical endpoints. 
Lesion details will be summarized in a table by visit and treatment group and displayed in 
data listings. 
7.5.6 
Physical Examinations 
General physical examination will be performed at Screening and any abnormal finding will be 
reported in the medical history form should the finding occur prior to randomization, or on the 
AE form post-randomization. Therefore, no physical examination data will be displayed. 
A breast exam will be performed at the Screening Visit and at all study visits except the 
Randomization Visit. Results of the exam will be summarized in a table by treatment group and 
included in a subject listing. Any other abnormal findings/conditions identified during the 
breast exam are reported in the medical history form or AE form. 
Prior digital rectal examination and current rectal examination results will be summarized by 
treatment group at the Screening, 6 Month, 12 Month, 18 Month and 24 Month Visits, as well 
as at the biannual (every 6 months) visits following the 24 Month Visit. Exam results will be 
also be displayed in a subject listing. 
7.6 
Analysis of PK 
Not Applicable 
7.7 
Analysis of PD 
Not Applicable. 
7.8 
Subgroups of Interest 
Subgroup analyses of time to progression will be performed to evaluate the treatment effect 
based on the following subgroups separately: age (<65, 65 to <75, and >=75), race (white, 
black or African American, and the combined categories of Asian, American Indian or 
Alaska native, Pacific islander), and BMI (<25; 25-30; and >30). 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not Applicable 


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7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
7.10.1 
Missing Data 
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates and relationship of AEs and CMs and visit windows. 
All analysis will be based on available data to summarize safety and efficacy results. 
However, a conservative approach to partial dates and missing adverse event relationships 
will be as follows: 
● 
For survival analyses, if a subject’s death month and year are provided but the day is 
missing, the day will be set to the first day of the month, unless other qualifying study 
data support survival until a later date in the same month. 
● 
For subjects in the enzalutamide arm, adverse events with partial dates with the same 
month and year as the first dose date of study drug will be considered as treatment- 
emergent adverse events. 
● 
For subjects in the enzalutamide arm, if an adverse event’s relationship is missing, it will 
be assumed to be related. 
● 
For subjects in the enzalutamide arm, if the AE or CM start day is missing, then impute the 
1st of the month unless month and year are the same as the month and year of first dose of 
study drug, then impute AE/CM start date with the first dose date. If the start month and 
day are both missing, then impute 01JAN unless the year is the same as first dose date, then 
impute AE/CM start date with the first dose date. If the entire start date is missing, then no 
imputation will be performed, but the AE will be considered treatment-emergent. 
● 
For subjects on active surveillance, if the AE or CM start day is missing, then impute the 
1st of the month unless month and year are the same as the month and year of 
randomization, then impute AE/CM start date with the randomization date. If the start 
month and day are both missing, then impute 01JAN unless the year is the same as 
randomization date, then impute AE/CM start date with the randomization date. If the 
entire start date is missing, then no imputation will be performed, but AE will be considered 
to have occurred on or after randomization date. 
● 
For subjects in the enzalutamide arm, if the adverse event or concomitant medication end 
day is missing, then impute the last day of the month unless month and year are the same 
as month/year of last dose of study drug, then impute last dose date. If the end month and 
day are both missing, then impute 31DEC unless year is the same as first dose date, then 
impute last dose date. If the entire end date is missing, then no imputation will be performed 
and the event will be considered “ongoing.” 
● 
For subjects on active surveillance, if the adverse event or concomitant medication end day 
is missing, then impute the last day of the month unless month and year are the same as 
month/year of last day of 1 year of active surveillance, then impute last date on active 
surveillance. If the end month and day are both missing, then impute 31DEC unless year 
is the same as randomization date, then impute last date on active surveillance. If the entire 
end date is missing, then no imputation will be performed and the event will be considered 
“ongoing.” 
All AE and concomitant medication imputation of missing dates and relationship will be 


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considered for tabular summaries but not for data listings. Data listings will display missing 
values. Subjects who do not receive the study drug to which they have been randomized 
will be analyzed as treated. 
7.10.2 
Outliers 
All values will be included in the analyses. 
7.10.3 
Visit Windows 
For reporting by nominal time point, assessments will be imputed with the following 
windowing conventions: 
 
Nominal Visit 
Target Study Day 
(per Section V of the 
Protocol) 
Study Day Window (inclusive) 
3 Month 
85 
43 to 130 
6 Month 
176 
131 to 221 
9 Month 
267 
222 to 312 
12 Month 
358 
322 to 406 
15 Month 
455 
407 to 500 
18 Month 
545 
501 to 590 
21 Month 
635 
591 to 682 
24 Month 
730 
683 to 754 
For nominal time points with a nominal visit corresponding, this value will be used. If no 
nominal assessment exists, but an unscheduled assessment is windowed into the time point, 
this windowed assessment will be used. If more than one unscheduled assessment exists in 
the window (and there is no nominal visit assessment), the latest value will be used. 
7.10.4 
Site Pooling 
Data will be pooled from sites for these analyses. The justification for pooling is made on a 
clinical basis (Meinert, 1986). The basis for pooling comes from three critical factors: 1) The 
study sites must implement one common protocol. 2) The sponsor must provide very close 
monitoring of study site compliance. 3) The study sites must use common data collection 
procedures. 


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8 
SAP DEPARTURES FROM THE PROTOCOL 
- 
 
 
- 
Primary and secondary analysis will be done separately for therapeutic and 
pathological progression, in addition to overall. 
- 
FAS and SAF would be different in the case of subjects randomized to 
enzalutamide treatment group end up discontinuing before taking a single 
dose of the study drug 
- 
It is unlikely but possible to have dose increases. Such a possibility has been 
accounted for in the relevant table and listing. 
- 
“Age” will be an additional fixed effect used in the statistical models. 
- 
“Site” will be an additional random effect used in the statistical models. 
- 
 
- 
ENACT study is conducted in patients with localized disease who are candidate for 
Active Surveillance, the use of questionnaire such as BFI, SF-12, MAX-PC and 
EPIC have not been validated in this patient population, as a result analysis of PROs 
will be limited to descriptive statistics. The details of descriptive analyses can be 
found in respective PRO sections.   
- 
All analyses will be performed separately by stratification factors [prostate cancer risk 
(low/intermediate) and type of biopsy performed (mpMRI targeted/non mpMRI 
targeted)]. 
CCI
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ISN/Protocol 9785-MA-1010 
9 
DOCUMENT REVISION HISTORY 
 
Version 
Date 
Changes 
Comment/rationale for change 
1.0 
21-SEP-2016 
Minor updates to verbiage 
Final v1.0 based on client review of 
second draft 
2.0 
16-OCT-2020 
Updates throughout document, 
including revised shells, additions to 
the exploratory analyses 
andrenumbered TFLs. 
Final v2.0 based on client review 


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10 
REFERENCES 
American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 
2015. Available from: http://www.cancer.org/cancer/prostatecancer/index. (Accessed Oct 
2015). 
Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, et al. Radical 
prostatectomy versus watchful waiting in early prostate cancer. New England Journal of 
Medicine 2011; 364:1708-1717. 
Cooperberg MR, Carroll PR. Trends in Management for Subjects with Localized Prostate 
Cancer, 1990-2013. Journal of the American Medical Association 2015; 314:80-82. 
doi:10.1001/jama.2015.6036. 
Cooperberg MR, Cowan JE, Hilton JF, Reese AC, Zaid HB, Porten SP, et al. Outcomes of 
active surveillance for men with intermediate-risk prostate cancer. Journal of Clinical 
Oncology 2011; 29:228-234. 
Fleshner NE, Lucia MS, Egerdie B, Aaron L, Eure G, Nandy I, et al. Dutasteride in localised 
prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled 
trial. The Lancet 2012; 379:1103-1111 
Klotz L, Vesprini D, Sethukavalan P, Jethava V, Zhang L, Jain S, et al. Long-term follow-up 
of a large active surveillance cohort of subjects with prostate cancer. Journal of Clinical 
Oncology 2015; 33:272-277. doi:10.1200/JCO.2014.55.1192. 
Lane JA, Donova JL, Davis M, Walsh E, Dedman D, Down L, et al. Active monitoring, 
radical prostatectomy, or radiotherapy for localized prostate cancer: study design and 
diagnostic and baseline results of the ProtecT randomized phase 3 trial. The Lancet Oncology 
2014; 15:1109-1118. 
Meinert, C. (1986). Clinical Trials: Design, Conduct, and Analysis. Oxford University Press, 
New York. 
Mohler J, Bahnson RR, Boston B, Busby E, D'Amico A, Eastham JA, et al. NCCN clinical 
practice guidelines in oncology: Prostate cancer. Journal of the National Comprehensive 
Cancer Network 2010; 8:162–200. 
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate Cancer 
Version 1.2015. 20th Annual Edition. Copyrighted 24-Oct-2014 
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health‐ related 
quality of life: the remarkable universality of half a standard deviation. Med Care. 2003; 
41:582‐ 592. 
Revicki D, Hayes R, Cella D, Sloan J. Recommended methods for determining 
responsiveness and minimally important differences for patient-reported outcomes. 
Journal of Clinical Epidemiology. 2008; 61, 2: 102-109. 
Ritch CR, Graves AJ, Keegan KA, Ni S, Bassett JC, Chang, SS, et al. Increasing use of 
observation among men at low risk for prostate cancer mortality. Journal of Urology 
2015; 193:801-806. 


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SEER 18 2005-2011, All Races, Males by SEER Summary Stage 2000. 
Tomlins et all. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk 
Assessment. Eur Urol. 2016 July; 70(1): 45–53. 
Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagino ED, Cookson MS, et al. 
Guideline for the management of clinical localized prostate cancer: 2007 update. Journal of 
Urology 2007; 177:2106-2131. 
Weiner AB, Patel SG, Etzioni R, Eggener SE. National trends in the management of low and 
intermediate risk prostate cancer in the United States. Journal of Urology 2015; 193:95-102. 
Wilt TJ. Management of Low Risk and Low PSA Prostate Cancer: Long Term Results from 
the Prostate Cancer Intervention Versus Observation Trial. In: Cuzick J, Thorat MA. Prostate 
Cancer Prevention. Berlin: Springer Berlin Heidelberg; 2014. p.149-169. 
Wilt TJ, Brawer MK, Jones KM, Barry MJ, Aronson WJ, Fox S, et al. Radical prostatectomy 
versus observation for localized prostate cancer. New England Journal of Medicine 2012; 
367:203-213. 


 
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11 
APPENDICES 
11.1 
Appendix 1: Key Contributors and Approvers 
 
List of Key Contributors and Approvers 
Key Contributors 
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role. 
 
 
Primary author (s) 
 
inVentiv Health Clinical 
 
Syneos Health 
Contributors and Reviewers 
 
inVentiv Health Clinical 
 
Astellas Pharma Global 
Development, Inc. 
 
PPD
PPD
PPD
PPD