Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: Xtandi Metastatic Castration Resistant Prostate Cancer Metastatic Prostate Cancer Chemotherapy Castration-resistant Enzalutamide
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
The purpose of the study was to understand if there is benefit in treatment with a medicine called enzalutamide in the re-treatment setting. Patients must have been previously treated with enzalutamide in the pre-chemotherapy setting for a minimum of 8 months and have disease progressed, followed by docetaxel and/or cabazitaxel for at least 4 cycles.

Detailed description:
Participants received treatment with open-label enzalutamide, until radiographic or clinical progression (such as pathological fracture, cord compression, worsened pain requiring radiation therapy, or opioid analgesic dose increase or initiation), or unacceptable toxicity. Participants were to be allowed to continue enzalutamide until the next treatment was initiated. If another non-cytotoxic, non-investigational, antineoplastic agent was initiated after protocol-defined progression had been determined, enzalutamide was to be continued as long as the participant was tolerating enzalutamide and continued androgen deprivation therapy. Participants were to have a safety follow-up visit approximately 30 days following the last dose of study drug or prior to the initiation of a subsequent anti-cancer drug or investigational agent, whichever occurred first. Disease progression and survival were to be followed every 12 weeks for a maximum of 3 years from first dose. The study should have ended when the last participant has been followed for 1 year from the date of first dose, but the study was terminated and results up to the last date of evaluation (15 March 2017) are reflected in this disclosure.

Arms:
arm 1: Participants received 160 mg enzalutamide orally once daily until radiographic or clinical progression, or unacceptable toxicity.

Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: Participants were administered four 40-mg capsules orally once daily and taken as close to the same time each day as possible and could be taken with or without food.

Protocol document:
Prot_000.pdf: 
A Multicenter, Open-label, Single-arm, Study of 
Enzalutamide Re-Treatment in Metastatic Castration-
Resistant Prostate Cancer, As First Treatment Post-
Chemotherapy in Patients who Have Previously Received
Enzalutamide in the Pre-Chemotherapy Setting
ISN/Protocol 9785-MA-1008
Final Version 3.0, dated 22-July-2016
ClinicalTrials.gov Identifier: NCT02441517
Sponsor: Astellas Scientific and Medical Affairs (ASMA)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD Medical Affairs, Americas
ISN/Protocol 9785-MA-1008
- CONFIDENTIAL -
22 JUL 2016
Astellas
Page 1 of 68
A Multicenter, Open-label, Single-arm, Study of Enzalutamide 
Re-Treatment in Metastatic Castration-Resistant Prostate Cancer, 
As First Treatment Post-Chemotherapy in Patients who Have 
Previously Received Enzalutamide in the Pre-Chemotherapy 
Setting
ISN/Protocol 9785-MA-1008
Version 3.0/22 July 2016
IND 74,563
Sponsor:
APGD Medical Affairs, Americas
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.


Sponsor: APGD Medical Affairs, Americas
ISN/Protocol 9785-MA-1008
- CONFIDENTIAL -
22 JUL 2016
Astellas
Page 2 of 68
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··························································································13
V.
SCHEDULE OF ASSESSMENTS ·····························································20
1
INTRODUCTION·················································································22
1.1
Background ····················································································22
1.2
Non-clinical and Clinical Data ······························································22
1.3
Summary of Key Safety Information for Study Drugs ···································26
1.4
Risk-Benefit Assessment·····································································27
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································27
2.1
Study Objectives ··············································································27
2.2
Study Design and Dose Rationale···························································27
2.2.1
Study Design·············································································27
2.2.2
Dose Rationale···········································································28
2.3
Endpoints·······················································································28
2.3.1
Primary Endpoint········································································28
2.3.2
Secondary Endpoints····································································29
2.3.3
Exploratory Endpoints ··································································29
3
STUDY POPULATION··········································································29
3.1
Selection of Study Population ·······························································29
3.2
Inclusion Criteria··············································································29
3.3
Exclusion Criteria ·············································································30
4
TREATMENT(S)··················································································32
4.1
Identification of Investigational Product(s) ················································32
4.1.1
Test Drug(s)··············································································32
4.1.2
Comparative Drug(s)····································································32
4.2
Packaging and Labeling ······································································32
4.3
Study Drug Handling ·········································································32
4.4
Blinding ························································································33
4.5
Assignment and Allocation ··································································33


Sponsor: APGD Medical Affairs, Americas
ISN/Protocol 9785-MA-1008
- CONFIDENTIAL -
22 JUL 2016
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5
TREATMENTS AND EVALUATION························································33
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················33
5.1.1
Dose/Dose Regimen and Administration Period ····································33
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································33
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ··················································································34
5.1.3.1
Previous Treatment (Medication and Non-Medication Therapy)············34
5.1.3.2
Concomitant Treatment (Medication and Non-Medication Therapy)·······34
5.1.4
Treatment Compliance··································································35
5.1.5
Criteria for Continuation of Treatment ···············································35
5.2
Demographics and Baseline Characteristics ···············································36
5.2.1
Demographics············································································36
5.2.2
Medical History··········································································36
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············36
5.2.4
Performance Status······································································36
5.2.5
Chest X-Ray and/or Chest CT ·························································36
5.3
Efficacy Assessment··········································································37
5.3.1
CT/MRI and Bone Scan ································································37
5.3.2
PSA ·······················································································37
5.3.3
Correlative Samples·····································································38
5.3.4
Survival Follow-up······································································38
5.4
Safety Assessment ············································································38
5.4.1
Vital Signs················································································38
5.4.2
Adverse Events ··········································································38
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································38
5.4.3
Laboratory Assessments································································39
5.4.4
Physical Examination···································································40
5.4.5
Electrocardiogram (ECG) ······························································40
5.4.6
Imaging ···················································································40
5.5
Adverse Events and Other Safety Aspects ·················································40
5.5.1
Definition of Adverse Events (AEs) ··················································40
5.5.2
Disease Progression·····································································41
5.5.3
Definition of Serious Adverse Events (SAEs) ·······································41
5.5.4
Special Situations········································································41
5.5.5
Criteria for Causal Relationship to the Study Drug ·································42


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5.5.6
Criteria for Defining the Severity of an Adverse Event ····························43
5.5.7
Reporting of Serious Adverse Events (SAEs) ·······································43
5.5.8
Follow-up of Adverse Events··························································44
5.5.9
Monitoring of Common Serious Adverse Events ···································44
5.5.10
Procedure in Case of Pregnancy·······················································45
5.5.11
Emergency Procedures and Management of Overdose ·····························45
5.5.12
Supply of New Information Affecting the Conduct of the Study··················45
5.6
Test Drug Concentration ·····································································45
5.7
Other Measurements, Assessments or Methods ···········································45
5.7.1
Blood Sample for Molecular Profiling of CTCs·····································45
5.7.2
Serum Sample for Biomarker Analysis···············································46
5.8
Total Amount of Blood·······································································46
6
DISCONTINUATION············································································46
6.1
Discontinuation of Individual Subject(s)···················································46
6.2
Discontinuation of the Site···································································47
6.3
Discontinuation of the Study·································································48
7
STATISTICAL METHODOLOGY ···························································48
7.1
Sample Size····················································································48
7.2
Analysis Set····················································································48
7.2.1
Full Analysis Set (FAS) ································································49
7.2.2
Per Protocol Set (PPS) ··································································49
7.2.3
Safety Analysis Set (SAF)······························································49
7.2.4
Biomarker Analysis Set (BAS) ························································49
7.3
Demographics and Other Baseline Characteristics········································49
7.4
Analysis of Efficacy ··········································································49
7.4.1
Analysis of Primary Endpoint ·························································49
7.4.1.1
Primary Analysis···································································49
7.4.1.2
Secondary Analysis································································49
7.4.1.3
Subgroup Analysis·································································49
7.4.2
Analysis of Secondary Endpoints ·····················································50
7.4.3
Analysis of Exploratory Endpoints····················································50
7.5
Analysis of Safety·············································································51
7.5.1
Adverse Events ··········································································51
7.5.2
Laboratory Assessments································································51


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7.5.3
Vital Signs················································································51
7.5.4
Physical Examination···································································51
7.5.5
ECGs······················································································51
7.6
Analysis of Pharmacogenomics ·····························································51
7.7
Protocol Deviations ···········································································51
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················51
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········52
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················52
8.1
Procedure for Clinical Study Quality Control ·············································52
8.1.1
Data Collection ··········································································52
8.1.2
Specification of Source Documents···················································52
8.1.3
Clinical Study Monitoring······························································53
8.1.4
Direct Access to Source Data/Documents············································53
8.1.5
Data Management ·······································································53
8.1.6
Protocol Deviations ·····································································53
8.1.7
End of Trial in All Participating Countries···········································54
8.2
Ethics and Protection of Subject Confidentiality··········································54
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································54
8.2.2
Ethical Conduct of the Study···························································55
8.2.3
Informed Consent of Subjects ·························································55
8.2.3.1
Subject Information and Consent················································55
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························55
8.2.4
Subject Confidentiality ·································································56
8.3
Administrative Matters ·······································································56
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····56
8.3.2
Documents and Records Related to the Clinical Study ·····························56
8.3.3
Protocol Amendment and/or Revision················································57
8.3.4
Signatory Investigator for Clinical Study Report····································57
9
QUALITY ASSURANCE········································································57
10
STUDY ORGANIZATION······································································58
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ···········58


Sponsor: APGD Medical Affairs, Americas
ISN/Protocol 9785-MA-1008
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22 JUL 2016
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11
REFERENCES ····················································································59
12
APPENDICES ·····················································································62
12.1
List of Prohibited and Restricted Concomitant Medications·····························62
12.2
Liver Safety Monitoring and Assessment ··················································64
12.3
Common Serious Adverse Events···························································67
13
SIGNATURES ·····················································································68


Sponsor: APGD Medical Affairs, Americas
ISN/Protocol 9785-MA-1008
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22 JUL 2016
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I.
SIGNATURES
1.  SPONSOR’S SIGNATURE
A Multicenter, Open-label, Single-arm, Study of Enzalutamide Re-Treatment in 
Metastatic Castration-Resistant Prostate Cancer, As First Treatment Post-
Chemotherapy in Patients who Have Previously Received Enzalutamide in the 
Pre-Chemotherapy Setting
ISN/Protocol 9785-MA-1008 /Version 3.0 dated 22 July 2016
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located at the end of this document.


Sponsor: APGD Medical Affairs, Americas
ISN/Protocol 9785-MA-1008
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22 JUL 2016
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2.  INVESTIGATOR’S SIGNATURE
A Multicenter, Open-label, Single-arm, Study of Enzalutamide Re-Treatment in 
Metastatic Castration-Resistant Prostate Cancer, As First Treatment Post-
Chemotherapy in Patients who Have Previously Received Enzalutamide in the Pre-
Chemotherapy Setting
ISN/Protocol 9785-MA-1008 /Version 3.0 dated 22 July 2016
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:
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
AA
Abiraterone Acetate
ADR
Adverse Drug Reaction
ADT
Androgen Deprivation Therapy
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase (GPT)
AR
Androgen Receptor
AR-V7
Androgen Receptor Splice Variant 7
AR-V12/v567es
Androgen Receptor Splice Variant 12/ Variant with Exons 5, 6 and 7 Skipped
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate Aminotransferase (GOT)
AUC
Area Under the Curve
AUST
Astellas US Technologies, Inc.
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CI
Confidence Interval
CLCR
Creatinine Clearance
CO2
Carbon Dioxide
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Circulating Tumor Cells
DHEA
Dehydroepiandrosterone
DILI
Drug-induced Liver Injury
dL
Deciliter
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
FAS
Full Analysis Set
GCP
Good Clinical Practice
g/dL
Grams per DeciLiter
GGT
Gamma-Glutamyl Transferase
GMP
Good Manufacturing Practices
GnRH
Gonadotropin-Releasing Hormone
GR
Glucocorticoid Receptor
HCT
Hematocrit
HgB
Hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IGF
Insulin-like Growth Factor 1


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Abbreviations
Description of abbreviations
IL6
Interleukin 6
IL8
Interleukin 8
INR
International Normalized Ratio
IRB
Institutional Review Board
ISN
International Study Number
JAK/STAT
Janus Kinase / Signal Transducer and Activator of Transcription
LA-CRF
Liver Abnormality Case Report Form
LBD
Ligand Binding Domain
LDH
Lactate Dehydrogenase
LFT
Liver Function Tests
LVEF
Left Ventricular Ejection Fraction
mCRPC
Metastatic Castration - Resistant Prostate Cancer
MedDRA
Medical Dictionary for Regulatory Activities
mg/dL
Milligram/Deciliter
mmHg
Millimeters of Mercury
mmol/L
Millimoles/Liter
MOA
Mechanism of Action
MRI
Magnetic Resonance Imaging
mTOR
Mammalian Target of Rapamycin
MUGA
Multiple Gated Acquisition
NASH
Non-alcoholic Steatohepatitis
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
Ng
Nanogram
nmol/L
Nanomole/Liter
NYHA
New York Heart Association
OS
Overall Survival
PCWG2
Prostate Cancer Clinical Trials Working Group
PGAS
Pharmacogenomic Analysis Set
PHI
Protected Health Information
PK
Pharmacokinetics
PSA
Prostate-Specific Antigen
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria In Solid Tumors
rPFS
Radiographic Progression-Free Survival
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
TBL
Total Bilirubin
TLF
Tables, Listings and Figures
sTNF1
Soluble Tumor Necrosis Factor Receptor – 1
TNF-alpha
Tumor Necrosis Factor - Alpha
TMF
Trial Master File
µL
Microliter
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell


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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.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Sponsor: APGD, Medical Affairs, Americas
Protocol Number:  9785-MA-1008
Name of Study Drug: Enzalutamide
Phase of Development: N/A
Title of Study: A Multicenter, Open-label, Single-arm, Study of Enzalutamide Re-Treatment in 
Metastatic Castration-Resistant Prostate Cancer, As First Treatment Post-Chemotherapy in Patients 
who Have Previously Received Enzalutamide in the Pre-Chemotherapy Setting
Planned Study Period: From Q3 2015 - Q3 2018
Study Objective(s): 
Primary:

To determine radiographic progression-free survival (rPFS) of re-treatment with enzalutamide 
+ GnRH analogue
Secondary:

Assess additional measures of efficacy: 
o
Overall survival rate at 1 year 
o
Time to PSA progression
o
PSA response rate [maximum decline of ≥30%, ≥50%, and ≥90% from baseline, (PSA30, 
PSA50, and PSA90), respectively] 
o
Objective response rate

Time to first use of a subsequent antineoplastic therapy

Assess safety of enzalutamide re-treatment in the post-chemo setting

Assess correlative science in the post-chemo setting
Planned Total Number of Study Centers and Location(s):  5-10 centers in the US
Study Population:  Patients previously treated with enzalutamide for a minimum of 8 months, 
followed by docetaxel and/or cabazitaxel chemotherapy for a minimum of 4 cycles. Exposure to 
intervening systemic anti-cancer therapies such as abiraterone prior to chemotherapy is allowed.
Number of Patients to be Enrolled / Randomized:  40
Study Design Overview:  
This is a US-based, multicenter, open-label, single-arm, study evaluating the efficacy, safety, and 
tolerability of open-label enzalutamide in the re-treatment setting.  A total of 40 patients will be 
enrolled. Patients must have been previously treated with enzalutamide in the pre-chemotherapy 
setting for a minimum of 8 months, followed by docetaxel and/or cabazitaxel for a minimum of 4 
cycles. Exposure to intervening systemic anti-cancer therapies such as abiraterone prior to
chemotherapy is allowed.  Subjects will receive treatment with open-label enzalutamide (160 mg 
daily), administered as four 40 mg capsules, by mouth, once daily, until radiographic or clinical 
progression (such as pathological fracture, cord compression, worsened pain requiring radiation 
therapy, or opioid analgesic dose increase or initiation), or unacceptable toxicity.  Per the 
Investigator’s clinical judgment and with sponsor approval, patients may be allowed to continue 
enzalutamide until the next treatment is initiated.  If another non-cytotoxic, non-investigational, 
antineoplastic agent is initiated after protocol-defined progression has been determined, enzalutamide 
may be continued per the Investigator’s clinical judgment and with sponsor approval as long as the 
patient is tolerating enzalutamide and continues androgen deprivation therapy.
The consensus guidelines of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the 


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Prostate Cancer Clinical Trials Working Group 2 (PCWG2) will be utilized to determine radiographic 
disease progression. Radiographic disease progression is defined by RECIST 1.1 for soft tissue 
disease.  Bone disease progression is considered when a minimum of two new lesions are observed. 
Progression on bone scan at time points prior to or at Week 9 requires a confirmatory scan performed 
six or more weeks later.  This confirmatory scan should demonstrate at least 2 additional new lesions 
compared to the Week 9 scan (PCWG2).
The following assessments of prostate cancer status will be collected during the course of the trial: 
soft tissue disease on computed tomography (CT) scan or on magnetic resonance imaging (MRI), 
bone disease on radionuclide bone scans, and PSA.
Study films (CT/MRI and bone scan) should be read on site. Each site should ideally designate the 
same reader who will evaluate the images for any one subject for the duration of the trial.
Throughout the study, safety and tolerability will be assessed by the recording of adverse events, 
monitoring of vital signs, physical examinations, and safety laboratory evaluations. 
Subjects will have a Safety Follow-Up visit approximately 30 days following the last dose of study 
drug or prior to the initiation of a subsequent anti-cancer drug or investigational agent, whichever 
occurs first.  Survival will be followed every 12 weeks for a maximum of 3 years from first dose. The 
study will end when the last subject has been followed for 1 year from date of first dose. 
Inclusion/Exclusion Criteria:
Inclusion Criteria:
1.
Histologically or cytologically confirmed adenocarcinoma of the prostate without signet ring
cell features. 
2.
Presence of metastatic disease (M1) as assessed by CT/MRI and/or whole-body radionuclide 
bone scan. 
3.
Subject has been previously treated with enzalutamide for at least 8 months, and stopped 
enzalutamide due to progressive disease (not due to adverse events), followed by at least
4 cycles of docetaxel and/or cabazitaxel chemotherapy, with or without other intervening 
anti-cancer therapies (including but not limited to aminoglutethimide, ketoconozole, 
abiraterone acetate, Rad-223, or sipuleucel-T) prior to receiving chemotherapy.  Note:  for 
patients who receive sequential taxanes, there must not have been progressive disease upon 
ending the first taxane or use of any anti-cancer agents between the two taxanes.   
4.
Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) 
analogue or prior bilateral orchiectomy (medical or surgical castration).  For patients who 
have not had bilateral orchiectomy, there must be a plan to maintain effective 
GnRH-analogue for the duration of the trial.
5.
Testosterone ≤ 1.73 nmol/L (≤ 50 ng/dL) at screening. 
6.
Age 18 years or older.  
7.
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).
8.
ECOG performance status of 0-2 at screening. 
9.
Estimated life expectancy of ≥ 6 months at screening. 
10. Ability to swallow study drug and to comply with study requirements throughout the study.
11. Throughout study, male subject and a female partner who is of childbearing potential must 
use 2 acceptable methods of birth control (1 of which must include a condom barrier method 


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of contraception) starting at screening and continuing throughout the study period and for 
3 months after 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 method 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 performed at least 6 months before 
screening;
v. Vasectomy or other procedure resulting in infertility (eg, bilateral 
orchiectomy), performed at least 6 months before screening
12. Must not donate sperm from screening through 3 months after final study drug administration.
Exclusion Criteria:
Patients will be excluded from participation if any of the following apply:
1.
Known or suspected neuroendocrine/small cell feature.
2.
Use of any antineoplastic treatment post-chemotherapy, including but not limited to 
aminoglutethimide, ketoconozole, abiraterone acetate, Rad-223, sipuleucel-T, or 
enzalutamide.  Continuing steroids is permitted.
3.
Palliative radiation therapy within 2 weeks of Day 1, or within 4 weeks of Day 1 if a 
radionuclide was utilized. 
4.
Use of an investigational agent within 4 weeks of Day 1 visit.
5.
Major surgery within 4 weeks prior to Day 1 visit. 
6.
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.
7.
History of clinically significant cardiovascular disease including:  
a.
Myocardial infarction or uncontrolled angina within 3 months; 
b.
History of congestive heart failure NYHA class 3 or 4 in the past, unless a screening 
echocardiogram or multi-gated acquisition scan performed within three months 
results in a left ventricular ejection fraction that is ≥ 45%;
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.
8.
Clinically significant cardiovascular disease at screening including:  
a.
Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mm 
Hg) at screening;
b.
Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening 
electrocardiogram (ECG) and on physical examination;
c.
Uncontrolled hypertension as indicated by at least 2 consecutive measurements of a 


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resting systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg 
at the screening visit.
9.
Subject has a known or suspected hypersensitivity to enzalutamide or any components of the 
formulation used.
10. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, 
would make the patient inappropriate for enrollment.
11. Known or suspected brain metastasis or leptomeningeal disease.
12. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease 
within last 3 months);
13. Absolute neutrophil count < 1,500/µL, platelet count < 75,000/µL, or hemoglobin 
< 5.6 mmol/L (9 g/dL) at screening.
14. Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 
times upper limit of normal (ULN) at screening.
15. Creatinine > 177 μmol/L (> 2 mg/dL) at screening.
16. Albumin < 30 g/L (3.0 g/dL) at screening.
17. Treatment with abiraterone acetate prior to enzalutamide for mCRPC in the pre-chemotherapy 
setting. (Note: Patients who have received concomitant enzalutamide and abiraterone acetate 
therapies are not excluded).
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):
None.
Background Therapy:
The study sites will provide GnRH agonist or antagonist from pharmacy stock.  
Concomitant Medication Restrictions or Requirements:
The following medications are prohibited while patients are on enzalutamide treatment and have not 
had disease progression:

Chemotherapy with anti-tumor activity against prostate cancer such as cabazitaxel, 
mitoxantrone, etc.

Sipuleucel-T

Rad-223

Androgen-receptor antagonists (bicalutamide, flutamide, nilutamide)

5α-reductase inhibitors (finasteride, dutasteride)

Estrogens

Cyproterone acetate

Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)

Ketoconazole


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
Abiraterone acetate 

Any other investigational agent
The dosage and regimen of the following medications and any chronic permitted medications should 
be stabilized during the screening period (> 4 weeks prior to randomization) and held constant 
through the study:

Denosumab and bisphosphonate

GnRH agonist/antagonist therapy
There is a potential for enzalutamide to affect exposures to other medicinal products, or for other
medicinal products to affect exposure to enzalutamide:

Strong CYP2C8 inhibitors (e.g., gemfibrozil) or CYP2C8 inducers (e.g. rifampicin) are to be 
avoided. If subject must be co-administered a strong CYP2C8 inhibitor, the dose of 
enzalutamide should be reduced to 80 mg once daily. If a 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.

Strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbital, rifampicin) or 
moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcilin, St. 
John’s Wort) should be avoided if possible as they may reduce enzalutamide plasma 
concentration if co-administered.  Selection of a concomitant medication with no or minimal 
CYP3A4 induction potential is recommended.  Enzalutamide is a strong inducer of CYP3A4 
and a moderate inducer of CYP2C9 and CYP2C19. Medicinal products with a narrow 
therapeutic range that are substrates of CYP3A4 (e.g. alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), 
CYP2C9 (e.g. phenytoin, warfarin), CYP2C19 (e.g. S-mephenytoin), or UGT1A1 should be 
avoided, as enzalutamide may decrease their exposure. If enzalutamide is co-administration
with warfarin cannot be avoided, additional INR monitoring should be conducted.

Enzalutamide is an inhibitor of human P-glycoprotein (p-gp) and may increase exposure to 
medicines that are P-gp substrates. Medicinal products with a narrow therapeutic range that 
are substrates for P-gp (e.g., digoxin, colchicine, dabigatran etexilate) should be used with 
caution when administered concomitantly with enzalutamide.
No other new systemic therapy or new radiotherapy for treatment (exception for spinal cord 
compression, pain management, etc.) for prostate cancer is permitted while subject is on the study. 
Subjects with pre-existing non-target lesions (e.g., bone metastases) receiving palliative radiography 
for pain treatment before participation in the study are allowed to continue receiving radiotherapy 
during the study.
Duration of Treatment:
Treatment on study will be continued until disease progression including radiographic or clinical 
progression (such as pathological fracture, cord compression, worsened pain requiring radiation 
therapy, or opioid analgesic dose increase or initiation), or unacceptable toxicity.
Endpoints for Evaluation:
Primary:

Radiographic progression-free survival (rPFS) 


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Secondary:

Overall survival rate at 1 year 

Time to PSA progression
PSA response rate [maximum decline of ≥30%, ≥50%, and ≥90% from baseline, (PSA30, PSA50, 
and PSA90), respectively] 

Objective response rate

Time to first use of a subsequent antineoplastic therapy

Safety (e.g., SAEs, AEs)
Exploratory:

Biomarker Assessment and correlation with efficacy endpoints
Statistical Methods:  
All endpoints will be descriptively summarized and their correlation with biomarkers and efficacy 
endpoints explored via regression models as appropriate.  One interim efficacy analysis is planned 
13 weeks after the 40th subject is enrolled. Final analysis will be conducted 12 months after last 
subject is enrolled.
Sample Size Justification:
Prior clinical trials data in the post-chemo setting have shown the following median rPFS for subject 
randomized to initial placebo, placebo+prednisone, or mitoxantrone+prednisone therapy:
o
AFFIRM: Placebo = 2.9 months
o
COU-301: Placebo + Prednisone = 3.6 months
o
TROPIC: Mitoxantrone + Prednisone = 1.4 months
With a sample size of 40 subjects and an assumed median rPFS of 4 months for the therapy defined in 
this single-arm study, approximately 34 events are expected over a 12-month accrual and 12-month 
minimum follow-up. Further assuming uniform accrual, 10% loss to follow-up, and an exponential 
distribution for the rPFS event times the expected lower bound of the 90% confidence interval for the 
median is approximately 2.5 months based upon simulations. 
Safety:
The severity of all adverse events will be evaluated by the investigator based on the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0 and all 
adverse events will be coded to preferred term, higher level term, and system organ class using the 
Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects 
with adverse events will be presented by MedDRA system organ class and preferred term, 
relationship to study treatment, and maximum CTCAE grade. Descriptive statistics will be used 
rather than inferential statistics.
Laboratory values will be classified by toxicity grade based on the NCI¬CTCAE, version 4.0. Tables 
of laboratory CTCAE grade shift from baseline to maximum CTCAE grade across subsequent visits 
will be provided.
Correlative Studies:
Objectives:

Explore the prevalence and dynamics of resistance biomarkers

Explore potential correlation of the resistance biomarkers with rPFS, PSA response, and PSA 
progression


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
Explore potential correlation of the sensitivity biomarkers with rPFS, PSA response, and PSA 
progression

Explore potential correlation of inflammatory proteins with rPFS, PSA response, and PSA 
progression

Explore potential correlation of AR and glucocorticoid receptor levels and 
mutations/polymorphism with rPFS, PSA response, and PSA progression
Blood samples will be collected to capture CTCs at Week 1, Week 13, and at the time of PSA 
progression and/or at the time of radiographic progression, for (but not limited to) assessment of the 
following:

Expression levels of androgen receptor variants (AR-V’s): AR-V7 and AR-V12/ARv567es

Expression levels of AR full length (AR-FL) and glucocorticoid receptor full length (GR-FL) 

AR mutations - e.g. L702H, W741C, F876L and T877A.
Serum samples will be collected at Week 1, Week 13, and at the time of PSA progression and/or at 
the time of radiographic progression for (but not limited to) inflammatory biomarkers, such as IL6, 
IL8, Tumor necrotic factor alpha (TNF-), and soluble TNF receptor-1 (sTNF1), and neuroendocrine 
(NE) markers such as chromogranin A (CgA), neuron specific enolase (NSE), and synaptophysin.




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d Weight is required at screening visit only.
e A MUGA scan or echocardiogram is required if the patient has a history of anthracycline treatment, or if the subject has congestive heart failure New York Heart Association 
(NYHA) class 3 or 4.
f Laboratory assessments include serum chemistries and hematology.
g  Collect a blood sample for additional safety testing if indicated.
hPSA progression, defined as a ≥ 25% increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir, needs to be confirmed by a second consecutive value obtained 3 or 
more weeks later.
iThe window for all radiological assessments is ± 7 days. At Weeks 9, 17, 25 and subsequent assessments prior to treatment discontinuation, all other procedures must be completed 
within the ± 3 day window. Bone progression at the first reassessment at Week 9 requires a confirmatory scan 6 or more weeks later. 
jAdverse events, serious or non-serious, will be collected from the time the patient signs the consent form until the Safety Follow-Up visit, regardless of initiation of another anti-
neoplastic therapy prior to last dose of enzalutamide.
k Long-term follow-up for radiographic progressions (until progression or initiation of new anti-neoplastic therapy), survival, and subsequent anticancer therapies should be performed 
every 12 weeks for a maximum of 3 years from first dose. The study will end when the last subject has been followed for 1 year from date of first dose.
l Enzalutamide will be administered until disease progression, including radiographic progression or unequivocal clinical progression. Per the Investigator’s clinical judgment and with 
sponsor approval, patients may be allowed to continue enzalutamide until the next treatment is initiated.  If another non-cytotoxic, non-investigational, antineoplastic agent is initiated 
after protocol-defined progression has been determined, enzalutamide may be continued per the Investigator’s clinical judgment and with sponsor approval as long as the patient is 
tolerating enzalutamide and continues androgen deprivation therapy
m Blood samples for CTC molecular profiling and serum samples will be collected at Week 1, Week 13, and at the time of PSA progression and/or at the time of radiographic 
progression.


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1
INTRODUCTION
1.1
Background
Other than skin cancer, prostate cancer is the most commonly diagnosed cancer among men.
The American Cancer Society estimates that 180,890 new cases will be diagnosed and
approximately 26,120 men will die of prostate cancer in the US during 2016.  Prostate cancer 
is the second leading cause of cancer death in America, behind only lung cancer [American 
Cancer Society 2016].The androgen receptor (AR) signaling pathway is critical for prostate 
cancer cell growth and survival. Androgen deprivation therapy (ADT) comprising
Gonadotropin-releasing hormone (GnRH) analogue or bilateral orchiectomy provides
effective suppression of serum testosterone and downstream AR transcriptional activity, 
resulting in symptomatic relief and reduction in serum levels of prostate-specific antigen 
(PSA). Disease progression often occurs despite ADT, as tumors resort to upregulation of 
AR, androgen biosynthesis in adrenal glands, or intratumoral androgen biosynthesis via 
conversion of adrenal precursors into testosterone and dihydrotestosterone 
[Montgomery et al, 2008]. Therefore, in the setting of metastatic castration-resistant prostate 
cancer (mCRPC), continued AR signaling inhibition remains a therapeutic goal. 
Among therapies that were shown to improve survival, namely enzalutamide [Scher et al, 
2012; Beer et al, 2014], abiraterone acetate (AA) [De Bono et al, 2011; Ryan et al, 2013], 
docetaxel [Tannock et al, 2004], cabazitaxel [De Bono et al, 2010], sipuleucel-T 
[Kantoff et al, 2010], and Radium-223 [Parker et al, 2013], act or partially act on the AR 
axis. Enzalutamide and AA targets AR signaling directly. The taxanes inhibit AR nuclear 
translocation through inhibiting microtubule polymerization [Thadani-Mulero et al, 2014].
Despite the advance, systemic treatment option is limited after disease progression from 
docetaxel. Recent data suggest cross-resistance between AA and enzalutamide. Loriot et al. 
reported a shorter duration of effect and less serum PSA kinetic change in 8 patients given 
abiraterone and prednisone after docetaxel and enzalutamide [Loriot et al, 2013]. Cabazitaxel 
is associated with significant toxicity: 82% grade 3-4 (Gr≥3) neutropenia (7% febrile), 98% 
anemia (11% Gr≥3), 48% thrombocytopenia (4% Gr≥3), 47% diarrhea (6% Gr≥3), 37% 
fatigue (5% Gr≥3), 34% nausea, 22% vomiting, 20% asthenia (5% Gr≥3), 13% peripheral 
neuropathy (motor/sensory), etc. [Cabazitaxel US Package Insert, 2014].  
1.2
Non-clinical and Clinical Data
Enzalutamide (formerly known as MDV3100) competitively binds to the ligand binding 
domain (LBD) of AR and inhibits AR translocation to the cell nucleus, recruitment of 
cofactors, and binding to DNA [Tran et al, 2009]. One of the mechanisms of resistance to 
enzalutamide is over-expression of constitutively active AR splice variants lacking LBD 
Androgen [Li et al, 2013]. It has been shown in prostate cancer cells and CRPC xenografts 
treated with enzalutamide or abiraterone that increased expression of two constitutively 
active AR-Vs, AR-V7 and ARv567es activate a distinct expression signature enriched for 
cell-cycle genes without requiring the presence of AR-FL [Hu et al, 2012].  Other resistance 
mechanisms include mutations of the LBD that result in AR activation by anti-androgens or 


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glucocorticoids/steroids [Duff et al 2005, Balbas et al 2013, Carreira et al. 2014], and 
cross-talk between AR and AR independent growth factor and oncogenic kinase pathways 
including IGF signaling, JAK/STAT signaling and modulation of mTOR [Szmulewitz et al, 
2014].
Pro-inflammatory proteins have been associated with aggressive and/or drug resistant tumors.  
Proteins associated with inflammation (e.g. IL6, IL8, TNF-alpha, TNF receptors) have been 
reported to be associated with aggressive prostate tumors and drug resistance (Chadha et al, 
2014; Eiro et al, 2014; Liu et al, 2014; Feng et al, 2009; Codony-Servat et al, 2013). 
Preclinical studies have demonstrated that the inflammatory cytokine IL6 is a driver of tumor 
cell aggressiveness and can confer resistance to androgen receptor inhibitors (Feng et al, 
2009; Liu et al, 2014).  Targeting IL6 was observed to reverse the resistance to an androgen 
receptor inhibitor (Liu et al, 2014), thereby supporting the molecular and biomarker link 
between the inflammatory cytokines such as IL6 with drug resistance to androgen receptor 
inhibitors (Feng et al, 2009; Liu et al, 2014).
Pharmacokinetics
The pharmacokinetics and metabolism of enzalutamide have been evaluated in patients with 
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.
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 show to have reduced the AUC of oral 
midazolam (CYP3A4 substrate), S-warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 
substrate) by 86%, 56% and 70%, respectively. Substrates of CYP3A4, CYP2C9 and 


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CYP2C19 with a narrow therapeutic index are to be avoided, as enzalutamide may decrease 
plasma exposure of these drugs. If enzalutamide is coadministered with warfarin (CYP2C9 
substrate), additional international normalized ratio (INR) monitoring is to be conducted. 
Enzalutamide (160 mg/day) did not have a clinically relevant effect on exposure to 
intravenous docetaxel (CYP3A4 substrate) or oral pioglitazone (CYP2C8 substrate). 
Human CYP2C8 and CYP3A4 are responsible for metabolism of enzalutamide; CYP2C8 is 
the primary enzyme responsible for the metabolism of enzalutamide and the subsequent 
formation of the active metabolite (N-desmethyl enzalutamide). 
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; therefore, 
strong CYP2C8 inhibitors are to be avoided. If coadministration with a strong CYP2C8 
inhibitor is necessary, the dose of enzalutamide is to be reduced to 80 mg once daily. 
Coadministration of itraconazole (strong CYP3A4 inhibitor) increased the composite AUC of 
enzalutamide plus N-desmethyl enzalutamide by 1.3-fold; as this small change is not 
clinically meaningful; no starting dose adjustment is needed when coadministering 
enzalutamide with CYP3A4 inhibitors. 
Coadministration 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 substrate 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 enzalutamide do not appear to be 
substrate for human breast cancer resistance protein (BCRP), however, enzalutamide and 
N-desmethyl enzalutamide are inhibitors of BCRP at clinically relevant concentrations.
Two phase III randomized trials have demonstrated significant activity of enzalutamide in 
men with mCRPC. In the phase III 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 OS of 18.4 versus 13.6 months was 
detected with enzalutamide (HR, 0.63; 95% CI, 0.53 to 0.75; P < .001).  Radiographic PFS 
(rPFS) was 8.3 versus 2.9 months (HR, 0.40; P < .001), PSA response was 54% versus 2% 
(P < .001), time to PSA progression was 8.3 versus 3.0 months (HR, 0.25; P < .001), and 
time to first skeletal-related event was 16.7 versus 13.3 months (HR, 0.69; P < .001), all in 
favor of enzalutamide. Overall QOL benefit was observed in 43% versus 18% (P < .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 III 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% vs 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 


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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% vs. 5%), 
the time until PSA progression (HR, 0.17), and a rate of decline of at least 50% in PSA 
(78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most 
common clinically relevant adverse events associated with enzalutamide treatment.
No clinical data are available on activity of enzalutamide after sequential treatment with 
enzalutamide and chemotherapy. Modest activity of enzalutamide after therapy with
abiraterone acetate and docetaxel were reported. The reported rate of ≥50% PSA decline 
range between13% to 46% [Bianchini et al, 2014; Azad et al, 2014; Schrader et al, 2014]. 
Clinical prevalence of biomarkers implicated in resistance has been reported. Approximately 
30-40% patients have circulating tumor cells positive for ARv7 after enzalutamide or AA 
therapy [Antonarakis et al, 2014]. No PSA response was observed on either enzalutamide or 
abiraterone among these patients.  ARv567es was reported to be expressed in at least 
1 metastatic lesion among 71% of 13 subjects who underwent biopsy [Sun et al, 2010].
Rationale for Enzalutamide re-treatment
Benefit of re-treatment with a molecularly targeted agent after intervening therapies that are 
not cross-resistant with the initial therapies have been observed in other tumor types such as 
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and in EGFR- mutant 
non-small cell lung cancer [Riely et al, 2007; Song et al, 2013].
To date, a study of enzalutamide re-treatment following enzalutamide and intervening 
chemotherapy has not been performed. Limited data are available on re-treatment with an 
AR-targeting agent. A retrospective review of a small cohort of patients that received AA 
re-treatment (n=12), no biochemical response was observed among patients who did not 
initially respond to AA; among the 7 patients who initially responded to AA, upon 
re-treatment, the rate of PSA reduction by 30% and 50% was 86% and 46%, respectively. 
Given the similarity in MOA, evaluation of enzalutamide re-treatment in men with limited 
other therapeutic options is warranted [Leibowitz-Amit et al, 2014].
Rationale for chemotherapy prior to Enzalutamide re-treatment 
Docetaxel may overcome resistance to enzalutamide in a manner that is both AR-dependent 
and AR-independent. Recent work suggests that the microtubule network of prostate cells is 
critical for androgen receptor nuclear translocation and activity. Unlike AR-V7, 
ARv567es/AR-V12 has hinge domain.  This allows ARv567es/AR-V12 to co-sediment with 
microtubules or co-precipitate with dynein motor protein in the same way as AR-FL.  
Docetaxel was shown to suppress ARv567es/AR-V12 nuclear translocation and transcription 
activation [Thadani-Mulero et al, 2014].  In addition, being a cytotoxic agent, docetaxel has 
been shown to induce mitotic catastrophe subsequent to G2/M arrest, and activation of bcl-2 
and bcl-xL gene dependent and independent apoptotic pathways [Fabbri et al, 2008]. This 
provides the AR-independent mechanism of overcoming the resistance. The study will enroll 
patients who have received at least 4 cycles of docetaxel and/or cabazitaxel to allow a 


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selection of a subset of patients for whom chemotherapy can overcome resistance. AR-V7 
and AR-V12, as well as AR mutations will be studied to help assess response to enzalutamide 
re-treatment. 
Cabazitaxel may overcome resistance to enzalutamide in a similar manner as docetaxel. 
Cases of reversions from AR-V7 positive to negative status following cabazitaxel treatment 
have been reported [Nakazawa et al, 2015].  
1.3
Summary of Key Safety Information for Study Drugs
The safety profile of enzalutamide in patients with metastatic CRPC is primarily derived 
from two randomized, placebo-controlled phase 3 studies AFFIRM and PREVAIL. Several 
other studies in patients with prostate cancer and healthy volunteers provide additional safety 
data. 
Enzalutamide treatment was generally well tolerated across all studies, and the safety profile 
in enzalutamide was generally consistent with that observed in CRPC. As expected for this 
patient population with advanced prostate cancer, nearly all enzalutamide-treated and 
placebo-treated patients experienced at least 1 adverse event (AE) during each study. In 
PREVAIL, a higher proportion of enzalutamide-treated patients experienced grade 3 or 
higher AEs compared with placebo-treated patients (42.9% vs 37.1%); the median time to 
first grade 3 or higher AE in PREVAIL was 22.3 months in the enzalutamide group versus 
13.3 months in the placebo group. A similar pattern was observed in time to first grade 3 or 
higher event in the combined population. 
Adverse events or laboratory abnormalities occurring in at least 5% of the patients and more 
frequently in the enzalutamide treatment group with at least a 2% higher absolute incidence 
over placebo are the following: constipation (23.9% vs. 20.7%), diarrhea (19.2% vs. 15.4%), 
fatigue (35.1% vs. 27.0%), asthenia (15.8% vs 10.9%), edema peripheral (12.8% vs. 9.3%), 
fall (8.8% vs. 4.0%), weight decreased (12.3% vs. 9.2%), decreased appetite (23.8% vs 
20.8%), back pain (27.5% vs. 23.0%),  arthralgia (20.9% vs. 16.5%), musculoskeletal pain 
(12.7% vs. 9.6%), muscular weakness (6.9% vs. 4.4%), headache (11.5% vs. 6.5%), 
dysgeusia (6.1% vs. 3.6%), spinal cord compression (5.9% vs. 3.9%), insomnia (8.4% vs. 
5.8%), anxiety (5.2% vs. 3.1%), mental impairment (including amnesia, memory impairment, 
cognitive disorder, disturbance in attention, 5.1% vs. 1.6%), haematuria (7.9% vs. 5.4%), hot 
flush (19.1% vs. 8.6%), hypertension (10.5% vs. 3.7%), neutropenia (15% vs. 6%).   
In PREVAIL, a higher incidence of serious adverse events (SAEs) was observed for 
enzalutamide compared with placebo (32.0% vs 26.8%), but with a longer median time to 
first SAE (not yet reached vs 23.3 months). A similar pattern was observed for the incidence 
of SAEs and time to first SAE in the combined population. 
Seizure occurred in 0.9% of patients receiving enzalutamide who previously received 
docetaxel, and in 0.1% of patients who were chemotherapy-naïve. There have been reports of 
posterior reversible encephalopathy syndrome (PRES) in patients receiving enzalutamide
For additional safety information, please refer to the Enzalutamide Full Prescribing 
Information and the Enzalutamide Investigator Brochure. 


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1.4
Risk-Benefit Assessment
In previous clinical studies, over 5500 patients with prostate cancer, over 400 women with breast 
cancer, and over 300 male subjects with no known cancer (including healthy men and subjects with 
liver impairment) have received at least 1 dose of enzalutamide in completed and ongoing clinical 
studies as of February 2016. The safety and tolerability of enzalutamide continues to be 
evaluated on an ongoing basis for all enzalutamide program studies. No study has been 
terminated early for safety reasons. 
The benefit of re-treatment with enzalutamide has not been established.  Considering the 
limited number of treatment options after chemotherapy, a well-tolerated safety profile for 
enzalutamide, and that chemotherapy may address resistance to enzalutamide via a non-cross 
resistant mechanism, this study of re-treatment with enzalutamide in mCRPC is warranted. 
The biomarker correlative component of the trial will provide additional data to inform 
strategies to overcome resistance to mCRPC treatment.
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
The primary objective is:
●
To determine radiographic progression-free survival (rPFS) of re-treatment with 
enzalutamide + GnRH analogue
The secondary objectives are:
●
To assess additional measures of efficacy: 
o
Overall survival rate at 1 year 
o
Time to PSA progression
o
PSA response rate [maximum decline of ≥30%, ≥50%, and ≥90% from baseline, (PSA30, 
PSA50, and PSA90), respectively]
o
Objective response rate
●
Time to first use of a subsequent antineoplastic therapy
●
To assess safety of enzalutamide re-treatment in the post-chemo setting.
●
To assess correlative science in the post-chemo setting. 
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a US-based, multicenter, open-label, single-arm, study evaluating the efficacy, safety, 
and tolerability of open-label enzalutamide in the re-treatment setting. A total of 40 patients 
will be enrolled. Patients must have been previously treated with enzalutamide in the 
pre-chemotherapy setting for a minimum of 8 months, followed by docetaxel and/or 
cabazitaxel for a minimum of 4 cycles. Exposure to intervening systemic anti-cancer 
therapies such as abiraterone prior to chemotherapy is allowed. Subjects will receive 
treatment with open-label enzalutamide (160 mg daily), administered as four 40 mg capsules, 
by mouth, once daily, until radiographic or clinical progression (such as pathological 


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fracture, cord compression, worsened pain requiring radiation therapy, or opioid analgesic 
dose increase or initiation), or unacceptable toxicity.  Per the Investigator’s clinical judgment 
and with sponsor approval, patients may be allowed to continue enzalutamide until the next 
treatment is initiated.  If another non-cytotoxic, non-investigational, antineoplastic agent is 
initiated after protocol-defined progression has been determined, enzalutamide may be 
continued per the Investigator’s clinical judgment and with sponsor approval as long as the 
patient is tolerating enzalutamide and continues androgen deprivation therapy.
The consensus guidelines of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
and the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) will be utilized to 
determine radiographic disease progression.  Radiographic disease progression is defined by 
RECIST 1.1 for soft tissue disease.  Bone disease progression is considered when a minimum 
of two new lesions are observed. Progression on bone scan at time points prior to or at 
Week 9 requires a confirmatory scan performed six or more weeks later.  This confirmatory 
scan should demonstrate at least 2 additional new lesions compared to the Week 9 scan 
(PCWG2).
The following assessments of prostate cancer status will be collected during the course of the 
trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance 
imaging (MRI), bone disease on radionuclide bone scans, and PSA.
Study films (CT/MRI and bone scan) should be read on site.  Each site should ideally 
designate the same reader who will evaluate the images for any one subject for the duration 
of the trial.
Throughout the study, safety and tolerability will be assessed by the recording of adverse 
events, monitoring of vital signs, physical examinations, and safety laboratory evaluations. 
Subjects will have a Safety Follow-p visit approximately 30 days following the last dose of 
study drug or prior to the initiation of a subsequent anti-cancer drug or investigational agent, 
whichever occurs first. Survival will be followed every 12 weeks for a maximum of 3 years 
from first dose. The study will end when the last subject has been followed for 1 year from 
date of first dose.  
2.2.2
Dose Rationale
A dose of 160 mg enzalutamide (four 40 mg capsules) once daily administered orally is the 
FDA approved daily dose.
2.3
Endpoints 
2.3.1
Primary Endpoint
The primary efficacy endpoint is:
●
Radiographic progression-free survival (rPFS).


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2.3.2
Secondary Endpoints 
Secondary endpoints are:
●
Overall survival rate at 1 year 
●
Time to PSA progression
●
PSA response rate [maximum decline of ≥30%, ≥50%, and ≥90% from baseline, 
(PSA30, PSA50, and PSA90), respectively] 
●
Objective response rate
●
Time to first use of a subsequent antineoplastic therapy
●
Safety (e.g., SAEs, AEs)
2.3.3
Exploratory Endpoints
The exploratory endpoint is:
●
Biomarker Assessment and correlation with efficacy endpoints
3
STUDY POPULATION
3.1
Selection of Study Population 
This study will enroll 40 patients previously treated with enzalutamide for a minimum of 
8 months, followed by docetaxel and/or cabazitaxel for a minimum of 4 cycles. Exposure to 
intervening systemic anti-cancer therapies such as abiraterone prior to chemotherapy is 
allowed.  
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Histologically or cytologically confirmed adenocarcinoma of the prostate without 
signet ring cell features. 
2.
Presence of metastatic disease (M1) as assessed by CT/MRI and/or whole-body 
radionuclide bone scan. 
3.
Subject has been previously treated with enzalutamide for at least 8 months, and 
stopped enzalutamide due to progressive disease (not due to adverse events), followed 
by at least 4 cycles of docetaxel and/or cabazitaxel chemotherapy, with or without 
other intervening anti-cancer therapies (including but not limited to 
aminoglutethimide, ketoconozole, abiraterone acetate, Rad-223, or sipuleucel-T), 
prior to receiving chemotherapy.  Note: for patients who receive sequential taxanes, 
there must not have been progressive disease upon ending the first taxane, or use of 
any anti-cancer agents between the two taxanes.    
4.
Ongoing androgen deprivation therapy with a gonadotropin releasing hormone 
(GnRH) analogue or prior bilateral orchiectomy (medical or surgical castration). For 
patients who have not had bilateral orchiectomy, there must be a plan to maintain 
effective GnRH-analogue for the duration of the trial.
5.
Testosterone ≤ 1.73 nmol/L (≤ 50 ng/dL) at screening.
6.
Age 18 years or older.  


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7.
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).
8.
ECOG performance status of 0-2 at screening. 
9.
Estimated life expectancy of ≥ 6 months at screening. 
10. Ability to swallow study drugs and to comply with study requirements throughout the 
study.
11. Throughout study, male subject and a female partner who is of childbearing potential 
must use 2 acceptable methods of birth control (1 of which must include a condom 
barrier method of contraception) starting at screening and continuing throughout the 
study period and for 3 months after 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 method of 
contraception by the female partner performed at least 6 months before 
screening;
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.
v. Vasectomy or other procedure resulting in infertility (e.g., bilateral 
orchiectomy), performed at least 6 months before screening
12. Must not donate sperm from screening through 3 months after final study drug 
administration.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply (waivers to the 
exclusion criteria will NOT be allowed):
1.
Known or suspected neuroendocrine/small cell feature.
2.
Use of any antineoplastic treatment post-chemotherapy, including but not limited to 
aminoglutethimide, ketoconozole, abiraterone acetate, Rad-223, sipuleucel-T, or 
enzalutamide.  Continuing steroids is permitted.


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3.
Palliative radiation therapy within 2 weeks of Day 1, or within 4 weeks of Day 1 if a 
radionuclide was utilized. 
4.
Use of an investigational agent within 4 weeks of Day 1 visit.
5.
Major surgery within 4 weeks prior to Day 1 visit. 
6.
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.
7.
History of clinically significant cardiovascular disease including:  
a.
Myocardial infarction or uncontrolled angina within 3 months; 
b.
History of congestive heart failure NYHA class 3 or 4 in the past, unless a 
screening echocardiogram or multi-gated acquisition scan performed within 
three months results in a left ventricular ejection fraction that is ≥ 45%;
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.
8.
Clinically significant cardiovascular disease at screening including:  
a.
Hypotension as indicated by systolic blood pressure < 86 millimeters of 
mercury (mm Hg) at screening;
b.
Bradycardia as indicated by a heart rate of < 45 beats per minute on the 
screening electrocardiogram (ECG) and on physical examination;
c.
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.
9.
Subject has a known or suspected hypersensitivity to enzalutamide or any 
components of the formulation used.
10. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the 
investigator, would make the patient inappropriate for enrollment.
11. Known or suspected brain metastasis or leptomeningeal disease.
12. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer 
disease within last 3 months);
13. Absolute neutrophil count < 1,500/µL, platelet count < 75,000/µL, or hemoglobin 
< 5.6 mmol/L (9 g/dL) at screening.
14. Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) ≥ 2.5 times ULN at screening.
15. Creatinine > 177 μmol/L (> 2 mg/dL) at screening.
16. Albumin < 30 g/L (3.0 g/dL) at screening.


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17. Treatment with abiraterone acetate prior to enzalutamide for mCRPC in the pre-
chemotherapy setting. (Note:  Patients who have received concomitant enzalutamide 
and abiraterone acetate therapies are not excluded).
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
Enzalutamide is an opaque white to off-white oblong liquid filled soft gelatin capsule for oral 
administration. Each capsule contains 40 mg enzalutamide.
4.1.2
Comparative Drug(s) 
Not applicable.
4.2
Packaging and Labeling
Enzalutamide is supplied by APGD, Medical Affairs, Americas. Enzalutamide will be 
packaged in high-density polyethylene bottles with child-resistant induction seal closure. 
Enzalutamide will be prepared, packaged, and labeled under the responsibility of qualified 
staff at Astellas US Technologies, Inc. (AUST) in accordance with APGD, Medical Affairs, 
Americas-AUST Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, ICH GCP guidelines, and applicable local laws/regulations.
4.3
Study Drug Handling 
Enzalutamide will be stored in a secure 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 enzalutamide is handled and stored according to labeled storage conditions,
●
that enzalutamide with appropriate expiry/retest and is only dispensed to study 
subjects in accordance with the protocol, and
●
that enzalutamide is returned to the Sponsor.
Drug inventory and accountability records for enzalutamide will be kept by the 
Investigator/or designee. Enzalutamide accountability throughout the study must be 
documented and reconciled. The following guidelines are therefore pertinent:
●
The investigator agrees not to supply enzalutamide to any persons except the eligible 
subjects in this study in accordance with the protocol.
●
The investigator or designee will keep the enzalutamide in a pharmacy or other 
locked and secure storage facility under controlled storage conditions, accessible only 
to those authorized by the investigator to dispense enzalutamide.


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●
An enzalutamide 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 enzalutamide to the Sponsor or designee at the end of the study 
or upon expiration.  
The study sites will provide GnRH agonist or antagonist from pharmacy stock.  
4.4
Blinding
This section is not applicable as this is an open-label study.
4.5
Assignment and Allocation
This is an open-label study, so subjects who meet all inclusion criteria and no exclusion 
criteria will be assigned to begin study treatment. Registration must occur following 
informed consent process and prior to initiation of investigational therapy. Each site will 
receive a unique Site ID and each subject at each site will be assigned a subject ID in 
sequential order as he enrolls in the study. Discontinued subjects will not be replaced. 
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 will receive treatment with enzalutamide (160 mg daily), administered as four 
40 mg capsules, by mouth, once daily, until radiographic or clinical progression, or 
unacceptable toxicity.
Study drug should be taken as close to the same time each day as possible. Study drug can be 
taken with or without food.
Subjects must also be receiving ongoing androgen deprivation therapy with a GnRH agonist,
antagonist, or have had a previous bilateral orchiectomy. The study sites will provide GnRH 
agonist or antagonist from pharmacy stock.  
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
Subjects who experience a Grade 3 or greater toxicity considered to be related to 
enzalutamide that cannot be ameliorated by the use of adequate medical intervention should 
have their treatment interrupted until the toxicity improves to a Grade 2 or lower severity. 


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Subjects may subsequently be re-started on study drug at a reduced dose following a 
discussion between the Investigator and the sponsor. 
5.1.3
Previous and Concomitant Treatment (Medication and Non-Medication
Therapy)
5.1.3.1 Previous Treatment (Medication and Non-Medication Therapy)
Medication taken within four weeks prior to Baseline (Day 1) and any medications 
prescribed chronically or intermittently during the study or dose adjustments of these 
medications must be captured on the case report form.
5.1.3.2 Concomitant Treatment (Medication and Non-Medication Therapy)
Concomitant medications will be captured from the Screening Visit through 30 days after last 
dose.
Prohibited Medications
The following medications are prohibited while patients are on enzalutamide treatment and 
have not had disease progression:
●
Chemotherapy with anti-tumor activity against prostate cancer such as cabazitaxel, 
mitoxantrone, etc.
●
Sipuleucel-T
●
Rad-223
●
Androgen-receptor antagonists (bicalutamide, flutamide, nilutamide)
●
5α-reductase inhibitors (finasteride, dutasteride)
●
Estrogens
●
Cyproterone acetate
●
Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)
●
Ketoconazole
●
Abiraterone acetate
●
Any other investigational agent
Restricted Medications
The dosage and regimen of the following medications and any chronic permitted medications 
should be stabilized during the screening period (> 4 weeks prior to randomization) and held 
constant throughout the study:
●
Denosumab and bisphosphonates
●
GnRH agonist/antagonist therapy
There is a potential for enzalutamide to affect exposures to other medicinal products, or for 
other medicinal products to affect exposure to enzalutamide:
●
Strong CYP2C8 inhibitors (e.g., gemfibrozil) or CYP2C8 inducers (e.g., rifampicin) 
are to be avoided. If subject must be co-administered a strong CYP2C8 inhibitor, the 
dose of enzalutamide should be reduced to 80 mg once daily. If a co-administration of 


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the strong inhibitor is discontinued, the enzalutamide dose should be returned to the 
dose used prior to initiation of the strong CYP2C8 inhibitor.
●
Strong CYP3A4 inducers (e.g. carbemezapine, phenobarbital, phenytoin, rifampin) or 
moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcilin, 
St. John’s Wort) should be avoided if possible as they may reduce enzalutamide 
plasma concentration if co-administered. Selection of a concomitant medication with 
no or minimal CYP3A4 induction potential is recommended.
●
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and 
CYP2C19. Medicinal products with a narrow therapeutic range that are substrates of 
CYP3A4 (e.g. alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g. phenytoin, warfarin), 
CYP2C19 (e.g. S-mephenytoin), or UGT1A1 should be avoided if possible, as 
enzalutamide may decrease their exposure.
●
If enzalutamide co-administration with warfarin cannot be avoided, additional INR 
monitoring should be conducted.
●
Enzalutamide is an inhibitor of human P-glycoprotein (P-gp) and may increase 
exposure to medicines that are P-gp substrates. Medicinal products with a narrow 
therapeutic range that are substrates for P-gp (e.g., digoxin, colchicine, dabigatran 
etexilate) should be used with caution when administered concomitantly with 
enzalutamide.
No other new systemic therapy or new radiotherapy for treatment (exception for spinal cord 
compression, pain management, etc.) for prostate cancer is permitted while subject is on the 
study. Subjects with pre-existing non-target lesions (e.g., bone metastases) receiving 
palliative radiography for pain treatment before participation in the study are allowed to 
continue receiving radiotherapy during the study.
5.1.4
Treatment Compliance
Study subjects 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 
period.  Compliance will be verified by the accounting of study drug at each study visit after 
Baseline. Compliance of the study drug will be monitored by the accounting of unused 
medication returned by the subject at visits. Compliance will be documented.
If compliance is less than 80% or more than 120%, the investigator or designee is to counsel 
the subject and ensure steps are taken to improve compliance. Subjects who are less than 
80% or more than 120% compliant with the dosage regimen for any two consecutive visit 
periods during the study should be withdrawn from the study.
5.1.5
Criteria for Continuation of Treatment 
Subjects will receive treatment until the time of disease progression, including radiographic 
or unequivocal clinical progression, or unacceptable toxicity. Per the Investigator’s clinical 
judgment and with sponsor approval, patients are allowed to continue study drug until next 
treatment is initiated.  If another non-cytotoxic, non-investigational, antineoplastic agent is 


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initiated after protocol-defined progression has been determined, study drug therapy may be 
continued per the Investigator’s clinical judgment and with sponsor approval as long as the 
patient is tolerating the study drug and continues androgen deprivation therapy.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
The subject’s date of birth, sex, race, ethnicity, and weight will be recorded at the Screening 
Visit.
5.2.2
Medical History
Medical history (other than for prostate cancer) will be obtained at the Screening Visit from 
each subject. All relevant past and present conditions, as well as prior surgical procedures 
will be recorded.
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 prostate cancer, Gleason 
score at time of diagnosis, dates and type of primary therapy and other disease specific 
information as designated in the eCRF.
5.2.4
Performance Status
The ECOG PS [Oken et al, 1982] will be used to assess performance status.
Table 2
ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair
5
Dead
ECOG PS score will be collected at the Screening Visit, Week 1 (Baseline), Week 13, Week 
25, at subsequent 12 week intervals, at any unscheduled visits, and at the Safety Follow-Up 
visit 30 days after last dose. 
5.2.5
Chest X-Ray and/or Chest CT
At the Screening Visit, a chest x-ray will be performed. A chest CT is required for efficacy 
assessment (see below) if the screening chest x-ray reveals suspected metastatic chest disease. 


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5.3
Efficacy Assessment
5.3.1
CT/MRI and Bone Scan
Imaging including abdominopelvic CT/MRI, chest CT (if screening chest x-ray leads to 
diagnosis of thoracic metastasis), and Technicium-99m (Tc-99m) bone scintiography will be 
performed at the Screening Visit and assessed at Week 9, Week 17, Week 25 and at 
subsequent 12 week intervals. For subjects that discontinue for reasons other than 
radiographic progression or initiation of a new anti-neoplastic therapy, the imaging will be 
conducted every 12 weeks until progression, initiation of new anti-neoplastic therapy, loss to 
follow-up or death. Imaging performed prior to informed consent may be used as baseline so 
long as it is performed within the Screening period (days -28 to -1).
Scans should be scheduled in such a way that the scan results are available at the regularly 
scheduled visit. 
The imaging method utilized for baseline scans must be utilized throughout the entire study.
Imaging may be performed at any time to confirm suspected progression of disease.
Radiographic evaluation of metastatic disease is determined separately for soft tissue and 
bone disease. Radiographic disease assessment for soft tissue disease is based on CT or MRI 
scan and is defined by RECIST 1.1. Radiographic disease assessment for bone lesions is 
based on bone scan and progression is considered when a minimum of two new lesions 
compared to baseline are observed. 
Progression on bone scan at time points prior to or at Week 9 require a confirmatory scan 
performed six or more weeks later. This confirmatory scan should demonstrate at least 
2 additional new lesions compared to the Week 9 scan (PCWG2). 
Assessment will include tumor measurements for target lesions, non-target lesions, and 
assessment for any new lesions. An overall assessment will be characterized for that time 
point evaluation. At the end of study for that subject, the overall best response to the study 
regimen will be characterized. 
Images (abdominopelvic [lung when applicable] CT/MRI and bone scan) should be read on 
site. Each site should ideally designate the same reader who will evaluate the images for any 
one subject for the duration of the study. 
The same imaging method used for an individual patient at baseline should be used 
throughout the entire study for that patient. 
PET scans should not be used to determine disease progression.
5.3.2
PSA
Samples for PSA will be collected and analyzed at the site’s local laboratory. PSA testing 
will be performed at the Screening Visit, Week 1 (Baseline), Week 9, Week 13, Week 17, 
Week 21, Week 25, at subsequent 12 week intervals, and at the Safety Follow-up visit 
30 days after last dose. 


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The PSA test performed at the Screening Visit does not need to be repeated on Day 1 if the 
Day 1 visit occurs within 72 hours of the Screening Visit.
5.3.3
Correlative Samples
Whole blood and serum samples will be collected at Week 1 (baseline), Week 13, and at the 
time of PSA progression and/or at the time of radiographic progression. See Sections 5.7.1
and 5.7.2 for details.
5.3.4
Survival Follow-up
For all subjects, survival status and subsequent anti-cancer therapies will be followed every 
12 weeks for a maximum of 3 years from first dose. The study will end when the last subject 
has been followed for 1 year from date of first dose.
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 Activities.
Please review the requirements related to the evaluation, reporting and analysis of 
Drug-Induced Liver Injury (DILI) information found in Appendix 12.2 (Liver Safety 
Monitoring and Assessment). In the event of a confirmed, marked hepatic abnormality as 
defined in Appendix 12.2, it is the Investigator’s responsibility to ensure contact with the
Sponsor/ delegated CRO by telephone or fax immediately (i.e., within 24 hours of awareness).
5.4.1
Vital Signs
Vital signs including blood pressure, heart rate, and temperature will be assessed at the 
Screening Visit, at every clinic visit while on study drug and at the 30-day Safety Follow-Up 
visit (see Table 1  Study Schedule of Activities). 
For each blood pressure measurement, the patient 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
AE collection will begin from the time of informed consent and continue through 30 days 
after last dose. 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.


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Subjects with AE’s of hepatic origin accompanied by Liver Function Test (LFT)
abnormalities should be carefully monitored. 
5.4.3
Laboratory Assessments
Routine laboratory assessments for hematology and chemistry will be collected and analyzed 
at the site’s local laboratory. Specifications regarding sample collection (including date and 
time) must be recorded in the source documentation. The site will provide all lab certification 
documents and reference ranges to Astellas. The same information will need to be stored in 
the Regulatory Binder. 
Laboratory assessments will be assessed at the Screening Visit, Week 1 (Baseline), Week 13, 
Week 25, at subsequent 12 week intervals, at any unscheduled visits, and at the Safety 
Follow-Up visit 30 days after last dose.
The laboratory assessments performed at the screening visit do not need to be repeated on 
Day 1 if the Day 1 visit occurs within 72 hours of the Screening Visit.
Laboratory assessments must be obtained prior to study drug administration.
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
See Table 1  Study Schedule of Activities for study visit collection dates. 
Screening, Week 1, 
Week 13, Week 25, 
at subsequent 12 
week intervals, at any 
unscheduled visits, 
and at the Safety 
Follow-Up visit 30 
days after last dose.
Hematology
CBC
RBC
HgB
HCT
WBC
Platelets
WBC Differential
Screening, Week 1, 
Week 13, Week 25, 
at subsequent 12 
week intervals, at any 
unscheduled visits, 
and at the Safety 
Follow-Up visit 30 
days after last dose.
Biochemistry
Sodium
Potassium
Calcium
Chloride
Magnesium
Phosphorus
Glucose
Creatinine
Alkaline phosphatase
bALP
LDH
ALT
AST
GGT
Total bilirubin
Total protein
Albumin
CO2
BUN


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Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician.
5.4.4
Physical Examination 
A complete physical exam, including weight, will be performed at the Screening Visit.  A 
brief physical exam is required at all subsequent office visits.  The physical examination 
performed at the Screening Visit does not need to be repeated on Day 1, if the Day 1 visit 
occurs within 72 hours of the Screening Visit. Any clinically relevant adverse changes will 
be recorded as AEs in the eCRF (see Section 5.5.6).  
5.4.5
Electrocardiogram (ECG) 
A 12-lead ECG will be recorded at the Screening Visit. The ECG will be taken with the 
subject in the sitting position.
All tracings will be read locally by the Investigator 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. 
5.4.6
Imaging
A MUGA scan or echocardiogram showing LVEF ≥ 45% is required at the Screening Visit 
only for subjects with a history of anthracycline or anthracenedione (mitoxantrone) treatment, 
or if the subject has congestive heart failure New York Heart Association (NYHA) class 3 or 
4.
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 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.


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5.5.2
Disease Progression
It is anticipated that a proportion of subjects will experience disease progression. Disease 
progression should not be reported as an adverse event. Clinical signs and symptoms due to 
disease progression will be collected as AEs. Individual signs and symptoms will be listed 
rather than the term “disease progression” with the following exception: if disease 
progression is the cause of death, this event may be recorded as an AE with “metastatic 
prostate cancer disease progression” as the reported term.
5.5.3
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 
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.
5.5.4
Special Situations
The following special situations, although not necessarily considered to be AEs or ADRs 
must be reported in the same way as ADRs, as described in Section 5.5.7 Reporting of 
Serious Adverse Events (SAEs): 
●
Off-label use: situations where a medicinal product is intentionally used for a medical 
purpose not in accordance with the authorized product information. 
●
Overdose: administration of a quantity of a medicinal product given per 
administration or cumulatively which is above the maximum recommended dose 
according to the authorized product information. Clinical judgment should always be 
applied. 


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●
Misuse of a medicinal product: situations where the medicinal product is intentionally 
and inappropriately used not in accordance with the authorized product information. 
●
Abuse of a medicinal product: persistent or sporadic, intentional excessive use of 
medicinal products which is accompanied by harmful physical or psychological 
effects. 
●
Medication errors: are broadly defined as any error in the prescribing, dispensing, or 
administration of a drug, irrespective of whether such errors lead to adverse 
consequences or not. 
●
Occupational exposure: this refers to the exposure to a medicinal product, as a result 
of one’s professional or non-professional occupation. 
All of the events of interest noted above should be recorded on the eCRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and the SAE worksheet.
5.5.5
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).


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5.5.6
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 
(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
5.5.7
Reporting of Serious Adverse Events (SAEs)
For patients known to be taking enzalutamide, all Serious Adverse Events, Special Situations 
(as outlined in Section 5.5.4) and non-serious AE’s considered related to this (and any) 
Astellas product must be reported by the investigator to Astellas Global Pharmacovigilance 
via email 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 Astellas Global Pharmacovigilance by email 
or fax immediately (within 24 hours of awareness).
All completed SAE forms should be sent to:
Astellas Global 
Pharmacovigilance 
Email: 
North America telefax numbers: 
 
(alternate
)
International telefax number: 
If the faxing of 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. 
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).


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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 
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 heads of the study sites/Investigators should provide written documentation of IRB/IEC 
notification for each report to the Sponsor.
5.5.8
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).
5.5.9
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 5.5.7 Reporting of Serious Adverse Events (SAEs). 


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5.5.10
Procedure in Case of Pregnancy
If a partner of a male subject becomes pregnant during the study dosing period or within 
30 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.
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
5.5.11
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.
5.5.12
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 for this study.
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for Molecular Profiling of CTCs
Whole blood samples will be collected at Week 1, Week 13 and at the time of PSA 
progression and/or at the time of radiographic progression. Seventeen milliliters (17 mL) of 


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whole blood in two 8.5 mL ACD Sol A tubes are needed at each time point to ensure at least 
5 mL for AR and GR analysis. Samples will be collected on Monday-Thursday and shipped 
overnight to 
 for testing per vendor instructions. Remaining samples 
may be stored for future biomarker analysis. Methods as described by Antonarakis et al., 
2014 will be used to capture CTC and quantification of messenger RNA (mRNA) of AR-FL, 
AR variants and GR-FL via Quantitative reverse-transcriptase–polymerase-chain-reaction
(RT-PCR) assays. AR DNA was polymerase chain reaction-amplified and the product will be 
analyzed.
5.7.2
Serum Sample for Biomarker Analysis
Serum samples collected at Week 1, Week 13, and at the time of PSA progression and/or at 
the time of radiographic progression, will be shipped to a central lab for testing for, but not 
limited to, the analysis of inflammatory proteins such as IL6, IL8, TNF-, soluble TNF1, etc. 
and neuroendocrine markers such as chromogranin A (CgA), neuron specific enolase (NSE), 
and synaptophysin. Five milliliters of blood will be collected to yield approximately 2 mL of 
serum. Remaining samples may be stored for future biomarker analysis.
5.8
Total Amount of Blood
The total amount of blood collected for routine laboratory tests and correlative biomarker 
analysis for each subject will vary depending on how long they stay on treatment. The 
maximum amount of blood collected for a subject within 24 hours during the treatment 
period is approximately 37 mL, including 15 mL for routine lab (i.e., CBC with differential, 
PSA, and comprehensive metabolic panel), and 22 mL for correlative biomarker analysis 
(Section 5.7). 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.
If a subject is discontinued from the study with an ongoing adverse event 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. 


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The following events will result in the removal of subjects from enzalutamide therapy: 
●
Subject develops an adverse event, intercurrent illness, or toxicity, where continued 
administration of study drug is deemed not in the subject’s best interest by the 
investigator and/or the sponsor. For example,
o
Seizure;
o
Posterior Reversible Encephalopathy Syndrome;
o
Laboratory abnormality defined by protocol as follows: 
Creatinine > 354 µmol/L (> 4.0 mg/dL); 
o
AST, ALT, or total bilirubin > 5 times ULN;
o
Absolute neutrophil count < 750/µL;
o
Platelet count < 50,000/mL.
●
Decision by the investigator and subject to initiate a new anti-neoplastic therapy;
●
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.
Unless the subject withdraws consent, all subjects discontinuing study drug for any reason 
will have a Safety Follow-up visit 30 days after their last dose of study drug or prior to 
initiation of subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first.
Subjects that discontinue study drug for a reason other than radiographic progression or 
initiation of a new anti-neoplastic therapy will have a PSA test performed 30 days from date 
of last dose and undergo long-term follow-up every 12 weeks from date of last dose. Long 
term follow-up will assess for survival, subsequent anti-neoplastic therapy for prostate cancer
and radiographic progression. Subjects will be followed for a maximum of 3 years from first 
dose. The study will end when the last subject has been followed for 1 year from date of first 
dose. Radiographic imaging will end when the patient has developed a radiographic 
progression, or initiated subsequent anti-neoplastic therapy. 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 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.


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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 Astellas. 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 
documented in the Clinical Study Report (CSR).
Prior to Database Lock, a Final Review of Data and 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.  Kaplan-Meier estimates will be used to 
estimate medians and provide figures for time-to-event data (e.g., rPFS, time to PSA 
progression, and time to first use of a subsequent antineoplastic therapy).
7.1
Sample Size
Prior clinical trials data in the post-chemo setting have shown the following median rPFS for 
subject randomized to initial placebo, placebo+prednisone, or mitoxantrone+prednisone 
therapy:
o
AFFIRM: Placebo = 2.9 months
o
COU-301: Placebo + Prednisone = 3.6 months
o
TROPIC: Mitoxantrone + Prednisone = 1.4 months
With a sample size of 40 subjects and an assumed median rPFS of 4 months for the therapy 
defined in this single-arm study, approximately 34 events are expected over a 12-month 
accrual and 12-month minimum follow-up. Further assuming uniform accrual, 10% loss to 
follow-up, and an exponential distribution for the rPFS event times, the expected lower 
bound of the 90% confidence interval for the median is approximately 2.5 months based 
upon simulations.
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.


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7.2.1
Full Analysis Set (FAS)
The full analysis set will consist of all subjects who are enrolled, receive at least one dose of 
study drug, and have at least one post baseline evaluation. This will be the primary analysis 
set for efficacy analyses.
7.2.2
Per Protocol Set (PPS)
Not applicable.
7.2.3
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least one dose of study medication, and will be used 
for safety analyses.
7.2.4
Biomarker Analysis Set (BAS)
The Biomarker analysis set (BAS) consists of the subset of the FAS population for which 
biomarker data are available to facilitate derivation of at least one of the correlative 
biomarkers.
7.3
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group for 
the SAF. Other baseline characteristics will include baseline disease severity measures and 
prior prostate cancer therapies.  Descriptive statistics will include number of subjects, mean, 
standard deviation, minimum, median and maximum for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.4
Analysis of Efficacy 
The primary efficacy analysis will be conducted on the FAS. 
7.4.1
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis
The primary efficacy endpoint, rPFS, will be analyzed using Kaplan-Meier methodology to 
account for censored outcomes (i.e. no observation of rPFS event within the study follow-up 
period).
Ninety percent (90%) confidence interval will be provided for the median rPFS.
7.4.1.2 Secondary Analysis
Not applicable.  
7.4.1.3 Subgroup Analysis
The analysis described in Section 7.4.1.1 may be repeated in subsets defined by baseline 
characteristics such as prior treatment, prior response to enzalutamide, biomarkers, etc. In 
addition, multivariable analyses may be conducted using multivariable analyses.  This 
analysis will be conducted using the FAS.


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7.4.2
Analysis of Secondary Endpoints 
The overall survival rate at 1 year will be estimated via Kaplan-Meier methodology with 
censoring defined by the time of last contact with the subject for those subjects who do not 
have a reported death.  This analysis will be repeated in each subset defined by prior 
treatment with exposure.
For patients with PSA declines, the PSA progression date is defined as the date that a ≥25% 
increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir is documented, 
which is confirmed by a second consecutive value obtained 3 or more weeks later. For 
patients with no PSA declines, the PSA progression date is defined as the date that a ≥25% 
increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the baseline is documented, 
which is confirmed by a second consecutive value 3 or more weeks later.  The time to PSA 
progression will then be estimated via Kaplan-Meier methodology with censoring defined by 
the time of the last available PSA measure. This analysis will be repeated in each subset 
defined by prior treatment with exposure.
The proportion of subjects achieving a maximum PSA decline from baseline of at least 30% 
(PSA30), 50% (PSA50), and 90% (PSA90), respectively, and having an objective response 
will provided along with 90% confidence intervals. Analyses for PSA response rates will 
include all subjects with at least one post-baseline PSA measure.  Analysis for objective 
response will include all subjects with measurable disease at baseline.  These analyses will be 
repeated in each subset defined by prior treatment with exposure.
The time to first use of a subsequent antineoplastic therapy will be estimated via Kaplan-
Meier methodology with censoring defined by the time of last contact with the subject for 
those subjects who do not have a reported use of antineoplastic therapy.  This analysis will be 
repeated in each subset defined by prior treatment with exposure.
The analysis described in Section 7.4.1.3 will be repeated for secondary endpoints as 
appropriate. 
7.4.3
Analysis of Exploratory Endpoints 
Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, maximum, 
frequency, and percentage) will be provided for baseline blood and plasma samples and by 
each post-baseline scheduled timepoint.  
Baseline biomarker measurements will be included in regression models to assess correlation 
with the following endpoints: rPFS, time to OS, PSA30, PSA50, PSA90, and objective 
response.  Time-to-event data endpoints will be modelled via Cox proportional hazards 
model.  Binary endpoints will be modeled via logistic regression.  Univariate models will be 
used to assess significance of individual biomarker measures.  Multivariable models may also 
be considered to control for baseline demographic, disease, and treatment characteristics.


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7.5
Analysis of Safety
7.5.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The number and percentage of AEs, SAEs, AEs leading to discontinuation, and 
AEs related to study drug will be summarized by system organ class and preferred term. The 
number and percentage of AEs by severity will also be summarized. All AEs will be listed.
7.5.2
Laboratory Assessments
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by time point. Laboratory values will be classified by 
toxicity grade based on the NCI-CTCAE, version 4.0. Tables of laboratory CTCAE grade 
shift from baseline to maximum CTCAE grade across subsequent visits will be provided.  
Laboratory data will be displayed in listings.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by time. Vital signs data will be displayed in listings.
7.5.4
Physical Examination
Physical examination will be listed.
7.5.5
ECGs
The 12-lead ECG results will be summarized by time point.
7.6
Analysis of Pharmacogenomics
See Section 7.4.3
7.7
Protocol Deviations
Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be summarized for 
all enrolled subjects overall 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)
An interim efficacy analysis will be conducted 13 weeks after enrollment of the 40th subject 
to report on PSA response rates.


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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. The imputed dates will be used to 
determine whether a medication was given concomitantly and whether an AE is/is not 
treatment emergent. Listings of the AEs and concomitant medications will present the actual 
partial dates; imputed dates will not be shown.
See the SAP for details of the definitions for windows to be used for analyses by visit.
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 the timeframe defined for the study.
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.
Routine laboratory tests will be performed locally and entered into the eCRF. The monitor 
should verify the data in the eCRFs with source documents and confirm that there are no 
inconsistencies between them. 
Correlative samples will be collected and analyzed at a central laboratory designated by the 
Sponsor. Laboratory data will be transferred electronically to the Sponsor or designee at 
predefined intervals during the study. The laboratory will provide the Sponsor or designee 
with a complete and clean copy of the data. 
For Screen failures, the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and Adverse Events 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 
●
Visit dates


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●
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 (if applicable)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
8.1.3
Clinical Study Monitoring
The Sponsor or delegated 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 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 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 Global Data Science of the Sponsor in 
accordance with the 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.


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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.
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 


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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, Medical Affairs, Americas-sponsored studies.
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. 
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.
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 


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subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must re-consent 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.
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, CRFs, and Investigator's File) and relevant correspondence.  These documents are to be 


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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 CRFs supplied 
for each subject. 
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.
Depending on the nature of the amendment, either 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).


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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
10.1
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s)
Not applicable.


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11
REFERENCES 
American Cancer Society . Prostate Cancer Key Statistics 2016. Atlanta: American Cancer 
Society:2016. Available from: 
http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to 
enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep;371:1028-1038.
Azad AA, Eigl BJ, Murray RN,  Kollmannsberger C, Chi KN. Efficacy of enzalutamide following 
abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer 
patients. Eur Urol. 2014 Jul. http://dx.doi/org/10.1016/j.eururo.2014.06.045.
Balbas MD, Evans MJ, Hosfield DJ, Wongvipat J, et al. Overcoming mutation-based resistance to 
antiandrogens with rational drug design. Elife. 2013 Apr 9;2:e00499.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CS, Higano CS, et al. Enzalutamide in 
metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul;371(5):424-433.
Bianchini D, Lorente D, Rodriguez-Vida A, Omlin A, Pezaro C, Ferraldeschi R, et al. Antitumour 
activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate 
cancer (CRPC) pre-treated with docetaxel and abiraterone. European Journal of Cancer. 2014 
Jan; 50(1):78-84. 
Carreira S, Romanel A, Goodall J, Grist E, et al. Tumor clone dynamics in lethal prostate cancer. Sci 
Transl Med 6, 254ra125 (2014)
Cabazitaxel [package insert]. Bridgewater (NJ): Sanofi-Aventis US LLC; 2014.
Chadha KC, Miller A, Nair BB, Schwartz AS, Trump DL, Underwood W. New serum biomarkers for 
prostate cancer diagnosis. Clin Cancer Investig J. 2014;3:72-79.
Codony-Servat J, Marin-Aguilera M, Visa L, Garcia-Albeniz X, Pineda E, Fernandez PL, et al. 
Nuclear factor-kappa B and interleukin-6 related docetaxel resistance in castration-resistant 
prostate cancer. The Prostate. 2013;73:512-521.
De Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased 
survival in metastatic prostate cancer. N Engl J Med. 2011 May;364(21):1995-2005.
De Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus 
cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after 
docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct;376(9747):1147-1154. 
Duff J and McEwan IJ. Mutation of histidine 874 in the androgen receptor ligand-binding domain 
leads to promiscuous ligand activation and altered p160 coactivator interactions. Mol 
Endocrinol. 2005 Dec;19(12):2943-54.
Eiro N, Bermudez-Fernandez S, Fernandez-Garcia B, Atienza S, Beridze N, Escaf S. Analysis of the 
expression of interleukins, interferon b, and nuclear factor-k B in prostate cancer and their 
relationship with biochemical recurrence. J Immunother. 2014;37:366-373.


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Fabbri F, Amadori D, Carloni S, Brigliadori G, Tesei A, Ulivi P, et al. Mitotic catastrophe and 
apoptosis induced by docetaxel in hormone-refractory prostate cancer cells. J. Cell. Physiol. 
2008;217:494–501.
Feng S, Tang Q, Sun M, Chun JY, Evans CP, Gao AC. Interleukin-6 increases prostate cancer cells 
resistance to bicalutamide via TIF2. Mol Cancer Ther. 2009 March;8(3):665-671.
Hu R,  Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct 
transcriptional programs mediated by the ligand-dependent full-length androgen receptor and 
its splice variants in castration-resistant prostate cancer. Cancer Res. 2012; 72(14); 3457–3462
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al.  Sipuleucel-T 
immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
Leibowitz-Amit R, Alimohamed N, Vera-Badillo FE, Seah JA, Templeton AJ, Knox JJ, et al. 
Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone. Prostate. 
2014 Oct;74(14):1462-1464.
Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants 
mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 
2013 Jan;73(2):483-489.
Liu C, Zhu Y, Lou W, Cui Y, Evans CP, Gao AC. Inhibition of constitutively active stat3 reverses 
enzalutamide resistance in LNCaP derivative prostate cancer cells. The Prostate. 
2014;74:201-209.
Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, et al. Antitumour activity of 
abiraterone acetate against metastatic castration-resistant prostate cancer progressing after 
docetaxel and enzalutamide (MDV3100). Ann Oncol. 2013;24(7):1807-1812.
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance 
of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant 
tumor growth. Cancer Res. 2008;68:4447-4454.
Nakazawa M, Lu C, Chen Y, Paller CJ, Carducci MA, Eisenberger MA et al. Serial blood-based 
analysis of ar-v7 in men with advanced prostate cancer. Ann Onc. 2015 Jun:
http://dx.doi.org/10.1093/annonc/mdv282.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-655.
Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 
and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-223.
Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, et al. Prospective assessment of 
discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to 
erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res. 
2007;13(17):5150-5155.
Ryan CJ, Smith MR, De Bono JS, Molina A, Logothetis CJ, De Souza P, et al. Abiraterone in 
metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 
Jan;368(2):138-48.


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Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg C, Miller K, et al. Increased survival with 
enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012
Sep. ;367(13):1187-1197.
Schrader AJ, Boegemann M, Ohlmann CH, Schnoeller TJ, Krabbe LM, Jentzmik F, et al. 
Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and 
abiraterone. European Urology. 2014 Jan;65(1):30-36. 
Song Z, Yu X, He C, Zhang B, Zhang Y.  Re-administration after the failure of gefitinib or erlotinib 
in patients with advanced non-small cell lung cancer. J Thorac Dis. 2013;5(4):400-405.
Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, et al. Castration resistance in 
human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J 
Clin Invest. 2010 Aug;120(8):2715-2730.
Szmulewitz RZ, Kregel S, Isikbay M, Cai Y, Chen JL, Vander Griend DJ, et al. Androgen receptor 
independent acquired mechanisms of resistance to enzalutamide in castration-resistant prostate 
cancer. J Clin Oncol. 2014;32 (Suppl 4; abstr 129).
Tannock IF, De Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12.
Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, et al. Androgen receptor 
splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 
2014;74(8):2270-2282.
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(5928):787-790.  


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12
APPENDICES
12.1
List of Prohibited and Restricted Concomitant Medications
Part A – Prohibited Medications
The following medications are prohibited while patients are on enzalutamide treatment and 
have not had disease progression:
●
Chemotherapy with anti-tumor activity against prostate cancer such as cabazitaxel, 
mitoxantrone, etc.
●
Sipuleucel-T
●
Rad-223
●
Androgen-receptor antagonists (bicalutamide, flutamide, nilutamide)
●
5α-reductase inhibitors (finasteride, dutasteride)
●
Estrogens
●
Cyproterone acetate
●
Androgens (testosterone, dehydroepiandrosterone [DHEA], etc.)
●
Ketoconazole
●
Abiraterone acetate
●
Any other investigational agent
Part B – Medications Permitted with Restrictions
The dosage and regimen of the following medications and any chronic permitted medications 
should be stabilized during the screening period (> 4 weeks prior to randomization) and held 
constant through the study:
●
Denosumab and bisphosphonate
●
GnRH agonist/antagonist therapy
There is a potential for enzalutamide to affect exposures to other medicinal products, or for 
other medicinal products to affect exposure to enzalutamide:
●
Strong CYP2C8 inhibitors (e.g., gemfibrozil) or CYP2C8 inducers (e.g. rifampicin) 
are to be avoided. If subject must be co-administered a strong CYP2C8 inhibitor, the 
dose of enzalutamide should be reduced to 80 mg once daily. If a 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.
●
Strong CYP3A4 inducers (e.g. carbemezapine, phenobarbital, phenytoin, rifampin) or 
moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcilin, 
St. John’s Wort) should be avoided if possible as they may reduce enzalutamide 
plasma concentration if co-administered. Selection of a concomitant medication with 
no or minimal CYP3A4 induction potential is recommended.
●
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and 
CYP2C19.  Medicinal products with a narrow therapeutic range that are substrates of 
CYP3A4 (e.g. alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g. phenytoin, warfarin), 


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CYP2C19 (e.g. S-mephenytoin), or UGT1A1should be avoided if possible, as 
enzalutamide may decrease their exposure.
●
If enzalutamide co-administration with warfarin cannot be avoided, additional INR 
monitoring should be conducted.
●
Enzalutamide is an inhibitor of human P-glycoprotein (P-gp) and may increase 
exposure to medicines that are P-gp substrates. Medicinal products with a narrow 
therapeutic range that are substrates for P-gp (e.g., digoxin, colchicine, dabigatran 
etexilate) should be used with caution when administered concomitantly with 
enzalutamide.
No other new systemic therapy or new radiotherapy for treatment (exception for spinal cord 
compression, pain management, etc.) for prostate cancer is permitted while subject is on the 
study. Subjects with pre-existing non-target lesions (e.g., bone metastases) receiving 
palliative radiography for pain treatment before participation in the study are allowed to 
continue receiving radiotherapy during the study.


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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 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%). 
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) 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 Event (SAE). The Sponsor should be contacted and informed of all subjects for 


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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: 
o
acute viral hepatitis (A,B, C, D, E or other infectious agents). 
o
ultrasound or other imaging to assess biliary tract disease
o
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 LFT’s, 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 ULN (“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
The following is a list of serious adverse events that the Sponsor considers to be associated 
with the disease state being studied. The list does NOT change your reporting obligations 
or prevent the need to report an adverse event meeting the definition of an SAE as 
detailed in Section 5.5.3 Definition of Serious Adverse Events (SAEs). 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”. You are required to follow the requirements detailed in Section 5.5.7 Reporting of 
Serious Adverse Events (SAEs).
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicate they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA. 
●
Anemia 
●
Anorexia 
●
Asthenia / Fatigue 
●
Back pain 
●
Bone pain 
●
Catheter related infection 
●
Dyspnea 
●
Haematuria 
●
Hydronephrosis 
●
Metastases to bone 
●
Metastases to central nervous system 
●
Nausea 
●
Obstructive uropathy 
●
Pain 
●
Prostate cancer metastatic 
●
Renal failure 
●
Renal failure acute 
●
Spinal compression fracture 
●
Spinal cord compression 
●
Urinary retention 
●
Urinary tract infection 
●
Urinary tract obstruction 
●
Vomiting 





SAP_001.pdf: 
A Multicenter, Open-label, Single-arm, Study of 
Enzalutamide Re-Treatment in Metastatic Castration-
Resistant Prostate Cancer, As First Treatment Post-
Chemotherapy in Patients who Have Previously Received
Enzalutamide in the Pre-Chemotherapy Setting
ISN/Protocol 9785-MA-1008
Final Version 1.0, dated 08-July-2015
ClinicalTrials.gov Identifier: NCT02441517
Sponsor: Astellas Scientific and Medical Affairs (ASMA)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.0
ISN/Protocol 9785-MA-1008
08-Jul-2015
Astellas
Page 1 of 30
STATISTICAL ANALYSIS PLAN
Final Version 1.0, dated 08-Jul-2015
Multicenter, open-label, single-arm, study of Enzalutamide Re-Treatment in Metastatic 
Castration-Resistant Prostate Cancer, As First Treatment Post-Docetaxel in Patients who 
Have Previously Received Enzalutamide in the Pre-Chemotherapy 
ISN: 9785-MA-1008
IND : 74,563
Sponsor:
Astellas Scientific and Medical Affairs (ASMA)
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.


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.0
ISN/Protocol 9785-MA-1008
08-Jul-2015
Astellas
Page 2 of 30
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 4
1
INTRODUCTION·················································································· 6
2
FLOW CHART AND VISIT SCHEDULE···················································· 7
3
STUDY OBJECTIVE(S) AND DESIGN······················································· 9
3.1
Study Objective(s) ············································································· 9
3.1.1
Primary Objectives······································································· 9
3.1.2
Secondary Objectives···································································· 9
3.2
Study Design···················································································· 9
3.3
Randomization·················································································10
4
SAMPLE SIZE ····················································································10
5
ANALYSIS SETS ·················································································11
5.1
Full Analysis Set (FAS) ······································································11
5.2
Per Protocol Set (PPS)········································································11
5.3
Safety Analysis Set (SAF) ···································································11
5.4
Biomarker Analysis Set (BAS)······························································11
6
ANALYSIS VARIABLES ·······································································11
6.1
Efficacy Endpoints············································································12
6.1.1
Primary Efficacy Endpoint(s)··························································12
6.1.2
Secondary Efficacy Endpoints·························································12
6.1.3
Exploratory Efficacy Endpoints ·······················································14
6.1.4
Other Efficacy Variables ·······························································15
6.2
Safety Variables···············································································15
6.3
Pharmacokinetic Variables···································································15
6.4
Pharmacodynamic Variables ································································15
6.5
Other Variables················································································16
7
STATISTICAL METHODOLOGY ···························································16
7.1
General Considerations·······································································16
7.2
Study Population ··············································································17
7.2.1
Disposition of Subjects ·································································17
7.2.2
Protocol Deviations ·····································································17
7.2.3
Demographic and Other Baseline Characteristics ···································17


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.0
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08-Jul-2015
Astellas
Page 3 of 30
7.2.4
Previous and Concomitant Medications ··············································19
7.3
Study Drugs····················································································19
7.3.1
Exposure··················································································19
7.3.2
Treatment Compliance··································································19
7.4
Analysis of Efficacy ··········································································20
7.4.1
Analysis of Primary Endpoint(s) ······················································20
7.4.2
Analysis of Secondary Endpoints ·····················································20
7.4.3
Analysis of Exploratory Endpoints····················································20
7.4.4
Analysis of Other Variables····························································22
7.5
Analysis of Safety·············································································22
7.5.1
Adverse Events ··········································································22
7.5.2
Clinical Laboratory Evaluation ························································23
7.5.3
Vital Signs················································································24
7.5.4
Electrocardiograms (ECGs)····························································25
7.5.5
Pregnancies···············································································25
7.5.6
Other Safety-Related Observations ···················································25
7.6
Analysis of PK·················································································25
7.7
Analysis of PD·················································································25
7.8
Subgroups of Interest ·········································································25
7.9
Other Analyses ················································································25
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················25
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········25
7.11.1
Missing Data ·············································································26
7.11.2
Outliers ···················································································26
7.11.3
Visit Windows ···········································································26
8
DOCUMENT REVISION HISTORY·························································26
9
REFERENCES ····················································································27
10
APPENDICES ·····················································································28
10.1
Appendix 1: Key Contributors and Approvers ············································28


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
IEC
Independent Ethics Committee
IGF
Insulin-like Growth Factor 1
IL6
Interleukin 6
IL8
Interleukin 8
INR
International Normalized Ratio
IRB
Institutional Review Board
ISN
International Study Number
JAK/STAT
Janus Kinase / Signal Transducer and Activator of Transcription
LA-CRF
Liver Abnormality Case Report Form
LBD
Ligand Binding Domain
LDH
Lactate Dehydrogenase
LFT
Liver Function Tests
LVEF
Left Ventricular Ejection Fraction
mCRPC
Metastatic Castration- Resistant Prostate Cancer
MedDRA
Medical Dictionary for Regulatory Activities
mg/dL
Milligram/Deciliter
mmHg
Millimeters of Mercury
mmol/L
Millimoles/Liter
MOA
Mechanism of Action
MRI
Magnetic Resonance Imaging
mTOR
Mammalian Target of Rapamycin
MUGA
Multiple Gated Acquisition
NASH
Non-alcoholic Steatohepatitis
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
Ng
Nanogram
nmol/L
Nanomole/Liter
NYHA
New York Heart Association
OS
Overall Survival
PCWG2
Prostate Cancer Clinical Trials Working Group
PGAS
Pharmacogenomic Analysis Set
PHI
Protected Health Information
PK
Pharmacokinetics
PSA
Prostate-Specific Antigen
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria In Solid Tumors
rPFS
Radiographic Progression-Free Survival
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
TBL
Total Bilirubin
TLF
Tables, Listings and Figures
sTNF1
Soluble Tumor Necrosis Factor Receptor – 1
TNF-alpha
Tumor Necrosis Factor - Alpha


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Abbreviations
Description of abbreviations
TMF
Trial Master File
µL
Microliter
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell
List of Key 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.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.
  


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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 for study 9785-MA-1008, 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 database hard lock, or accumulation of substantial 
amount of data in an open-label study 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 APGD-US. 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 of data and 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 hard lock.




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g
Laboratory assessments include serum chemistries and hematology.
h
Collect a blood sample for additional safety testing if indicated.
i
PSA progression, defined as a ≥25% increase and an absolute increase of ≥2 μg/L (2 ng/mL) above the nadir, needs to be confirmed by a second consecutive value obtained 3 or 
more weeks later.
j
The window for all radiological assessments is ± 7 days. At Weeks 9, 17, 25 and subsequent assessments prior to treatment discontinuation, all other procedures must be 
completed within the ± 3 day window. Bone progression at the first reassessment at Week 9 requires a confirmatory scan 6 or more weeks later. 
k
Adverse events, serious or non-serious, will be collected from the time the patient signs the consent form until the Safety Follow-Up visit, regardless of initiation of another anti-
neoplastic therapy prior to last dose of enzalutamide.
l
Long-term follow-up for radiographic progressions (until progression or initiation of new anti-neoplastic therapy), survival, and subsequent anticancer therapies should be 
performed every 12 weeks for a maximum of 3 years from first dose. The study will end when the last subject has been followed for 1 year from date of first dose.
m
Enzalutamide will be administered until the disease progression, including radiographic progression or unequivocal clinical progression. Per the Investigator’s clinical judgment 
and with sponsor approval, patients may be allowed to continue enzalutamide until the next treatment is initiated.  If another non-cytotoxic, non-investigational, antineoplastic 
agent is initiated after protocol-defined progression has been determined, enzalutamide may be continued per the Investigator’s clinical judgment and with sponsor approval as 
long as the patient is tolerating enzalutamide and continues androgen deprivation therapy
n
Blood samples for CTC molecular profiling and serum samples will be collected at baseline, week 13, time of PSA progression, and time of radiographic progression.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objectives
The primary objective is to determine radiographic progression-free survival (rPFS) of 
re-treatment with enzalutamide + GnRH analogue
3.1.2
Secondary Objectives
The secondary objectives are:
●
Assess additional measures of efficacy: 
o
Overall survival rate at 1 year 
o
Time to PSA progression
o
PSA response rate [maximum decline of ≥30%, ≥50%, and ≥90% from baseline, (PSA30, 
PSA50, and PSA90), respectively] 
o
Objective response rate
●
Time to first use of a subsequent antineoplastic therapy
●
Assess safety of enzalutamide re-treatment in the post-chemo setting
●
Assess correlative science in the post-chemo setting
3.2
Study Design
This is a US-based, multicenter, open-label, single-arm, study evaluating the efficacy, safety, 
and tolerability of open-label enzalutamide in the re-treatment setting.  A total of 40 patients 
will be enrolled. Patients must have been previously treated with enzalutamide in the 
pre-chemotherapy setting for a minimum of 8 months, followed by docetaxel for a minimum 
of 6 cycles. Exposure to intervening systemic anti-cancer therapies such as abiraterone prior 
to docetaxel is allowed.  Subjects will receive treatment with open-label enzalutamide 
(160 mg daily), administered as four 40 mg capsules, by mouth, once daily, until 
radiographic or clinical progression (such as pathological fracture, cord compression, 
worsened pain requiring radiation therapy, or opioid analgesic dose increase or initiation), or 
unacceptable toxicity.  Per the Investigator’s clinical judgment and with sponsor approval, 
patients may be allowed to continue enzalutamide until the next treatment is initiated.  If 
another non-cytotoxic, non-investigational, antineoplastic agent is initiated after protocol-
defined progression has been determined, enzalutamide may be continued per the 
Investigator’s clinical judgment and with sponsor approval as long as the patient is tolerating 
enzalutamide and continues androgen deprivation therapy.
The consensus guidelines of the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
and the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) will be utilized to 
determine radiographic disease progression. Radiographic disease progression is defined by 
RECIST 1.1 for soft tissue disease.  Bone disease progression is considered when a minimum 
of two new lesions are observed. Progression on bone scan at time points prior to or at 
week 9 requires a confirmatory scan performed six or more weeks later.  This confirmatory 


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scan should demonstrate at least 2 additional new lesions compared to the Week 9 scan 
(PCWG2).
The following assessments of prostate cancer status will be collected during the course of the 
trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance 
imaging (MRI), bone disease on radionuclide bone scans, and PSA.
Throughout the study safety and tolerability will be assessed by the recording of adverse 
events, monitoring of vital signs, physical examinations, and safety laboratory evaluations. 
Subjects will have a safety follow-up visit approximately 30 days following the last dose of 
study drug or prior to the initiation of a subsequent anti-cancer drug or investigational agent, 
whichever occurs first.  Survival will be followed every 12 weeks for a maximum of 3 years 
from first dose. The study will end when the last subject has been followed for 1 year from 
date of first dose.
Further details of the efficacy assessments can be found in the following sections of the 
protocol:
1) CT/MRI (imaging) Section 5.3.1
2) PSA Section 5.3.2
3) Correlative samples (biomarker) Section 5.3.3
4) Survival follow-up Section 5.3.4
3.3
Randomization
Not applicable to this study.
4
SAMPLE SIZE
Prior clinical trials data in the post-chemo setting have shown the following median rPFS for 
subject randomized to initial placebo, placebo+prednisone, or mitoxantrone+prednisone 
therapy:
○
AFFIRM: Placebo = 2.9 months
○
COU-301: Placebo + Prednisone = 3.6 months
○
TROPIC: Mitoxantrone + Prednisone = 1.4 months
With a sample size of 40 subjects and an assumed median rPFS of 4 months for the therapy 
defined in this single-arm study, approximately 34 events are expected over a 12-month 
accrual and 12-month minimum follow-up. Further assuming uniform accrual, 10% loss to 
follow-up, and an exponential distribution for the rPFS event times, the expected lower 
bound of the 90% confidence interval for the median is approximately 2.5 months based 
upon simulations.


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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)
The full analysis set will consist of all subjects who are enrolled in this study, receive at least 
one dose of study drug, and have at least one post baseline evaluation. This will be the 
primary analysis set for efficacy analyses.
5.2
Per Protocol Set (PPS)
Not applicable to this study.
5.3
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least one dose of study medication.
The SAF will be used for summaries of demographic and baseline characteristics and all 
safety and tolerability related variables.
5.4
Biomarker Analysis Set (BAS)
The Biomarker analysis set (BAS) consists of the subset of the FAS population for which 
biomarker data are available to facilitate derivation of at least one of the correlative 
biomarkers. The Total N used in summaries and analyses for each unique biomarker will be 
the number of subjects with data available for that unique biomarker.
6
ANALYSIS VARIABLES
The primary efficacy endpoint is:
●
Radiographic progression-free survival (rPFS).
The secondary endpoints are:
●
additional measures of efficacy: 
o
Overall survival rate at 1 year 
o
Time to PSA progression
o
PSA response rate [maximum decline of ≥30%, ≥50%, and ≥90% from baseline, (PSA30, 
PSA50, and PSA90), respectively] 
o
Objective response rate
●
Time to first use of a subsequent antineoplastic therapy
●
Safety of enzalutamide re-treatment in the post-chemo setting
  


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Other efficacy endpoints:
●
Composite PFS (cPFS), defined as the earliest date of either radiologic progression, 
clinical progression, or death
The exploratory endpoints are:
●
Correlative science in the post-chemo setting.
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is radiographic progression-free survival (rPFS), which is 
defined as time from first dose to the radiological progression event or death. 
The radiological PFS event is either radiological disease progression defined by either soft 
tissue tumor progression defined by RECIST 1.1, or the bone progression defined by the 
Prostate Cancer Clinical Trials Working Group 2 (PCWG2). The bone progression per 
PCWG2 is defined as a minimum of two new lesions are observed. Progression on bone scan 
at time points prior to or at Week 9 requires a confirmatory scan performed six or more 
weeks later.  This confirmatory scan should demonstrate at least 2 additional new lesions 
(PCWG2) compared to the week 9 scan.
rPFS will be censored in the following scenarios:
●
If patient has neither PD nor death, the PFS will be censored at last radiological tumor 
assessment date.
●
If patient had PD or Death occurred more 24 weeks (168 days) after previous tumor 
radiological assessment. The PFS will be censored at last radiological tumor 
assessment date.
●
If patient does not have post baseline tumor assessment, nor death within 24 weeks 
(168) after first dose, the PFS will be censored at Day 1.
●
If patient took any new anti-cancer therapy before any PD event, the PFS will be 
censored at the last radiological tumor assessment date prior to the date of new 
anti-cancer therapy.
6.1.2
Secondary Efficacy Endpoints
Time to PSA Progression
For patients with PSA declines, the PSA progression date is defined as the date that a ≥ 25% 
increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir is documented, 
which is confirmed by a second consecutive value obtained 3 or more weeks later. 
For patients with no PSA declines, the PSA progression date is defined as the date that a 
≥25% increase and an absolute increase of ≥2 μg/L (2 ng/mL) above the baseline is 
documented, which is confirmed by a second consecutive value 3 or more weeks later.
Baseline is defined as last PSA measurement prior to first dose.


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Time to PSA progression is defined as the PSA progression date minus date of first dose + 1, 
which will be censored in the following scenarios:
●
If patient does not have any PSA progression, it will be censored at last PSA sample 
date.
●
If patient does not have post baseline PSA assessment, it will be censored at Day 1.
●
If patient took any new anti-cancer therapy before any PSA event, the time to PSA 
progression will be censored at the PSA sample date prior to the date of new 
anti-cancer therapy. 
Overall Survival Rate at 1 Year
Overall Survival is defined date of death due to any cause minus date of first dose +1. If a 
patient has not died, overall survival is censored at the last known alive date. 
The last known alive date will be derived based on the maximum of last known alive dates in 
the survival follow up CRF page,last visit, or last SAE onset date.
Overall survival rate at 1 year is defined as the corresponding Year 1 (Day 365) Kaplan-
Meier estimate on survival curve.
Time to first use of a subsequent antineoplastic therapy
Time to first use of a subsequent antineoplastic therapy is defined as date of the first systemic 
antineoplastic therapy minus first dose date +1. If a patient has not started the antineoplastic 
therapy, the time to event analysis is censored at the last dose date of study medication.
PSA response
PSA response is defined in below categories:
●
PSA30 (maximum decline of ≥ 30% decline from baseline at lowest post baseline)
●
PSA50 (maximum decline of ≥ 50% decline from baseline at lowest post baseline)
●
PSA90 (maximum decline of ≥ 90% decline from baseline at lowest post baseline)
Objective response rate
Objective Response Rate (ORR) is the proportion of patients whose best overall response is 
Complete Response (CR) or Partial Response (PR) per RECIST 1.1. Only patients with 
measurable disease at baseline will be included in the analysis of ORR.
Best Overall Response is derived based on the time point response information on the CRF 
according to RECIST criteria for both subjects with measureable and non-measureable
disease: 
●
CR
●
PRNon Cr/Non Pd
●
SD
●
NE


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The derivation of BOR is implemented using SAS based solely on investigator assessed 
information across all timepoints. Confirmation of response is not required according to the 
protocol.
6.1.3
Exploratory Efficacy Endpoints
Samples were collected serially at baseline, week 13, at time of PSA progression, and time of 
radiographic progression and analyzed at central labs for:
1) Androgen receptor 
a.
AR-V7 
b. AR-FL 
c.
AR-V7/AR-FL ratio
2) Glucocorticoid receptor 
a.
GR-FL 
3) AR mutations;
a.
L702H 
b. W741C 
c.
F876L 
d. T877A
4) Circulating tumor cell detected
5) Inflammatory biomarkers
a.
IL6 
b. IL8 
c.
TNF-α (tumor necrotic factor alpha) 
d. sTNFR1 (soluble TNF receptor-1) 
6) Neuroendocrine biomarkers
a.
CgA (chromogranin A) 
b. NSE (neuron specific enolase) 
c.
Synaptophysin 
Other biomarkers may be identified for analysis and SAP will be amended accordingly prior 
to database lock.


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6.1.4
Other Efficacy Variables
A composite endpoint of time to composite progression free survival (cPFS), defined as the
earliest date of either radiologic progression, clinical progression, or death, will be analyzed.  
Radiologic events will be defined as described in Section 6.1.1.  Date of clinical progression 
is the earliest onset date of any AE determined by investigator to be clinical progression.
cPFS will be censored in the following scenarios:
●
If patient has no composite PD event the cPFS will be censored at last visit date.
●
If patient took any new systemic anti-cancer therapy before any composite PD event, 
the cPFS will be censored at the last visit date prior to the date of new anti-cancer 
therapy.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; frequency, severity, seriousness, and
relationship to study drug).
●
Clinical laboratory variables (hematology, biochemistry including liver enzymes and 
total bilirubin, and urinalysis)
●
Vital signs (systolic and diastolic blood pressure and pulse rate)
●
ECOG PS
TEAE is defined as an adverse event observed after first dose of study medication. All 
adverse events collected that begin within 7 days after taking the last dose of study drug will 
also be counted as TEAE. Any AE with missing onset date will be considered as TEAE, 
unless the year and month are prior to the first dose of study medication.
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
Serious adverse events (SAEs) include adverse events that are flagged as serious by the 
investigator on eCRF, or upgraded by the Sponsor based on review of the Sponsor’s list of 
Always Serious term. 
The adverse events will be coded by body system using a MedDRA® dictionary.  The 
severity of adverse event will be graded by NCI CTCAE Grade.
6.3
Pharmacokinetic Variables
Not applicable.
6.4
Pharmacodynamic Variables
Not applicable.


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6.5
Other Variables
●
The duration of exposure
For each subject, the duration of exposure will be calculated in days, using the following 
formula:
(‘Date last dose of study drug’# - ‘Date first dose*) + 1
●
Dose Intensity 
Dose Intensity will be examined for subjects in the safety population whose total capsule 
count is known. Number of capsules which should have been taken depends on the 
number of days between the date of last and first capsule taken, including both daytimes 
(further details are given in the Tables Manual):
[Total number of capsules consumed by subject]
--------------------------------------------------------------- x 100
[Total number of  capsules subject should have taken]
Where, total number of capsules consumed will be calculated as:
(total number of capsules dispensed) – (total number of capsules returned). 
Where total number of capsules should have taken will be calculated by duration of exposure 
times 4.
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken before the date of 
the first dose of study drug. 
Concomitant medication is defined as medication with at least one dose taken between the 
date of first dose (inclusive) and the date of last dose (inclusive) of study drug.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the relevant section.  
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e., will add up to 100%. 
All data processing, summarization, and analyses will be performed using SAS® Version 
9.1.3 or higher on Unix. 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 first dose of study 
medication;
●
Number and percentage of subjects in each analysis set;
●
Number and percentage of subjects completed and discontinued treatment, by primary 
reason for treatment discontinuation; 
●
Number and percentage of subjects completed and discontinued the study, by primary 
reason for study discontinuation; 
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all dosed patients. The number and percentage of subjects meeting any 
criteria will be summarized for each criterion and overall. Subjects deviating from a criterion 
more than once will be counted once for the corresponding criterion. Any subjects who have 
more than one protocol deviation will be counted once in the overall summary. 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.
7.2.3
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics that have been collected on the eCRF will be 
summarized by descriptive statistics.
Number and percentage of subjects randomized in each country and site will be presented.
Descriptive statistics for:
Baseline and demographic characteristics:
1) Age (Informed consent date- DOB+1)/365.25
2) Race
3) Ethnicity
4) Screening ECG
5) Weight


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6) ECOG Status
7) Measureable disease (y/n)
8) Number of bone lesions at screening
9) Disease sites at screening
Disease History;
1) Time from initial diagnosis to informed consent date (Informed consent date- Initial 
dx date+1)/365.25
2) Primary Gleason score at initial diagnosis
3) Secondary Gleason score at initial diagnosis
4) Total Gleason score at initial diagnosis
5) PSA result at initial diagnosis
6) Primary tumor assessment at initial diagnosis
7) Pathologic tumor stage at initial diagnosis
8) Clinical lymph node stage at initial diagnosis
9) Pathological lymph node stage at initial diagnosis
10) Distant metastasis at initial diagnosis
11) Anatomic staging at initial diagnosis
12) Time from CRPC diagnosis to informed consent date (Informed consent date- CRPC
dx date+1)/365.25
13) CRPC diagnosis criteria
14) Time from initial diagnosis of metastasis to informed consent date (Informed consent 
date- Metastasis dx date+1)/365.25
  
Prior Radiation:
1) Prior radiation therapy (y/n)
2) Type of prior radiation therapy
3) Area radiated
  
Prior Procedures:
1) Any prior procedures (y/n)
2) Type of prior procedures


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This will be done for FAS.
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone (in descending order) for the FAS.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF.
As with previous medication, concomitant medication will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF. Subjects taking the same medication multiple times will be counted once per 
medication and investigational period. A medication which can be classified into several 
chemical and/or therapeutic subgroups is presented in all chemical and therapeutic subgroups.  
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for the SAF:
●
Descriptive statistics for cumulative amount of the drug subject was exposed to and 
average daily dose; and
●
Number and percent of subject with dose increases, decreases or interruptions.
Duration of exposure will be summarized in two ways.
●
Descriptive statistics will be presented.
●
Exposure time will be categorized according to the following categories:
○
less than or equal to 28 days
○
greater than 28 days, less than or equal to 84 days 
○
greater than 84 days, less than or equal to 168 days 
○
Greater than 168 days
○
Unknown.
Counts and percentages of subjects in each of these categories will be summarized for each 
for the SAF.
Counts and percentages of dose reductions, dose interruptions, and dose discontinuations will 
be presented.
7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known.
Percent overall compliance will be summarized in two ways for the SAF:
●
Descriptive statistics will be presented.
●
Percent compliance will be categorized according to the following categories:


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○
less than  80%
○
greater than or equal to 80% and  less or equal to 120%
○
greater than 120%
7.4
Analysis of Efficacy 
7.4.1
Analysis of Primary Endpoint(s)
The primary analysis will be performed on the Radiographic progression-free survival 
(rPFS). rPFS will be summarized using descriptive statistics. The survival curve and the 
median will be estimated using the Kaplan-Meier method. A two-sided 90% confidence 
interval will be provided for these estimates by use of the Brookmeyer and Crowley method 
and will be reported along with the corresponding 90% CI.
The SAS code used to produce median from Kaplan-Meier estimates and corresponding 
90% CI will be similar to that shown below:
proc lifetest data=adtte plots=(s) outsurv=surv;
time survtime*censor(0);
run;
An analysis of the primary endpoint will be conducted by subgroups.
7.4.2
Analysis of Secondary Endpoints 
Overall Survival, time to PSA progression, and time to first use of a subsequent 
antineoplastic therapy will be analyzed in the same manner as the primary endpoint.
PSA response rate (PSA30, PSA50, and PSA90) and objective response rate along with exact 
90% confidence interval (Clopper-Pearson) will be calculated.
7.4.3
Analysis of Exploratory Endpoints 
Unless otherwise noted, all continuous biomarker values will be summarized after log base 2 
transformation. Descriptive statistics (e.g., N, mean, standard deviation, minimum, median, 
maximum for continuous variables; or N, frequency, and percentage for categorical 
variables) will be provided for baseline blood and plasma samples and by each post-baseline 
scheduled time point for the following endpoints;
1. AR-V7 (positive/negative status, continuous log base 2 for positive status only)
2. AR-V7 status change from baseline during the study (unchanged, positive to negative, 
negative to positive)
3. AR-V12/v567es (positive/negative status, continuous log base 2 forpositive status 
only)
4. AR-V7 positive or AR-V12 positive (yes/no)
5. AR-FL (continuous log base 2)
6. Ratio of (log base 2 AR-V7)/(log base 2 AR-FL) (for positive status AR-V7)


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7. GR-FL (continuous log base 2)
8. L702H (yes/no, only descriptive statistics)
9. W741C (yes/no, only descriptive statistics )
10. F876L (yes/no, only descriptive statistics )
11. T877A (yes/no, only descriptive statistics )
12. CTC detected (yes/no)
13. IL6 (continuous log base 2)
14. IL8 (continuous log base 2)
15. TNF-α (tumor necrotic factor alpha) (continuous log base 2)
16. sTNF R1 (soluble TNF receptor-1) (continuous log base 2)
17. CgA (chromogranin A) (categorical split TBD, continuous log base 2) 
18. NSE (neuron specific enolase) (categorical split TBD, continuous log base 2)
19. Synaptophysin (categorical split TBD, continuous log base 2)
Three baseline binary AR predictors: 1) AR-V7 status; 2) a composite status (yes/no) of 
either AR-V7 positive  or AR/V-12 positive; and 3) CTC status will be assessed individually,
as independent variables, to predict rPFS, time to PSA progression, OS, and composite 
progression free survival (cPFS) using a single variable Cox model.
Multivariable AR Cox models will then be run on the same endpoints:
1) Using log base 2 transformed baseline AR-FL as a covariate in combination with 
baseline AR-V7 status;
2) Using log base 2 transformed baseline AR-FL as a covariate in combination with 
baseline composite AR-V7/V12 response;
Four baseline continuous log base 2 transformed inflammatory cytokine predictors: 1) IL6, 
2) IL8,  3) TNF-α, and 4) sTNF R1 will be assessed individually, as independent variables, 
to  predict  rPFS, time to PSA progression, OS, and composite progression free survival 
(cPFS) using a single variable Cox model.
Three baseline continuous log base 2 transformed neuroendocrine predictors: 1) CgA, 
2) NSE, and 3) synaptophysin will be assessed individually, as independent variables, to 
predict  rPFS, time to PSA progression, OS, and composite progression free survival (cPFS) 
using a single variable Cox model.
Hazard ratio point estimates, n, standard errors, p-values, and 90% confidence intervals will 
be displayed in a single table for all the AR, inflammatory cytokine, and neuroendocrine Cox 
models.


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KM plots, medians, and 90% confidence intervals for the binary AR predictors will be 
presented for rPFS, time to PSA progression, OS and cPFS. 
Waterfall plot of maximum reduction in PSA from baseline with AR-v7, AR-v12, and
AR mutation status labeled on the plot. 
The AR-V7 and the composite AR-V7/V12 composite  predictors will be individually 
assessed as an independent variables to predict PSA30, PSA50, PSA90, and objective 
response using Fisher’s exact test. Note that objective response will be evaluated using 
subjects that are both BAS and have measureable disease. 
Counts, frequencies, differences in frequencies and 90% Clopper-Pearson methodology will 
be displayed for the binary AR predictors.
Reported p-values for hazard ratios will use Wald (chi-square) test statistics, and p-values for 
comparing Kaplan-Meier curves will use log-rank (score) test statistics. Breslow method will 
be used for handling ties.
In the event that additional exploratory analyses are required for the Clinical Study Report, 
the SAP will be amended accordingly.
7.4.4
Analysis of Other Variables 
Not Applicable.
7.5
Analysis of Safety
All analysis of safety will be presented for SAF, unless specified otherwise. 
7.5.1
Adverse Events
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with causally drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of TEAEs leading to permanent discontinuation of study drug,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, and
●
Number of deaths.


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The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized. Summaries will be provided for:
●
TEAEs,
●
TEAEs by NCI CTCAE grade
●
drug related TEAEs, 
●
serious TEAEs, 
●
serious TEAE by NCI CTCAE grade
●
drug related serious TEAEs, 
●
drug related serious TEAEs by NCI CTCAE grade
●
TEAEs leading to permanent discontinuation of study drug, 
●
drug related TEAEs leading to permanent discontinuation of study drug, 
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 5.0%, and 
●
common TEAEs that equal to or exceed a threshold of 5.0 %. 
The number and percentage of subjects with TEAEs, as classified by PT only, will be 
summarized in descending frequency.
The number of TEAEs and the number and percentage of subjects with TEAEs, as classified 
by SOC and PT will also be summarized by NCI CTCAE grade to study drug. In the subject 
count, if a subject has multiple TEAEs with the same SOC or PT, but with differing severity, 
then the subject will be counted only once with the worst severity , however, if any of the 
severity values are missing then the subject will be counted only once with missing severity.  
In the adverse event count, the adverse events will be presented in each category they were 
classified to. Drug related TEAEs will be presented in a similar way by severity only.
TEAEs of special interest will be summarized by the number and percentage of subjects with 
the following AEs: fatigue, fall, hypertension, non-pathological fractures, cognitive/memory 
impairment, loss of consciousness, neutropenia, and convulsion.
7.5.2
Clinical Laboratory Evaluation
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, and urinalysis will 
be summarized using mean, standard deviation, minimum, maximum and median at each 
visit. Additionally, a within-subject change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way. Baseline is 
defined as the last available measurement prior to the first study drug dose. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be 
presented at each visit.
Laboratory results will also be graded using NCI-CTCAE, where possible. Parameters that 
have criteria available for both low and high values, i.e., hypo- and hyper-, will be 
summarized for both criteria. The same subject can be counted for both values if the subject 
has different laboratory values meeting each criterion. NCI-CTCAE grade of laboratory 
evaluations will be summarized by number and percentage of subjects for each visit. Shift 


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tables of lab parameters NCI-CTCAE grade change from baseline to worst post-baseline 
grade will also be presented.
7.5.2.1 Liver Enzymes and Total Bilirubin
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the 
investigational period will be used. 
Parameter
Criteria
ALT, AST, Total Bilirubin
≥ 2xULN
≥ 3xULN
≥ 5xULN 
ALT or AST
≥ 2xULN
≥ 3xULN
≥ 5xULN
ALT and/or AST 
(ALT and/or AST ≥ 3xULN) and total bilirubin ≥ 2xULN
And Total Bilirubin(*)
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
function tests during the investigational period will be presented.
The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the investigational period will be presented.
7.5.3
Vital Signs
The baseline visit is the last measurement taken prior to initial study drug administration.  
Vital signs (systolic blood pressure, diastolic blood pressure, ECG parameters (collected only 
at baseline/screening), and pulse rate) will be summarized using mean, standard deviation, 
minimum, maximum and median by visit. Additionally, a within-subject change will be 
calculated per visit as the post-baseline measurement minus the baseline measurement and 
summarized.
Tables for potentially clinically significant vital signs will be generated using baseline value 
for each subject for each treatment group.
The following potentially clinically significant criteria are defined for each parameter:


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Vital Sign Variable
Criteria
SBP
≥180 mmHg AND ≥20 mmHg change from baseline
DBP
≥105 mmHg AND ≥15 mmHg change from baseline
Pulse Rate
≥120 bpm AND ≥15 bpm change from baseline
7.5.4
Electrocardiograms (ECGs)
No post baseline ECG is collected. Not applicable.
7.5.5
Pregnancies
Not applicable.
7.5.6
Other Safety-Related Observations
ECOG PS will be summarized by counts and frequencies by visit
7.6
Analysis of PK
Not applicable.
7.7
Analysis of PD
Not applicable.
7.8
Subgroups of Interest 
rPFS, time to PSA progression, and PSA30 will be analyzed for the subgroups defined on the 
basis of the categorized variables at baseline listed below:
●
Ensure to capture subgroups from AFFIRM, plus the following groups of interest to 
this study
●
CTC detected (yes vs no)
●
AR-v7 (yes vs no)
●
Prior abiraterone
●
PSA90 on prior enzalutamide
●
Prior enzalutamide treatment duration > median
●
PSA50 on prior docetaxel
●
Prior docetaxel treatment duration >= median
7.9
Other Analyses  
Not applicable.
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim efficacy analysis with no adjustments will be conducted using a cutoff date 
corresponding to the week 13 visit of 40th subject to report internally on PSA response rates 
for internal review.  
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Refer to the data specification document in which more details are provided. 


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7.11.1
Missing Data
As a general principle, no imputation of missing data for other variables will be done. 
Exceptions are the start and stop dates of AEs and concomitant medication. If day is missing 
from any date in a derivation then calculate the derived value using 15th day of month. If 
month or year is missing from any date in a derivation then set the derived value to missing.
Adverse events with missing relationship will be summarized as ‘Related to Study Drug’. 
Adverse events with missing severity grade will be handled as ‘missing’.
Incomplete onset dates default AEs to treatment emergent. Listings of the AEs and 
concomitant medications will present the actual partial dates; imputed dates will not be shown.
Cases where the onset date of an AE is (partially) missing, will be addressed prior to or during 
the DRM in order to determine whether the AE must be considered treatment emergent or not. 
Imputation on missing date of initial diagnosis (cancer duration) and cancer treatment history 
(start date, stop date, or date of procedure) will be done as follows:
●
Incomplete Day: use the 15th day of the month 
●
Incomplete Month: use 1st of July if the Year is before Year of dosing, otherwise 
missing.
●
Incomplete Year: no imputation, the derived variable is considered to be missing.
Imputation methods will not be used to determine other endpoints.
Listings will always show the original date information without imputation, but derived 
parameters (TEAE indicator, start day, end day, study day) will be flagged.
7.11.2
Outliers
All values will be included in the analyses.
7.11.3
Visit Windows
Not applicable.
8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
DD-MMM-YYYY
NA
Document finalized
2.00
DD-MMM-YYYY
Additional ECG 
analysis added
Added due to protocol amendment 1.0
Additional subgroup 
added
Recent publications suggest relevance of 
XXX subgroup for safety analysis


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9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(2007). U.S. Department of Health and Human Service, FDA. Rockvill, MD.
Statistical Review and Evaluation of Xtandi (enzalutamide) on Metastatic Castration-resistant prostat 
cancer in patients have have previously received docetaxel.
CDER, FDA May 21, 2012


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10
APPENDICES
10.1
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)
, MS, Study (support) Statistician
 
Contributors and Reviewers
, MPH, 
, BS, 
Global Data Science
Global Data Science
, MS, M.D.,
Medical Affairs
Oncology
, Ph.D., 
Medical Affairs
Oncology 
, Ph.D., 
Bioanalysis Lab-US
, Ph.D.,
Bioanalysis Lab-US


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Author and Approver Signatories
, MS, 
 was the study (support) statistician for this study.
_______________________________________            ___-__-____      
  
, MS                                                           mmm-dd-yyyy
 BS,  
was the biostatistics peer reviewer of 
this Statistical Analysis Plan
_______________________________________            ___-__-____      
, BS                                                                  mmm-dd-yyyy
This Statistical Analysis Plan was approved by:
, MS, M.D. 
_______________________________________            ___-__-____      
, MS, M.D.                                                           mmm-dd-yyyy
This Statistical Analysis Plan was approved by:
, MPH, 
_______________________________________            ___-__-____      
, MPH                                                mmm-dd-yyyy


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This Statistical Analysis Plan was approved by:
, Ph.D.,  
_______________________________________            ___-__-____      
, Ph.D.                                                             mmm-dd-yyyy