Clinical trial NCT01790126
Conditions: Prostate Cancer
Keywords: Men with Biochemically Relapsed Hormone Sensitive Prostate Cancer
Sponsor: Aragon Pharmaceuticals, Inc.
Start date: 2013-03-04; Completion date: 2019-03-01
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed clinical trial will study the effects of 12 months of therapy with ARN-509 alone, or in combination with an LHRH agonist (LHRHa), each compared with LHRHa alone, in men with a rapidly rising serum PSA after prior definitive local therapy for prostate cancer. The endpoints selected reflect measurable short term effects of androgen deprivation therapy (ADT), including quality of life and several metabolic parameters. In addition, the relative effect of each treatment strategy on PSA suppression as well as testosterone recovery (and subsequent PSA progression) after 12 months of therapy will be evaluated.

Detailed description:

Arms: arm 1: ARN-509 Tablets, 240 mg/day administered orally arm 2: Choice of LHRHa per investigator discretion/site practice guidelines (e.g, Eligard®, Zoladex®, Lupron Depot®, Trelstar®) and ARN-509 Tablets, 240 mg/day administered orally arm 3: Choice of LHRHa per investigator discretion/site practice guidelines (e.g., Eligard®, Zoladex®, Lupron Depot®, Trelstar®).
Interventions: intervention 1: ARN-509 intervention 2: LHRH Agonist
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
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The Role of Highly Selective Androgen Receptor (AR) 
Targeted Therapy in Men with Biochemically Relapsed 
Hormone Sensitive Prostate Cancer 
 
 
Protocol #115523  
(Aragon Protocol ARN-509-002) 
 
Study Drug:  ARN-509 
 
Version Number: 15.0 
Version Date: 01 February 2019 
 
 
IND #: 104,676 (Held by Aragon Pharmaceuticals, Inc.*) 
 
*Aragon Pharmaceuticals, Inc. is a wholly-owned subsidiary of Johnson & Johnson. Janssen 
Research & Development, LLC is part of the Janssen Pharmaceutical Companies of Johnson & 
Johnson and provides various services to its affiliated company, Aragon Pharmaceuticals, Inc. 
 
Study Chair 
Rahul Aggarwal, M.D. 
Assistant Clinical Professor 
Division of Hematology/Oncology, Department of Medicine 
University of California 
 
  
 
 
 
UCSF Co-Investigators: 
, M.D., Professor of Medicine 
, M.D., Assistant Clinical Professor of Medicine 
, M.D., Professor of Medicine and Urology 
, M.D., Assistant Clinical Professor of Medicine 
, M.D., Associate Professor in Residence 
 M.D., Assistant Clinical Professor of Medicine 
Statistician: 
 Ph.D, Biostatistics Core 
 
 
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Revision History 
Version 15.0 
02-01-19 
Version 14.0 
08-16-16 
Version 13.0 
08-15-16 
Version 12.0 
06-15-16 
Version 11.0 
06-13-16 
Version 10.0 
06-01-16 
Version 9.0 
09-30-15 
Version 8.0 
09-28-15 
Version 7.0 
09-12-14 
Version 6.0 
06-03-14 
Version 5.0 
01-31-13 
Version 4.0 
07-06-12 
Version 3.0 
04-13-12 
Version 2.0 
01-11-12 
Version 1.0 
11-20-11 
 
Document No.: EDMS-ERI-81729384 
 
Participating Centers 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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NCT01790126


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NCT01790126


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Protocol Agreement 
I confirm that I have read this protocol. I will comply with the protocol and the principles of 
Good Clinical Practice (GCP), as described in the United States Code of Federal Regulation 
(CFR) 21 Parts 11, 50, 54, 56, and 312 and the appropriate International Conference on 
Harmonisation guidance documents. 
 
Protocol: 
ARN-509-002, Version 15.0, Amendment 9, 01 February 2019 
 
Protocol Title: The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in 
Men with Biochemically Relapsed Hormone Sensitive Prostate Cancer 
 
 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site #  ___________ 
 
 
Site Name  _______________________________________ 
 
 
NCT01790126


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ABSTRACT 
 
 
Title 
The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in 
Men with Biochemically Relapsed Hormone Sensitive Prostate Cancer 
Study 
population 
Key Eligibility Criteria: 
• 
Histologically proven adenocarcinoma of the prostate 
• 
Rising PSA after prior definitive local therapy (radical prostatectomy, external beam 
radiation, or brachytherapy) or combination of radical prostatectomy and radiotherapy  
• 
Prior primary or salvage radiation or not a candidate for localized salvage radiation due 
to subject preference or clinical assessment based upon disease characteristics and/or 
subject co-morbidities. 
• 
PSA doubling time ≤12 months  
• 
No evidence of metastatic disease by computed tomography (CT)/magnetic resonance 
imaging (MRI) abdomen/pelvis and whole body bone scan. Abdominal/pelvic lymph 
nodes measuring less than or equal to 2 cm in short axis are allowed.  
• 
Minimum PSA 1.0 ng/mL if prior radical prostatectomy +/- adjuvant or salvage 
radiation; nadir + 2.0 ng/mL if prior RT without prior radical prostatectomy 
• 
No androgen deprivation therapy (ADT) within 6 months prior to randomization 
• 
No prior ADT for biochemical relapse 
• 
No 5-alpha reductase inhibitor or anti-androgen within 6 weeks prior to randomization 
• 
Prior chemotherapy is allowed only in the (neo) adjuvant setting, and if last dose was 
>6 months prior to randomization  
• 
Serum testosterone ≥ 150 ng/dL  
• 
No prior use of bone-modifying agent within 3 months prior to randomization 
• 
QTc interval ≤ 480 msec 
• 
No history of seizures or medical conditions, which may lower seizure threshold 
Rationale for 
Study 
Prostate cancer patients with biochemical relapse (BCR), and a PSA doubling time (PSADT) of 
12 months or lower represent a subset of patients at significant risk for the development of 
metastases and prostate cancer-specific mortality.  In general, ADT is an appropriate approach 
for these patients, but carries risks of its own, including a potential impact on quality of life 
(QOL), and the potential for clinically significant metabolic derangements.  Consequently, new 
strategies that can mitigate these adverse effects represent an important unmet need.  Two 
potential strategies in this group of patients are a) to utilize a highly active second generation 
androgen receptor (AR) inhibitor as monotherapy and b) to add a highly active second generation 
AR inhibitor to conventional luteinizing hormone releasing hormone (LHRH) agonist (LHRHa) 
intermittent androgen deprivation (IADT).  The first approach is predicated on the expectation 
that AR inhibitor monotherapy will have fewer adverse events, while the second approach is 
based on the expectation that more effective combination therapy will result in greater anti-
cancer activity, and consequently, after a finite period of therapy, allow a longer period of time 
off ADT (and hence improved QOL) as part of an intermittent ADT approach. 
The proposed clinical trial will study the effects of 12 months of therapy with ARN-509 (a highly 
potent second generation AR antagonist) alone, or in combination with an LHRHa, each 
compared with LHRHa alone, in men with a rapidly rising serum PSA after prior definitive local 
therapy for prostate cancer.  Endpoints selected reflect measurable short-term effects of ADT, 
including QOL and several metabolic parameters.  In addition, the relative effect of each 
treatment strategy on PSA suppression as well as testosterone recovery (and subsequent PSA 
progression) after 12 months of therapy will be evaluated.  Favorable results suggesting an 
improvement in QOL for either strategy will provide justification for larger definitive trials of 
second generation AR inhibitors as a treatment alternative or addition to LHRHa therapy in the 
BCR disease population. 
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Primary 
Objectives 
• 
To compare the mean change from baseline in QOL as measured by total FACT-P score 
over a period of 12 months of therapy with ARN-509 monotherapy vs. LHRHa 
monotherapy in men with BCR to test for superiority with ARN-509 monotherapy 
• 
To compare the mean change from baseline in QOL as measured by total FACT-P score 
over a period of 12 months of therapy of ARN-509 + LHRHa vs. LHRHa monotherapy in 
men with BCR to test for non-inferiority with ARN-509 + LHRHa 
Secondary 
Objectives 
• 
Other Quality of Life Instruments: To compare (a) ARN-509 monotherapy vs. LHRHa 
monotherapy and (b) ARN-509 + LHRHa vs. LHRHa monotherapy with regards to change 
over time in QOL 
• 
To compare (a) ARN-509 monotherapy vs. LHRHa monotherapy and (b) ARN-509 + 
LHRHa vs. LHRHa monotherapy with regards to PSA modulation: 
• 
To compare (a) ARN-509 monotherapy vs. LHRHa monotherapy and (b) ARN-509 + 
LHRHa vs. LHRHa monotherapy with regards to metabolic and hormonal effects: 
• 
To characterize the safety profile of ARN-509 monotherapy and in combination with 
LHRHa. 
• 
Biomarker analyses will be conducted on formalin-fixed paraffin-embedded (FFPE) blocks 
or slides, plasma, and whole blood samples collected from consented subjects to assess 
ARF876L mutation and other resistance markers from all 3 treatment groups. 
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Study Design 
Phase 2, randomized, open-label 3-arm multicenter study evaluating 12 months of treatment with 
LHRHa monotherapy, ARN-509 monotherapy, or the combination in men with non-metastatic 
biochemically relapsed prostate cancer with rapidly rising PSA levels after prior definitive 
therapy for localized prostate cancer.  Subjects will be stratified by PSADT (< 6 months vs. 6-12 
months) and age (≤ 70 vs. > 70) and randomized with equal probability from within each of the 4 
strata to 1 of the 3 study arms.  There will be 2 periods of 12 months each in the 24 month-long 
treatment period: (1) an On-therapy Period lasting 12 months, during which time subjects receive 
randomly assigned protocol therapy, and (2) an Off-therapy Observation Period also lasting 
12 months. 
 
Number of 
subjects 
Ninety men, with a rising serum PSA after prior definitive therapy including radical 
prostatectomy and/or radiation therapy, who have a PSADT of less than or equal to 12 months, 
will be enrolled. 
Duration of 
Therapy 
Subjects will receive protocol therapy for a maximum of 12 months, or shorter duration if 
evidence of PSA/radiographic progression or unacceptable toxicity during protocol therapy or 
subject/physician withdrawal from the study.  If there is no evidence of disease progression after 
12 months of protocol therapy, subjects will enter the therapy Off-therapy Observation period 
(Months 13-24).  
Duration of 
Follow up 
If there is no evidence of PSA or radiographic progression after 24 months from Day 1 of the 
On-Treatment Period, subjects will enter a Follow-up Period.  Subjects will remain on study until 
the time of PSA or radiographic progression or initiation of non-protocol therapy or 
subject/physician withdrawal from the study, whichever occurs first. Subjects in the Follow-up 
Period will be discontinued at the time of the final clinical cutoff described in the following 
section.  
Duration of 
study 
With estimated accrual duration of 12 months, the data-cutoff for analysis of primary and 
secondary endpoints will be at 36 months from the time the study opens to accrual. The Sponsor 
will establish a final clinical cutoff date after all subjects have completed the Month 24 Visit. 
Data collection will cease at this time. The final clinical study report will be written based on 
these data. The total study duration is 6 years; the last patient was consented at 4 years and the 
final clinical cutoff is 2 years (24 months) after last patient was consented. 
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Study Drugs 
1. ARN-509 
With Amendment 7 (Version 8.0), subjects receiving the softgel capsules will switch to tablets 
starting at the next cycle and all newly enrolled subjects will receive tablets.  
Drug Substance: ARN-509 drug substance is an almost white to slightly brown powder.   
Formulation: The ARN-509 tablet supplied for this study contains 60 mg of JNJ-56021927. It 
will be manufactured and provided under the responsibility of the Sponsor.    
Dose and Route of Administration: ARN-509 will be administered orally on a continuous daily 
dosing regimen at a dose of 240 mg per day (4 x 60-mg tablets) with or without food.   
2. LHRH Agonist 
Choice of specific LHRHa to be used in this study will be per investigator discretion/site practice 
guidelines.  Options include Eligard®, Lupron Depot®, Zoladex®, or Trelstar®.  Dosing schedule 
will be per individual investigator discretion. The use of LHRH antagonists (e.g. degarelix) will 
not be permitted.  
Route of Administration: The LHRHa injections will be delivered either subcutaneously 
(Eligard®, Zoladex®) or intramuscularly (Lupron Depot®, Trelstar®) by a trained health care 
provider while on protocol therapy. 
Safety 
Assessments 
Safety Assessments: During each monthly study visit during protocol therapy, the maximum 
grade observed for each toxicity will be tabulated, as graded by National Cancer Institute 
(NCI)-Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.  
Interim Safety Review: Will be performed after 20 subjects have completed at least 1 month of 
therapy with either ARN-509 monotherapy or ARN-509 + LHRHa.  If there are > 5 subjects with 
Grade 3 or higher toxicities not typically related to ADT, that the study investigator deems as 
possibly, probably, or definitely treatment-related, the study will be terminated. Study accrual 
will continue during the interim safety review.  
Study 
Endpoints 
Primary Endpoint: Mean change from baseline in total FACT-P score at 12 months  
Secondary Endpoints: 
Additional Quality of Life Measures:  
• 
Mean change from baseline in total FACT-P, EORTC QLQ-C30/PR25, and SHIM 
scores over time   
PSA Modulation: 
• 
Time to PSA progression 
• 
Proportion of subjects without PSA or radiographic progression and recovery of serum 
testosterone to > 150 ng/dL at 24 months. 
• 
Proportion of subjects with a serum PSA < 0.2 ng/mL after 7 months of protocol 
therapy 
Metabolic and Hormonal: 
• 
Mean change from baseline in markers of insulin resistance (BMI, fasting 
glucose/insulin, hemoglobin A1C), fasting lipids, bone mineral density (as measured by 
DEXA at the femoral neck, and lumbar spine) over time  
• 
Time to testosterone recovery to > 50 ng/dL and > 150 ng/dL during the Off-therapy 
Observation Period 
• 
Mean change from baseline in serum DHT and estradiol levels over time  
Safety: 
• 
Incidence and severity of adverse events  
• 
Abnormal findings in physical exams and laboratory tests 
Correlative studies 
• 
Frequency of subjects emerging with ARF876L mutation at the end of treatment and 
progression.  
• 
Frequency of subjects expressing various RNA markers previously demonstrated to 
confer resistance ARN-509 at baseline, end of treatment, and progression 
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Unique 
Aspects of 
the Study 
This study represents the first clinical trial investigating the use of ARN-509, a potent, second 
generation AR antagonist in a hormone-sensitive prostate cancer disease population.  
Furthermore, the study endpoints, including QOL and changes in metabolic markers represent 
clinically relevant, measurable study endpoints, which can be utilized in initial Phase 2 
randomized trials comparing novel treatment paradigms vs. standard ADT in biochemically 
relapsed disease as a means of justifying the further study of a novel agent in this disease setting.  
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List of Abbreviations 
 
ADT  
androgen deprivation therapy 
AlkP  
alkaline phosphatase 
ALT  
alanine aminotransferase 
AR 
 
androgen receptor 
ASCO  
American Society of Clinical Oncology 
AST 
 
aspartate aminotransferase 
ASTRO 
American Society for Therapeutic Radiology and Oncology 
BCR  
biochemical relapse 
BMD  
bone mineral density  
BMI 
 
body mass index 
CAB  
combined androgen blockade 
CBC  
complete blood count 
CI 
 
confidence interval 
eCRF  
electronic case report form 
CRPC  
castrate-resistant prostate cancer 
CT 
 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAO  
data as observed 
DEXA  
dual energy x-ray absorptiometry 
DHT  
dihydrotestosterone 
DLT  
dose-limiting toxicity 
ECOG  
Eastern Cooperative Oncology Group 
eDC 
 
electronic data capture 
EORTC 
European Organization for Research and Treatment of Cancer 
FACT-P 
Functional Assessment of Cancer Therapy – Prostate 
FDA  
Food and Drug Administration 
FFPE  
formalin-fixed paraffin-embedded 
HDL  
high-density lipoprotein 
HR 
 
hazard ratio 
IADT  
intermittent androgen deprivation therapy 
ITT 
 
intent-to-treat 
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LDL  
low-density lipoprotein 
LHRH  
luteinizing hormone-releasing hormone 
LHRHa 
LHRH agonist 
MRI 
 
magnetic resonance imaging 
NCI 
 
National Cancer Institute 
NCIC  
National Cancer Institute of Canada 
OS 
 
overall survival 
PAB  
peripheral androgen blockade 
PBMC  
peripheral blood mononuclear cells 
PQC  
product quality complaint 
PSA 
 
prostate-specific antigen 
PSADT 
PSA doubling time 
QOL  
quality of life 
RT 
 
radiation therapy 
RTOG  
Radiation Therapy Oncology Group 
TSH 
 
thyroid stimulating hormone 
SHIM  
Sexual Health Inventory for Men 
 
 
 
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Table of Contents 
PROTOCOL AMENDMENTS ................................................................................................. 16 
1 
Background .......................................................................................................................... 31 
1.1 
Biochemically Relapsed Prostate Cancer ................................................................ 31 
1.2 
Risk Adapted Therapy for BCR Prostate Cancer Patients ....................................... 31 
1.3 
Therapeutic Options in BCR Prostate Cancer Patients ............................................ 32 
1.3.1 
Combined Androgen Blockade (CAB) ........................................................... 32 
1.3.2 
Intermittent ADT (IADT) ............................................................................... 32 
1.3.3 
Peripheral Androgen Blockade (PAB)............................................................ 33 
1.4 
Second Generation AR Antagonists in BCR Hormone Sensitive Prostate Cancer . 33 
1.5 
Demonstrating Benefit of Novel Hormone Therapies in BCR Prostate Cancer 
Patients ..................................................................................................................... 35 
1.5.1 
Quality of Life................................................................................................. 35 
1.5.2 
Metabolic Parameters...................................................................................... 36 
1.6 
Overall Study Rationale ........................................................................................... 37 
2 
Hypothesis and Study Objectives ....................................................................................... 38 
2.1 
Hypothesis #1: ......................................................................................................... 38 
2.2 
Hypothesis #2: ......................................................................................................... 38 
2.3 
Study Objectives ...................................................................................................... 38 
2.3.1 
Primary Objectives.......................................................................................... 38 
2.3.2 
Secondary Objectives...................................................................................... 38 
3 
Study Design ......................................................................................................................... 40 
3.1 
Overall Study Characteristics .................................................................................. 40 
3.2 
Study Endpoints ....................................................................................................... 40 
3.2.1 
Primary Endpoint: ........................................................................................... 40 
3.2.2 
Secondary Endpoints: ..................................................................................... 40 
3.3 
Study Schema........................................................................................................... 42 
3.4 
Study Timelines ....................................................................................................... 42 
3.4.1 
Primary Completion: ....................................................................................... 42 
3.4.2 
Study Completion: .......................................................................................... 42 
4 
Study Population .................................................................................................................. 43 
4.1 
Study Population ...................................................................................................... 43 
4.2 
Inclusion Criteria ..................................................................................................... 43 
4.3 
Exclusion Criteria .................................................................................................... 44 
5 
Prohibitions and restrictions .............................................................................................. 46 
6 
Study Rationale .................................................................................................................... 47 
6.1 
Rationale for the Study Population .......................................................................... 47 
6.2 
Rationale for Treatment Arms ................................................................................. 47 
6.2.1 
LHRHa Monotherapy as Control Arm ........................................................... 47 
6.2.2 
ARN-509 Monotherapy .................................................................................. 47 
6.2.3 
ARN-509 + LHRHa ........................................................................................ 48 
6.3 
Rationale for Study Treatment Schedule ................................................................. 48 
6.4 
Rationale for the Selection of Study Evaluations .................................................... 49 
6.4.1 
Primary Endpoint ............................................................................................ 49 
6.4.2 
Secondary Endpoints ...................................................................................... 49 
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7 
Study Activities .................................................................................................................... 54 
7.1 
Study Schedule: On- Therapy Period (Day 1 – Month 12) ..................................... 54 
7.2 
Study Schedule: Off-Therapy Observation Period (Months 13-24) and follow-up 
period (MOnth 25+) ................................................................................................. 57 
7.3 
Screening Period/Pre-Study Evaluation ................................................................... 58 
7.3.1 
Clinical Assessments ...................................................................................... 58 
7.3.2 
Laboratory Assessments ................................................................................. 58 
7.3.3 
Radiographic Studies ...................................................................................... 58 
7.4 
Randomization: ........................................................................................................ 59 
7.5 
Study Period I: On-therapy PERIOD (Months 1 to 12) ........................................... 59 
7.5.1 
Day 1 of Study Treatment ............................................................................... 60 
7.5.2 
LHRH Agonist ................................................................................................ 60 
7.5.3 
ARN-509 ......................................................................................................... 60 
7.5.4 
Concomitant Medications ............................................................................... 60 
7.5.5 
Safety Assessment .......................................................................................... 61 
7.5.6 
QOL ................................................................................................................ 61 
7.5.7 
Laboratory Assessments ................................................................................. 62 
7.5.8 
Radiographic Assessments.............................................................................. 62 
7.6 
Study Period II: Off-therapy Observation PERIOD (Months 13 to 24) .................. 62 
7.6.1 
Safety Assessment .......................................................................................... 63 
7.6.2 
QOL ................................................................................................................ 63 
7.6.3 
Laboratory Assessments ................................................................................. 63 
7.6.4 
Radiographic Assessment ............................................................................... 63 
7.7 
Follow Up Period (Month 25+) ............................................................................... 63 
7.8 
Reasons for Study Discontinuation .......................................................................... 64 
8 
Study Drug Information...................................................................................................... 65 
8.1 
ARN-509 .................................................................................................................. 65 
8.2 
LHRH Agonist ......................................................................................................... 66 
9 
Dosage Modifications/Toxicity ........................................................................................... 67 
9.1 
Toxicity .................................................................................................................... 67 
9.2 
Dose Modifications for ARN-509 ........................................................................... 67 
9.3 
Dose Modifications for LHRHa............................................................................... 67 
10 Assessment of Investigational product............................................................................... 69 
10.1 
FACT-P Scale .......................................................................................................... 69 
10.2 
EORTC QLQ-C30/QLQ-PR25 ................................................................................ 69 
10.3 
Sexual Health Inventory for Men (SHIM) ............................................................... 69 
10.4 
Administration of QOL Questionnaires ................................................................... 70 
10.5 
Metabolic Parameters............................................................................................... 70 
10.5.1 
Markers of Insulin Resistance ......................................................................... 70 
10.5.2 
Fasting Lipid Panel ......................................................................................... 70 
10.5.3 
Bone Mineral Density ..................................................................................... 70 
10.5.4 
Serum Hormone Levels .................................................................................. 70 
10.6 
PSA Measurement ................................................................................................... 71 
10.7 
Optional Sample collection for Banking, RNA, and Biomarker analysis ............... 71 
11 Planned Statistical Methods................................................................................................ 72 
11.1 
Determination of Sample Size and Study Power ..................................................... 72 
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11.2 
Clinical Cutoffs ........................................................................................................ 72 
11.2.1 
Interim Analysis .............................................................................................. 72 
11.2.2 
Final Clinical Cutoff ....................................................................................... 72 
11.3 
Analysis Populations ................................................................................................ 73 
11.4 
Methods for Analysis ............................................................................................... 73 
11.4.1 
Analytic Plan for the Primary Endpoint.......................................................... 73 
11.4.2 
Analytic Plan for the Secondary Endpoints .................................................... 73 
12 Reporting and Documentation of Adverse Events ........................................................... 76 
12.1 
Definitions of Adverse Events ................................................................................. 76 
12.1.1 
Adverse Event (AE) ........................................................................................ 76 
12.1.2 
Serious Adverse Event (SAE) ......................................................................... 76 
12.1.3 
Expectedness ................................................................................................... 77 
12.1.4 
Attribution ....................................................................................................... 77 
12.1.5 
Severity ........................................................................................................... 78 
12.2 
Special reporting Situations ..................................................................................... 79 
12.3 
Procedures ................................................................................................................ 79 
12.3.1 
All Adverse Events ......................................................................................... 79 
12.3.2 
Serious Adverse Events .................................................................................. 79 
12.3.3 
Pregnancy ........................................................................................................ 80 
13 Product Quality Complaint Handling ............................................................................... 82 
13.1 
Procedures ................................................................................................................ 82 
14 DATA COLLECTION, RETENTION AND MONITORING ........................................ 83 
14.1 
Data Collection Instruments .................................................................................... 83 
14.2 
Data Quality Control and Reporting ........................................................................ 84 
14.3 
Archival of Data ....................................................................................................... 84 
14.4 
Availability and Retention of Investigational Records ............................................ 84 
14.5 
Monitoring ............................................................................................................... 85 
14.6 
Subject Confidentiality ............................................................................................ 85 
15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................... 86 
15.1 
Protocol Amendments .............................................................................................. 86 
15.2 
Institutional Review Boards and Independent Ethics Committees .......................... 86 
15.3 
Informed Consent Form ........................................................................................... 87 
15.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ...... 87 
15.5 
Sponsor Discontinuation Criteria ............................................................................. 88 
15.6 
Use of information and publication ......................................................................... 88 
16 References ............................................................................................................................. 90 
Appendix 1. FACT-P .................................................................................................................... 94 
Appendix 2. EORTC QLQ-C30/QLQ-PR25 ................................................................................ 97 
Appendix 3. Sexual Health Inventory for Men (SHIM) ............................................................. 101 
Appendix 4. ECOG Performance Status Scale ........................................................................... 102 
Appendix 5. List of Medications and Supplements Either Prohibited Or Not Recommended 
While On Study: .................................................................................................... 104 
Appendix 6. Peripheral Blood Collection, Processing, and Shipping Instructions .................... 106 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Version dated 01 February 2019 
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Page 16 of 108 
This document is confidential. Do not disclose or use except as authorized 
 
PROTOCOL AMENDMENTS 
Protocol Version  
Issue Date 
Original Protocol 
20 November 2011 
Amendment 1  
11 January 2012 
Amendment 2 
13 April 2012 
Amendment 3 
7 June 2012 
Amendment 4 
31 January 2013 
Amendment 5 
3 June 2014 
Amendment 6  
12 September 2014 
Amendment 7 
30 September 2015 
Amendment 8 
16 August 2016 
Amendment 9 
01 February 2019 
 
*All previous amendment changes are provided in separate summary documents (EDMS-ERI-83833142) 
 
Amendments are listed beginning with the most recent amendment. 
 
Amendment 9 (01 February 2019) 
The overall reasons for the amendment: The protocol was amended to clarify the time of the final clinical 
cutoff and to refer to the central laboratories generically rather than specifically name these centers. 
Applicable Section(s) 
Description of Change(s) 
Rationale: Clarified the time of the final clinical cutoff date and that subjects continuing in the Follow-up 
Period at this time will be discontinued. 
Abstract, Duration of 
Follow up; 
Abstract, Duration of 
Study; 
3.1 Overall Study 
Characteristics; 
11.2 Interim Analysis 
 
 
 
The Abstract (under Duration of Study), explains that the Sponsor will establish a 
final clinical cutoff date after all subjects have completed the Month 24 Visit. Data 
collection will cease at this time. The final clinical study report will be written based 
on these data. Clarified that the total study duration is 6 years, ie, the last patient was 
consented at 4 years and the final clinical cutoff is 2 years (24 months) after last 
patient was consented. The 6-year study duration (previously 5 years) was also 
mentioned in Section 3.1. In the body of the protocol, this information has been 
placed in new Section 11.2.2. The original information under Section 11.2 (titled 
Interim Analysis) was placed under new Section 11.2.1 and Subheader 11.2 was 
retitled Clinical Cutoffs. Also, the Abstract (under Duration of Follow Up) and 
Sections 3.1 and 11.2.2, note that subjects in the Follow-up Period will be 
discontinued at the time of the final clinical cutoff (and the appropriate section is 
referenced for additional information in the Abstract and in Section 3.1).  
Rationale: Specific laboratory names and information related to a specific laboratory were removed, as the 
storage location for specimens has changed. 
Appendix 6 
Mentions of USCF and LabConnect were replaced with “a central laboratory” and the 
following sentences were removed from the fourth paragraph of this appendix: 
“Specimen and data registries will be kept by the UCSF-HDFCCC. This registry will 
have a coordinated database to protect subject confidentiality and safety.” 
 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
S t u d y  D r u g :   A R N - 5 0 9  
 
Version dated 01 February 2019 
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Amendment 8 (16 August 2016) 
The overall reasons for the amendment: The main reason for the amendment is to add collection of optional 
archival formalin-fixed (FFPE) blocks or slides in order to gain understanding of biology and identify markers 
associated with response or resistance to complete androgen annihilation (apalutamide+ luteinizing hormone 
releasing hormone agonist [LHRHa]) compared with apalutamide or LHRHa alone. 
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Optional archival FFPE blocks or slides were added as samples for biomarker research.  
Abstract Secondary 
Objectives; 2.3.2 
Secondary 
Objectives;  6.4.2.4 
Correlative Studies: 
Exploratory 
Biomarkers;  7.1 Study 
Schedule: On-therapy 
Period (Day 1-Month 
12); 7.5.1 Day 1 of 
Study Treatment; 10.7 
Optional Sample 
Collection for 
Banking, RNA, and 
Biomarker Analysis; 
11.4.2 Analytic Plan 
for Secondary 
Endpoints; Appendix 6 
(Sections  V & VI) 
Added language for inclusion of archival FFPE blocks or slides.  
Rationale: The PSA modulation endpoint will not be analyzed using a Kaplan-Meier approach. 
11.4.2.Analytic Plan 
for Secondary 
Endpoints 
The following revision was made: The proportions by treatment will be estimated 
using the Kaplan Meier approach to account for censoring and then be compared 
using the chi square test or Fisher’s exact test as appropriate. Results will be 
summarized at 24 months from Day 1 with 95% confidence intervals for each 
treatment arm. Subjects who withdraw from the study prior to 24 months after Day 1 
will not be included censored in this analysis. Different censoring rules may be 
applied as sensitivity analyses. Details can be found in the statistical analysis plan 
(SAP). 
Rationale: Minor revision to description of analysis of secondary endpoints. 
11.4.2 Analytic Plan 
for Secondary 
Endpoints 
Removed “product limit” method for description of Kaplan-Meier, the additional 
language is redundant terminology.  
Rationale: Secondary objective for biomarkers in Section 2.3.2 did not match the abstract.  
2.3.2 Secondary 
Objectives 
Matched wording in Section 2.3.2 and abstract. 
Rationale: Allow more time to obtain laboratory assessments before study visits. 
7.1 Study Schedule: 
On-therapy Period 
(Day 1-Month 12) 
Added the following to footnote 3: Window for laboratory assessments before 
study visits is -7 days. 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
S t u d y  D r u g :   A R N - 5 0 9  
 
Version dated 01 February 2019 
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Page 18 of 108 
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Applicable Section(s) 
Description of Change(s) 
 
Amendment 7 (30 September 2015) 
The overall reasons for the amendment: The main reason for this amendment is to switch softgel capsules to tablets 
(commercial formulation) for subjects currently receiving the softgel capsules and to administer tablets to newly 
enrolled subjects. Updated drug-drug interaction language and other recent updates to standard wording in ARN-509 
protocols were incorporated, where relevant. Editorial changes made throughout to remove redundancy and improve 
clarity.  
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Switch of softgel capsules to tablets is incorporated. Vitamin E is not included in the tablet formulation. 
Twice daily dosing is no longer needed with the tablet formulation because of the reduced pill burden and change in 
excipients.  
Throughout 
Changed “softgel capsules” or “capsules” to “tablets.”  
Abstract Study Drugs 
1. ARN-509; 
Section 7.5.3 
ARN-509; Section 8.1 
ARN-509 
Replaced all information on the capsules with information on the tablets. Added 
instructions for the switch from softgel capsules to tablets for subjects receiving softgel 
capsules and for subjects who enroll on or after implementation of this amendment. A 
table was included in Section 8.1 showing the conversion from capsule to tablet and 
clarifying that the conversion is 2:1.   
Section 7.5.4.3 
Restricted 
Medications; 
Section 8.1 ARN-509: 
Section 9.2 Dose 
Modifications for 
ARN-509; 
Appendix 5 
Removed vitamin E restrictions, no longer applicable with the tablet formulation.  
Section 9.2 Dose 
Modifications for 
ARN-509 
Revised the dose modification section for alignment with other ARN-509 protocols and to 
incorporate changes for the switch from softgel capsules to tablets.   
Rationale: For all eligibility criteria with a timing interval , the interval was revised to be relative to randomization 
rather than study entry, which is consistent with other ARN-509 protocols.   
Abstract Study 
Population; 
Section  4.2 Inclusion 
Criteria; Section 4.3 
Exclusion Criteria; 
Section 6.1 Rationale 
for the Study 
Population 
Revised Inclusion Criteria # 6, 8, and 16 and Exclusion Criteria 1, 2, 4, 5, 6, 7, and 8. 
Made corresponding revisions in the abstract.  
Rationale: Revised objectives and endpoints for better clarity, consistency, and to allow more flexibility regarding 
evaluating changes over time.  
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Version dated 01 February 2019 
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Applicable Section(s) 
Description of Change(s) 
Abstract Primary 
Objectives, Secondary 
Objectives, Study 
Endpoints;  
Section 2.3.1 Primary 
Objectives; 
Section 2.3.2 
Secondary Objectives; 
Section 6.4.1 Primary 
Endpoint; Section 
6.4.2 Secondary 
Endpoints 
Modified to include “changes from baseline” and over a period of time rather than specific 
timelines. Simplified the objectives and removed “endpoint” information.   
Rationale: Revised the hypotheses for consistency with the revisions to the objectives and endpoints 
Section 2.1 
Hypothesis #1; 
Section 2.2 
Hypothesis #2 
Minor editorial revisions were made for consistency with objectives and endpoints and 
consistency between the 2 hypotheses.  
Rationale: Updated information on drug-drug interactions based on new information.  
Section 7.5.4.3 
ARN-509: Restricted 
Medications, 
Appendix 5 
Deleted current wording on CYP3A4 and CYP2C8 drug-drug interactions, refer to 
Appendix 5. Updated Appendix 5 with new information.  
Rationale: Revisions to the study schedules were incorporated for improved clarity and for consistency with other 
sections of the protocol. Additional changes were also incorporated into the Study Schedules as outlined.  
Section 7.1, Study 
Schedule On-therapy 
Period (Day  1-
Month  12); 
Section 7.2, Study 
Schedule Off-therapy 
Therapy Observation 
Period (Months 
13-24) and Follow-up 
Period (Month 25+)   
Revised footnotes, as needed for consistency with other sections of the protocol or because 
of changes in other sections. For both study schedules clarified that the Progression Visits 
take place at the time of progression if progression occurs before the end of the period.  
Additional “optional” when referring to the samples collected for banking, RNA, and 
biomarker research.  
Checked for consistency across the 2 schedules. In some cases, an “X” was placed in a 
manner that was inconsistent.  For example, if an assessment was to occur at each monthly 
visit (On-therapy Period) or every 2 months (Off-therapy Period), it would also cover the 
other monthly visits, therefore an additional “X” was not needed. 
Section 7.1, Study 
Schedule On-therapy 
Period 
(Day  1-Month 12) 
Added a row for the collection of concomitant medications. 
In order to have sufficient study drug supply for each “monthly” visit (28-day, 28-day, 
35-day sequence) of therapy, the visit window was reduced from ±7 days to ±2 days.  
Revised the timing for collection of optional samples to Day 1 rather than screening. 
Clarified that these samples and serum PSA sample should be taken predose. 
Revised footnote “5” for timing of visits. All subjects should be following a 28-day, 
28-day, 35-day schedule (±2 days).    
For subjects who discontinue therapy without proceeding to the Off-therapy Period, AE 
reporting should continue until 30 days after the last dose of protocol therapy.  
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Applicable Section(s) 
Description of Change(s) 
Section 7.2, Study 
Schedule Off-therapy 
Therapy Observation 
Period (Months 
13-24) and Follow-up 
Period (Month 25+);    
Revised heading for the Follow-up Period from Month 24+ to Month 25+. 
Rationale: Several sections contained redundant information. For improved clarity and to avoid the need to make 
changes in several sections of the protocols with amendments, these sections were edited. The studies activities 
sections were condensed and made consistent with the Study Schedules. 
Section 7.3 Screening 
Period/Pre-study 
Evaluation; Section 
7.5 Study Period 1: 
On-therapy Period 
(Month 1 to 12); 
Section 7.6 Study 
Period II: Off-therapy 
Period (Months 
13 to  24); Section 7.7 
Follow-up Period 
(Month 25+); 
previous Section 12.2 
Accrual 
Revisions were made in each of these sections to ensure to consistency with the Study 
Schedules and to remove redundancy. Section 12.2 Accrual was removed because the 
information was redundant . 
Rationale: The statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used in analyzing the data is outlined in the protocol. Details will be 
provided in the Statistical Analysis Plan (SAP). Approaches for analysis of repeated measures will be used to 
account for multiple data points from the same subjects and potential missing records.  
Section 11 Planned 
Statistical Methods; 
Section 11.4.1 
Analytic Plan for the 
Primary Endpoint; 
Section 11.4.2 
Analytic Plan for the 
Secondary Endpoints; 
removed Section 10.6 
Demographics and 
Baseline 
Characteristics 
Added sentence to Section 11 stating that the sponsor will be performing the statistical 
analysis and that details will be provided in the SAP.  
Primary and secondary endpoints (QOL, metabolic and hormonal parameters) will be 
analyzed using a mixed model for repeated measures (MMRM). 
Abnormal findings in physical exams and laboratory tests will be summarized.  
Removed Section 10.6, details will be provided in the SAP. 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Applicable Section(s) 
Description of Change(s) 
Rationale: It is preferable, but not required to have the PSA evaluations obtained from the same laboratory.  
Section 4.2 Inclusion 
Criteria, Criterion #5; 
Section 7.1 Study 
Schedule On-Therapy 
Period (Day 1-Month 
12); Section 7.2 Study 
Schedule Off-therapy 
Observation Period 
(Month 13-24) and 
Follow-up Period 
(Month 25+); 
Section  7.3.2 
Laboratory; 
Section 10.6 PSA 
Measurements 
Added wording that it be preferable to have the PSA evaluations obtained from the same 
laboratory. 
Rationale: The Investigator’s Brochure should be the source for the most up to date Reference Safety Information 
for ARN-509. The applicable product insert or summary of product characteristics should be source for safety 
information on LHRH agonists 
Section 1.4 Second 
Generation AR 
Antagonists in BCR 
Hormone Sensitive 
Prostate Cancer; 
Section 8.1 ARN-509 
Section 8.2 LHRH 
Agonist 
Removed safety information and add reference to the Investigator’s Brochure. Added 
source information for the safety information on LHRH agonists.   
Section 12.1.3 
Expectedness 
Removed wording that was not consistent with other ARN-509 protocols. Added the 
following for LHRH agonist therapy: For LHRHa with a marketing authorization, the 
expectedness of an AE will be determined by whether or not it is listed in the applicable 
package insert or summary of product characteristics. 
Rationale: Subject initials should not be used for identification purposes 
Section 14.1 Data 
Collection 
Instruments; 
Section 14.6 Subject 
Confidentiality; 
Section 15 
Administrative, 
Ethical, Regulatory 
Considerations  
Reference to subject initials was removed. 
Rationale: Refer to Appendix 6 for details on collection, processing, and shipping of peripheral blood and urine 
samples to avoid repetition and need for updating in several sections of the protocol if changes occur.  
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Applicable Section(s) 
Description of Change(s) 
Section 7.1, Study 
Schedule On-therapy 
Period (Day  1-
Month  12); Section 
7.2, Study Schedule 
Off-therapy 
Observation Period 
(Months 13-24) and 
Follow-up Period  
(+25 Months);   
Section 7.3.2 
Laboratory 
Assessments; Section 
7.5.7 Laboratory 
Assessments; 
Section 7.6.3 
Laboratory 
Assessments; 
Section 7.7 Follow up 
Period (±25 months) 
Removed details and refer to Appendix 6. 
Rationale: Updated eligibility criteria and added a prohibitions and restrictions section regarding sexual activity for 
consistency with other protocols.  
Section 4.2 Inclusion 
Criteria; 
Section 4.3 Exclusion 
Criteria  
Updated Inclusion Criterion #17, removed Exclusion Criterion #11. Added Section 5 
Prohibitions and Restrictions and updated numbering for the subsequent sections. 
Rationale: Limited discussion of nonclinical and clinical data to ARN-509 as this study is providing no comparison 
with enzalutamide. 
Section 1.4 Second 
Generation AR 
Antagonists in BCR 
Hormone Sensitive 
Prostate Cancer 
Removed enzalutamide data from this section and removed references from the reference 
list.  
Rationale: Updated references 
References 
Updated Rathkopf abstract with publication (Ref#32), removed outdated Investigator’s 
Brochure reference, and removed enzalutamide references.  
Rationale: Minor edits were made for improved clarity or to correct a formatting or typographical error. 
Throughout 
Minor edits, formatting or corrections.  
 
 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Amendment 6 (12 September 2014) 
The overall reasons for the amendment: Incorporate investigator feedback to improve the quality and clarity of the 
protocol. Revisions to several eligibility criteria were made to improve clarity, to increase enrollment or for 
consistency with the informed consent form. Additional revisions were made to the safety section for consistency with 
the Spongsor’s standard protocol template language. Changes in data management were also incorporated.  
 
Applicable Section(s) 
Description of Change(s) 
Rationale: Eligibility criteria were numbered to align with the electronic case report form (eCRF) and several criteria 
were modified to improve clarity and to help increase enrollment. Added eligibility criteria for required contraception 
and timing before donation of sperm or fathering children for consistency with the informed consent form. Changes 
also affected other sections of the protocol.  
Abstract; Section 4.2, 
Inclusion Criteria  
Criterion # 5: Revised to include all recorded PSA values obtained over the past 6 months 
instead of 12 months. 
Criterion #6: Clarified the description of lymph node size. 
Criterion # 8 Changed from 12 months to 6 months 
Added Criterion #16 
Abstract; Section 4.3, 
Exclusion Criteria; 
Section 6.3.2, 
Laboratory (within 
14 days prior to 
treatment initiation) 
Section 6.3.4, 
Radiographic Studies 
(within 12 weeks prior 
to treatment 
initiation); 
Section 6.5.4, 
Concomitant 
Medications 
Criterion #1: Changed from 3 months to 6 weeks. 
Criterion #2: Changed from 12 months to 6 weeks. 
Criterion #4 Changed from 12 months to 6 months and removed redundant wording 
Criterion #8: Clarified exclusion for use of bone-modifying agents and timing, and removed 
the requirement for osteoporosis assessement  
Section 4.2, Inclusion 
Criteria; Section 4.3, 
Exclusion Criteria 
Added Inclusion Criterion #17: Agrees to use a condom (even men with vasectomies) and 
another effective method of birth control if he is having sex with a woman of childbearing 
potential or agrees to use a condom if he is having sex with a woman who is pregnant. Must 
also agree not to donate sperm during the study and for 3 months after receiving the last dose 
of study drug. 
 
Added Exclusion Criterion #11: Subject plans to father a child while enrolled in this study or 
within 3 months after the last dose of study drug 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Applicable Section(s) 
Description of Change(s) 
Rationale: Per investigator feedback, the Study Schedules were modified for greater clarity. Revisions were also made 
as needed in other sections of the protocol.  
Section 3.1, Overall 
Study Characteristics; 
Section 6.1, Study 
Schedule “On 
Therapy” Period 
(Day  1-Month  12); 
Section 6.2, Study 
Schedule “Off 
Therapy” Observation 
Period (Months 13-24) 
and Follow-up Period  
(+24 Months);  
Section 6.5.8, 
Duration of Therapy 
“On Therapy” Period; 
Section 6.6.4, 
Duration of “Off 
Therapy” Observation  
Period 
In addition to minor edits, footnotes to the Study Schedules were revised and reworded for 
greater clarity. 
Additional instructions for follow-up period (24+ months) were included for subjects who 
discontinue in the absence of progressive disease. 
Rationale: Consistency between Study Schedule and subsections in Section 6 were not consistent 
All subsections of 
Section 6, Study 
Activities 
All subsections were checked against the Study Schedules to ensure consistency. 
Rationale: Description of study periods and timing of assessments were inconsistent.  
Throughout the 
protocol 
Revised for consistency in the description of the study periods (ie “on therapy” period and 
“off therapy” observation period). Revised description of the timing of assessments for 
greater clarity and consistency.  
Rationale: Clarified that the 3 month schedule be such that treatment period completes at exactly 12 months 
Section 6.1, Study 
Schedule “On 
Therapy” Period 
(Day 1-Month  12); 
Section 6.5.3, 
ARN-509; 
Section 6.5.8, 
Duration of Therapy 
“On Therapy” Period 
Added text: 
To align ARN-509 monthly dosing with LHRHa treatment on a 3-month schedule, the 
visits should be divided into 28-days, 28-days, and 35-days. This ensures an exact 
12 month treatment period. 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Applicable Section(s) 
Description of Change(s) 
Rationale: More information provided for the radiographic progression-free survival endpoint. Only Investigator 
review will be used to assess radiographic progression-free survival.  
Section 6.3.3 
Radiographic Studies 
(within 6 weeks prior 
to treatment 
initiation); 
Section  6.5.7 
Radiographic 
Assessment; 
Section 6.6.3, 
Radiographic 
Assessment 
Added text:  
Subjects who are intolerant of IV CT contrast agents may have CT scans performed with 
oral contrast or without, as long as method is identical each time new scans are done. 
There will be no central reading of the scans and radiographic progression will be based 
upon investigator assessment 
Rationale: Added thyroid stimulating hormone (TSH) to laboratory evaluations during treatment per request of the 
Investigational Review Board (IRB) 
Section 6.1, Study 
Schedule “On 
Therapy” Period 
(Day 1-Month 12); 
add other sections; 
Section 6.3.2, 
Laboratory (within 
14 days prior to 
treatment initiation) 
Section 6.5.6, 
Laboratory 
Assessments  
(±7 days) 
Added separate column for timing of TSH laboratory evaluation to the study schedule and 
separate bullets in the other sections.  
Rationale: The window for the scheduled luteinizing hormone releasing hormone agonist (LHRHa) injection was 
changed from ±14 days to ±7 days.  
Section 6.1, Study 
Schedule “On 
Therapy” Period 
(Day 1-Month 12); 
Section 6.5.2, LHRH 
Agonist 
If a subject does not receive a scheduled LHRHa injection within ±7 days of the scheduled 
due date for injection, he will be removed from study. 
Rationale: Height is measured only at the screening visit. 
Section 6.5.1, Day 1 
of Study Treatment 
Height was removed. 
Rationale: Added language to ensure that collection of QOL information is completed during for subjects who 
discontinue therapy prior to Month 12.  
NCT01790126


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Applicable Section(s) 
Description of Change(s) 
Section 6.5.8, 
Duration of “On 
Therapy” Period 
Added text: Efforts will be made to ensure that subjects who develop progressive disease 
or unacceptable toxicity prior to Month 12 still complete QOL scales at 3 and 12 months. 
Rationale: Clarification of sample collection during the follow-up period.  
Section 6.7, Follow-up 
Period (24+ Months) 
Added text: If no progressive disease occurred during Months 1 to 24 and it occurred 
during the follow-up period, whole blood RNA and Plasma for banking samples need to be 
collected during the follow-up period. These samples will be shipped to UCSF, banked, 
and subsequently analyzed (see Appendix 6 for collection/shipping instructions). Data 
entry needs to occur on the follow-up visit in which the progressive disease was observed. 
Rationale: Dose medication for toxicity related to ARN-509 was clarified.  
Section 8.2, Dose 
Modification for 
ARN-509.  
Revised previous text to read:  
For subjects receiving ARN-509 (with or without LHRHa) and who experience Grade 1 or 
2 adverse events related to study therapy, the decision to change ARN-509 dosing from 
QD to BID dosing, to delay treatment (“treatment break” of maximum 28 days), dose 
reduce (to 180 mg QD, no lower dose allowed) or to discontinue treatment in such a 
situation will be per individual investigator discretion. 
Rationale: Revisions to data collection plans and addition of procedures for corrections to the electronic case report 
form (eCRF).  
Section 13.1, Data 
Collection 
Instruments; 13.2, 
Data Quality Control 
and Reporting 
Electronic data capture and other procedures for data collection have been updated. 
Deleted the previous Section 13.2 Data Management Procedures.  
Rationale: Correction made, DLTs are not being collected in this study, this is a Phase 2 study not Phase 1.  
Section 10.7.2, 
Secondary Endpoints 
Removed the bullet: Incidence of DLT (Phase 1). 
Rationale: In statistical method section, removed redundant text, revised analysis descriptions.  
Section 10.8, Methods 
for Analysis; 
Section  10.8.2, 
Analytic Plan for the 
Secondary Objectives 
Revised the definition of the safety analysis population.  
Revised the analysis description for the secondary objective (PSA Modulation). 
Deleted redundant text. 
NCT01790126


P r o t o c o l  # 1 1 5 5 2 3  ( A R N - 5 0 9 - 0 0 2 )        
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Applicable Section(s) 
Description of Change(s) 
Rationale: Updated with new references  
Section 1.4, Second 
Generation AR 
Antagonist in BCR 
Hormone Sensitive 
Prostate cancer 
Section 6.5.8, 
Duration of Therapy 
“On Therapy” Period 
Throughout the 
protocol 
Section 15, References  
Added reference #35. 
 
 
 
 
Added reference #64. 
 
Renumbered references, as relevant 
  
Added new references and renumbered, as relevant. 
Rationale: Safety section updated for consistency with other Janssen protocols and the informed consent form. 
Section 11 
Updated this Section with standard Janssen template wording. 
 
 
Amendment 5 (3 June 2014) 
The overall reasons for the amendment: The overall reasons for the amendment are to incorporate biomarker 
research, update sections for consistency with other protocols, update safety and publication section for alignment with 
the Janssen template and procedure, add reference and requirements for the DEXA scan, incorporate changes to 
Exclusion Criteria that were previously included in an addendum to the protocol. Other changes were also included for 
clarity or consistency.  
 
Applicable Section(s) 
Description of Change(s) 
Rationale: A biomarker research plan was incorporated. 
Abstract 
2.3.2 Secondary 
Objectives 
5.4.2.4 Correlative 
Studies: Exploratory 
Biomarkers 
Biomarker analyses will be conducted on plasma and whole blood samples from all 
consented subjects to assess ARF876L mutations and other resistance markers from the 
3 treatment groups 
 
Added Section 5.4.2.4 to the protocol  
6.1 Study Schedule 
6.2 Study Schedule 
Added columns for whole blood and plasma for biomarker testing. Added footnotes 7 and 
10.  
6.3.2 Laboratory 
Assessments (within 
14 days prior to 
treatment initiation); 
6.5.6 Laboratory 
Assessments 
(±7 days);  
Added information on sample collection. 
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Applicable Section(s) 
Description of Change(s) 
9.7 Optional Whole 
Blood and Plasma 
Collection for 
Biomarker Analysis 
Added this new section. 
10.7.2 Secondary 
Endpoints; 
10.8.2 Analytic Plan 
for the Secondary 
Objectives 
Added biomarker analysis plan 
15. References 
Added reference 62 
Appendix 6 
Added information on processing of samples. 
Rationale: Exclusion criteria had previously been modified in an addendum, now incorporated into the protocol 
4.3 Exclusion Criteria 
Added clarification for bullet 4 regarding prior hormonal treatment with ADT 
Added requirement for DEXA scan to bullet 8 
 
Rationale: Clarification of DEXA scan requirements and reference added 
Abstract, Study 
Endpoints 
3.2.2 Secondary 
Endpoints 
6 Study Activities 
6.5.7 Radiographic 
Assessments 
9.5.3 Bone Mineral 
Density 
10.7.2 Secondary 
Endpoints 
10.8.2 Analytic Plan 
for the Secondary 
Objectives 
Removed total hip from DEXA scans 
6.1 Study Schedule 
Added footnote 6 for timing of the baseline assessment 
Added footnote 9 for reference 
6.3.4 Radiographic 
Studies 
New section added with DEXA reference information 
Rationale: Alignment of safety reporting and safety wording with Janssen protocol template and process.  
Throughout 
Changed “toxicity” to safety when describing safety assessments or analyses. The National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) was 
mentioned frequently in the protocol and was updated to Version 4.03.  
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Applicable Section(s) 
Description of Change(s) 
6.1 Study Schedule; 
6.5.5 Safety 
Assessment; 6.6.1 
Safety Assessment 
Clarified that reporting of adverse events starts with the signing of the informed consent form 
and that adverse events will be collected up to 30 days after the last dose of study medication.  
 
Added footnote 8 to the Study Schedule 
 
6.5.5 Safety 
Assessment; 6.6.1 
Safety Assessment 
11.1.1 Adverse 
Events; 11.1.2 Serious 
Adverse Events; 
11.1.4 Attribution; 
11.1.6 Pregnancy; 
11.5 Expedited 
Reporting 
Incorporated Janssen protocol template wording. For Sections 6.5.5 and 6.6.1 the attribution 
wording was removed and a link to Section 11.1.4 was added.  
Rationale: The safety analysis information included in the protocol was not sufficient.  
Abstract, Secondary 
Endpoints; 3.2.2 
Secondary Endpoints; 
10.7.2 Secondary 
Endpoints 
Added more detail on the planned safety analysis 
Rationale: Incorporation of product quality complaint handling 
12. Product Quality 
Complaint Handling 
Added a new section incorporating Janssen template wording and renumbered the 
subsequent sections of the protocol. 
Rationale: Incorporation of Janssen  use of information and publication policy   
14.6 Use of 
Information and 
Publication 
Revised this section to incorporate Janssen protocol template wording.  
Rationale: For consistency across protocols, prohibited and restricted medication information while on ARN-509 
treatment were incorporated into the protocol.  
6.5.4.1 ARN-509: 
Prohibited 
Medications; 6.5.4.2 
ARN-509: Restricted 
Medications 
Added these sections to the protocol 
Rationale: Updated study drug information and handling section.  
7.1 ARN-509 
Added that clinical formulation-specific and batch-specific storage instructions can be found 
in the packaging label.  
Under Drug Supply: added that ARN-509 is to be ordered directly from a designee indicated 
by the Sponsor.  
Clarification of procedure for the return of clinical supplies.  
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Applicable Section(s) 
Description of Change(s) 
Rationale: Clarified timing for the completion of eCRFs following a visit or to address a query. 
13.1 Data Collection 
Instruments 
Previous wording “as soon as possible” was revised to 5 days 
Rationale: This is the first protocol amendment since Aragon Pharmaceuticals, Inc became a wholly-owned subsidiary 
of Johnson & Johnson. The study chair has changed.  
Cover page 
Updated the cover page to reflect the change for Aragon. Investigator list was updated. 
Added document repository number (page 2). 
Rationale: Minor clarifications were made, as appropriate, based on feedback from investigators.  
Throughout 
Revised wording as needed for greater clarity 
 
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1 BACKGROUND  
1.1 BIOCHEMICALLY RELAPSED PROSTATE CANCER 
Prostate cancer is the second most common cancer in men worldwide, with an estimated 
incidence of 900,000 cases and 258,000 deaths in 2008 [1].  In the United States, approximately 
222,000 cases were diagnosed in 2010 [2], of which an estimated two-thirds undergo radical 
prostatectomy or definitive radiation therapy (RT).  Approximately 25%-35% of patients treated 
with definitive surgical or radiation therapy for localized adenocarcinoma of the prostate will 
recur in the form of rising serum PSA without overt metastatic disease, termed biochemical 
relapse (BCR) [3,4].  An estimated 40,000 - 50,000 men in the U.S develop biochemically 
relapsed prostate cancer each year, yet treatment of men in this disease state is far from 
standardized.  The optimal time to initiate treatment and the choice of specific therapy for such 
patients remains controversial and highly variable in clinical practice.  This may be due to 
several potential reasons, including (1) a dearth of prospective randomized trial data 
demonstrating an overall survival advantage for one particular therapeutic approach and (2) a 
biologically heterogeneous population with a variable natural disease course. 
The kinetics of PSA change over time has emerged as an important independent prognostic 
factor for patients with BCR, both with respect to time to development of metastases as well as 
the risk of prostate cancer-specific mortality.  In a cohort study of 8,669 men treated with 
localized therapy, of the 1,451 men with PSA recurrence, a PSA doubling time (PSADT) less 
than 3 months was associated with an approximately 50% chance of prostate-cancer specific 
mortality at 5 years; in contrast, those with a PSADT greater than 12 months had less than 10% 
prostate cancer-specific mortality during the same time interval [5].  In another study of 1,650 
patients previously treated with external beam radiotherapy, at the time of PSA recurrence, the 
3 year risk of distant metastases for a PSADT of 0-3 months, 3-6 months, 6-12 months, and 
> 12 months was 49%, 41%, 20%, and 7%, respectively (P <0 .001) [6].   
1.2 RISK ADAPTED THERAPY FOR BCR PROSTATE CANCER PATIENTS 
Risk stratifying patients with biochemical recurrence may allow for more optimal and 
individualized selection of treatment [7].  A prolonged PSADT, as well as other factors such as 
low Gleason grade, positive surgical margins, and pre-treatment PSA level < 2.0 ng/mL, may 
help to predict which patients may benefit from localized salvage therapy such as radiotherapy 
after prior prostatectomy [8].  For those patients with a PSADT greater than 12 months, active 
surveillance may be the optimal treatment approach, especially in elderly patients with other 
potentially life-limiting co-morbidities who are not candidates for locally directed salvage 
therapy.  For patients with a very short PSADT, who are at significant risk of prostate-cancer 
specific mortality over the next 5-10 years, early treatment with continuous androgen deprivation 
therapy (ADT), in the form of luteinizing hormone releasing hormone (LHRH) agonists (eg, 
goserelin, leuprolide acetate) with or without an androgen receptor (AR) antagonist (eg, 
flutamide, bicalutamide), has been one standard approach.  
There are no randomized data in this higher risk population demonstrating an overall survival 
advantage for early continuous ADT versus deferred therapy until the time of progression to 
metastatic disease.  Nevertheless, retrospective data and extrapolation from randomized clinical 
trials of patients with high-risk localized disease (eg, node positive post-radical prostatectomy or 
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high risk radiation therapy patients) favor earlier treatment with ADT [9-11].  For example, in a 
prior clinical trial of 98 men with node-positive prostate cancer who have undergone prior 
radical prostatectomy and lymph node dissection, randomized to receive either immediate ADT 
or deferred until detection of distant metastases or symptomatic recurrences (ie, not started at the 
time of rising PSA only), men randomized to the immediate ADT arm showed a significant 
improvement in overall survival after a median follow up of 11.9 years (hazard ratio [HR] 1.84; 
95% confidence interval [CI] 1.01-3.35, p = 0.04; median overall survival [OS] 13.9 vs. 11.3 
years) [10].  In clinical trial RTOG 85-31, 173 prostate cancer patients  with either clinical stage 
T3 or positive regional lymph nodes (radiographically or histologically) were randomized to 
receive either radiation therapy + immediate long term continuous ADT vs. RT + deferred ADT 
initiated at the time of disease relapse [9].  On multivariate analysis, RT + immediate ADT had a 
significant impact on absolute survival (p = 0.030), disease-specific failure (p = 0.014), 
metastatic failure (p = 0.005).  While these studies are generally underpowered, and don’t 
directly test the hypothesis of early vs. deferred ADT in the BCR patient population, they do 
raise a provocative question as to whether early ADT provides a clinical benefit in these patients.  
1.3 THERAPEUTIC OPTIONS IN BCR PROSTATE CANCER PATIENTS 
1.3.1 Combined Androgen Blockade (CAB) 
Combined androgen blockade (CAB) refers to the combination of medical castration with an 
LHRH agonist (LHRHa) and a (first generation) antiandrogen such as flutamide or bicalutamide. 
There are currently no completed randomized clinical trials comparing CAB with LHRHa 
monotherapy in men with biochemically relapsed prostate cancer.  In the metastatic hormone-
sensitive disease population, several meta-analyses demonstrate a small 5 year overall survival 
benefit with the addition of a first generation antiandrogen to LHRHa therapy, with a slim 
absolute 5-year survival benefit of 2-3% [12, 13].  The American Society of Clinical Oncology 
(ASCO) guidelines state CAB can be considered as an option for the metastatic 
hormone-sensitive disease population [14].  In the non-metastatic BCR disease setting, the use of 
CAB is quite variable across clinical practices, ranging from no use to temporary use of 
antiandrogen at the time of initiation of ADT to continuous CAB. 
While continuous, long term treatment with ADT is effective in terms of decreasing PSA levels, 
disease progression in the setting of castrate levels of testosterone is a near universal event.  
Furthermore, over the past decade, there has been a growing appreciation for the significant 
short-term and longer-term toxicities of continuous ADT, in which serum testosterone is 
maintained at a castrate level.  Side effects developing shortly after the initiation of ADT include 
fatigue, gynecomastia, decreased libido, impotence, decreased physical capacity, mood changes, 
and hot flashes.  Over the long term, serious metabolic side effects can often emerge, including 
decreased bone mineral density and risk for osteoporotic fractures, anemia, increased risk of 
insulin resistance and overt diabetes mellitus, dyslipidemia, and potentially, an increased risk of 
cardiovascular mortality [15-21].  
1.3.2 Intermittent ADT (IADT) 
Given the toxicities of long term, continuous ADT, more contemporary treatment strategies 
involving intermittent ADT (IADT) have emerged for men with BCR.  The threshold at which to 
stop and start ADT during the course of IADT is variable in prior clinical trials and clinical 
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practice [22-25].  Nevertheless, numerous Phase 2 and 3 trials comparing IADT to continuous 
ADT, though not adequately powered for non-inferiority, have shown comparable overall and 
prostate-cancer specific survival and improved quality of life (QOL) [22-25].  More recently, a 
randomized Phase 3, non-inferiority trial of continuous vs. IADT in 1,386 patients with BCR 
after prior definitive radiation treatment was conducted by the NCIC.  There was no difference in 
overall survival after a median follow up of 6.9 years (HR = 1.02, 95% CI 0.86 – 1.21) and 
significantly better QOL with IADT [26].  The results of this trial provide further justification to 
consider treatment alternatives to continuous ADT in the BCR disease setting. 
1.3.3 Peripheral Androgen Blockade (PAB) 
Peripheral androgen blockade, utilizing an androgen receptor antagonist (e.g. flutamide or 
bicalutamide), with or without a 5-alpha reductase inhibitor, inhibits intra-tumoral activation of 
the AR, thereby potentially slowing disease progression.  Yet in contrast to ADT, PAB does not 
decrease serum testosterone levels to a castrate state.  In theory, this may lead to an improvement 
in quality of life and the metabolic profile of patients treated with PAB versus traditional ADT, 
while hopefully preserving response to treatment.  Preliminary data provide some support for this 
hypothesis.  In a pooled analysis of 480 men with locally advanced (T3/T4 with serologic 
progression) non-metastatic prostate cancer and 805 men with metastatic prostate cancer 
randomized to high-dose bicalutamide versus medical or surgical castration, there was no 
statistical difference in overall survival between the two treatment groups (HR 1.05, p = 0.70).  
Those patients randomized to the bicalutamide therapy had improved quality of life with regards 
to sexual interest (p =0.029) and physical capacity (p = 0.046) compared with surgical castration 
[27].  Similarly in a separate (underpowered) study of 220 men with non-metastatic (n = 92) and 
metastatic (n = 128) prostate cancer randomized to receive either high-dose bicalutamide or ADT 
with flutamide plus goserelin, there was no detriment in overall survival and improved quality of 
life in the bicalutamide treatment arm [28].  In a more contemporary study, monotherapy with 
bicalutamide was compared to LHRHa therapy in patients with prostate cancer with no bone 
metastases.  After 1 year of therapy, bicalutamide was shown to improve bone density (increase 
of 2.5% vs. decrease of 2.5% of bone density in the posterior-anterior lumbar spine), lessen 
increase in fat mass (6.4% vs. 11.1% increase), and diminish fatigue, loss of sexual interest and 
vasomotor flushing [29].  Although the earlier studies were underpowered, and additional 
metabolic profiling was not undertaken in this more recent study, in aggregate, these data suggest 
that monotherapy with an AR antagonist is promising, and warrants further investigation.  The 
recent availability of significantly more potent second generation inhibitors of the AR makes 
such a study even more compelling. 
1.4 SECOND GENERATION AR ANTAGONISTS IN BCR HORMONE 
SENSITIVE PROSTATE CANCER 
First generation AR antagonists such as flutamide and bicalutamide have relatively low AR 
binding affinity relative to dihydrotestosterone (DHT) and may exhibit partial agonist activity 
and may eventually lead to disease progression through putative activation of the AR.  To 
overcome the potential deficiencies of first generation antiandrogens, second generation 
antiandrogens have been developed which potently inhibit AR activation, nuclear translocation, 
binding to co-activators, and AR-mediated gene expression.  Furthermore, these second 
generation antiandrogens do not have any agonist activity.  ARN-509 is a second generation 
antiandrogen currently  being evaluated in men with a more advanced, potentially AR-amplified, 
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castrate-resistant disease state.  ARN-509 demonstrates a higher affinity for the AR than first 
generation AR inhibitors such as bicalutamide (see figure 1 below) [30].  Furthermore, ARN-509 
lacks agonist activity, and additionally, inhibits AR nuclear translocation and DNA binding to 
androgen response elements, thereby modulating AR-mediated gene expression that drives 
prostate cancer growth [30, 31]. 
 
Figure 1. Competitive Binding Curve of AR in LNCaP/AR Cells 
 
ARN-509 binding affinity for AR was evaluated in a whole cell binding assay in which competitive inhibition of 18-
FDHT (18-fluorodihydrotestosterone) equilibrium binding to AR in LNCaP/AR cells was monitored. ARN-509 is a 
potent, competitive binder of AR, with a mean IC50 of 16 nM.  In comparison, IC50 value for bicalutamide was 
160 nM. 
ARN-509 was recently evaluated in a Phase 1/2 trial of men with metastatic castrate-resistant 
prostate cancer (CRPC) (NCT01171898).  Thirty patients received ARN-509 at doses 30, 60, 90, 
120, 180, 240, 300, 390, and 480 mg/day [32].  There was 1 dose-limiting toxicity (DLT) 
observed in the 300 mg/day cohort, a Grade 3 abdominal pain, which resolved upon study drug 
interruption and subsequent dose reduction.  As a result of this DLT, an additional 3 patients 
were enrolled in the 300 mg/day cohort; there were no additional DLTs observed.  The most 
commonly reported Grade 1-2 treatment-related adverse events were fatigue, abdominal pain, 
dyspnea, nausea, and arthralgia.  Grade 1 or 2 hypothyroidism was also reported as a 
treatment-related adverse event. There were no Grade 4 or 5 adverse events observed. 
Pharmacokinetic (PK) studies demonstrated that ARN-509 was rapidly absorbed, with 
measurable plasma concentrations within 30 minutes after ingestion of a single oral dose of 30 to 
480 mg.  On average, peak plasma concentrations occurred 2 to 3 hours after administration in 
each dose cohort.  The increases in plasma maximum concentration (Cmax) and in the area under 
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the plasma concentration vs. time (AUC) were linear and dose proportional. Based on the clinical 
safety and pharmacokinetic profile observed, 240 mg/day was selected as the recommended 
Phase 2 dose of ARN-509 [32]. The Phase 2 portion of the study is ongoing to evaluate the 
safety and efficacy of ARN-509 in subjects with high-risk (PSADT ≤10 months or serum PSA 
value ≥8 ng/mL obtained within 3 months prior to enrollment) non-metastatic (CRPC) and 
subjects with mCRPC who had or had not received prior treatment with abiraterone acetate. The 
safety profile of ARN-509 in these patient populations is consistent with the Phase 1 data in 
patients with mCRPC.  
Refer to the Investigator’s Brochure for comprehensive information on the nonclinical and 
clinical data for ARN-509.  
Given the fact that patients with hormone-sensitive BCR have AR dependent, yet likely non-AR 
amplified cancer, with a low tumor burden, potent blockade of the AR with a second generation 
antiandrogen may demonstrate significant cytotoxic effect and clinical efficacy. 
1.5 DEMONSTRATING BENEFIT OF NOVEL HORMONE THERAPIES IN 
BCR PROSTATE CANCER PATIENTS 
Developing new therapeutics and therapeutic strategies for men with BCR presents some unique 
study design challenges.  The relatively long median metastasis-free and overall survival with 
ADT require trials enrolling large numbers of patients with long term follow up to demonstrate 
statistically non-inferior or superior progression-free or overall survival of a new treatment 
strategy pitted against continuous ADT.  However, there exist a number of other clinically 
relevant and statistically rigorous endpoints, including quality of life and impact on metabolic 
parameters, which can be addressed in smaller randomized Phase 2 trials.  In addition to 
addressing important clinical issues, favorable results from such trials can then provide the basis 
and justification to support larger clinical trials with primary efficacy endpoints of metastasis-
free or overall survival.   
1.5.1 Quality of Life 
The potential side effects and adverse effect on quality of life with traditional ADT, coupled with 
an expected median overall survival of men with BCR on the order of 5 years or longer, even 
among those with a short PSADT, makes preservation of quality of life (QOL) an important goal 
for new therapeutics tested in the BCR disease population.  There are several validated quality of 
life scales which have been used in prior prostate cancer clinical trials, including the Functional 
Assessment of Cancer Therapy- Prostate (FACT-P) [33], the EORTC QLQ-C30 plus EORTC 
QLQ-PR25 prostate cancer-specific subscale [34, 35], the UCLA Prostate Cancer Index (PCI) 
[36], the Expanded Prostate Cancer Index Composite (EPIC) [37], and the Sexual Health 
Inventory for Men (SHIM) [38].  For the current study proposal, FACT-P, EORTC QLQ-
C30/QLQ-PR25, and the SHIM instruments will be used to measure various aspects of quality of 
life among men treated with hormonal therapy for biochemically relapsed prostate cancer. 
1.5.1.1 
FACT-P 
Although there is no QOL scale specifically designed and validated for use in the BCR disease 
population, perhaps the most widely used and validated QOL scale used in clinical trials of men 
with advanced prostate cancer is the FACT-P scale [33].  The FACT-P includes a 27-item “core” 
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quality of life measure (FACT-G), grouped into 4 sub-scales: physical, social/family, emotional, 
and functional well-being.  The prostate cancer-specific subscale contains an additional 12 items, 
which address changes in weight, appetite, pain control, bowel/bladder function, and erectile 
dysfunction [see Appendix 1], which encompass many of the QOL issues expected with ADT.  
1.5.1.2 
EORTC QLQ-C30/QLQ-PR25 
The EORTC QLQ-C30is a well validated [34], and widely used measure of health-related quality 
of life among cancer patients.  The EORTC QLQ-C30 consists of 30 items, which list the 
functioning and symptoms of cancer patients.  Five multi-item function scales are scored: 
physical function (PF), role function(RF), emotional function (EF), social function (SF), and 
global health status/quality of life.  Furthermore, nine single-item scales(symptoms) are scored, 
including fatigue, pain, dyspnea, and gastrointestinal problems.  The QLQ-PR25 is a well 
validated [35] 25 item subscale specific to prostate cancer patients, including items specific to 
the use of ADT such as those pertaining to hot flushes, weight gain, fatigue, and libido [see 
Appendix 2]. 
1.5.1.3 
Sexual Health Inventory for Men (SHIM) 
For men on ADT, one of the most impactful side effects on QOL is the potential for impotence 
and decrease in sexual function.  The SHIM is a well validated [38] and widely used 5 item scale 
used to assess the severity of erectile dysfunction which has been included in prior prostate 
cancer studies [39].  
1.5.2 Metabolic Parameters 
1.5.2.1 
Markers of Insulin Resistance and Metabolic Syndrome 
Androgen deprivation therapy has numerous effects on the metabolic profile, including increased 
insulin resistance, development of obesity and increased waist circumference, unfavorable 
changes in the lipid panel, and ultimately increased risk of diabetes and potentially 
cardiovascular mortality [15-21].  To detect differences in the incidence rate of new diabetes or 
cardiovascular events between treatment arms, studies in the BCR disease setting would require 
large numbers of patients and long term follow up, given the low annual incidence rate of these 
co-morbidities for men on ADT.  Measuring changes in metabolic risk factors for these 
processes, including surrogate markers of insulin resistance such as fasting glucose and insulin, 
body mass index, hemoglobin A1C, along with changes in the fasting lipid panel, may serve as 
intermediate, exploratory endpoints in initial phase 2 trials.  Favorable results with respect to 
these metabolic parameters may then serve as the basis for larger trials of new therapeutic agents, 
in which the incidence rate for diabetes or cardiovascular disease could serve as more 
quantifiable endpoints.  
1.5.2.2 
Bone Mineral Density (BMD) 
Bone mineral density, as measured by dual energy x-ray absorptiometry (DEXA) scan, remains 
the standard method of diagnosing osteoporosis and estimating osteoporotic fracture risk, defined 
as vertebral compression fractures or fractures after a fall from a standing height or less in the 
absence of other significant trauma.  In general, for each standard deviation decrease in BMD by 
DEXA scan, the risk of osteoporotic fracture doubles [40].  Prior studies have shown that 
continuous treatment with ADT decreases BMD. For example, in a prior study of 65 men who 
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had proximal femur BMD measured at baseline and again after 12 months of ADT with LHRHa 
therapy, the mean BMD decreased by 1.9 ± 2.7% (p < 0.001) [41], demonstrating that even 
1 year of ADT can adversely affect BMD. In addition, patients on ADT appear to be at increased 
risk for osteoporotic fracture.  In a prior retrospective cohort study of the 50,613 men who were 
listed in the linked database of the Surveillance, Epidemiology, and End Results program and 
Medicare as having received a diagnosis of prostate cancer in the period from 1992 through 
1997, of those men surviving at least 5 years after diagnosis, 19.4% of those receiving ADT 
sustained a fracture, compared with 12.6% of those not receiving ADT (p< 0.001) [42]. 
Measuring changes in BMD may serve as an intermediate, exploratory endpoint for a therapeutic 
agent tested in the BCR disease population.  Favorable results with respect to better preservation 
of BMD over time compared to traditional ADT would then serve as the basis for larger trials 
with longer follow up using a more definitive endpoint such as incidence of osteoporotic 
fractures.  
1.6 OVERALL STUDY RATIONALE 
Prostate cancer patients with BCR, and a PSADT of 12 months or lower represent a subset of 
patients at significant risk for the development of metastases and prostate cancer-specific 
mortality.  In general, ADT is an appropriate approach for these patients, but carries risks of its 
own, including a potential impact on QOL, and the potential for clinically significant metabolic 
derangements.  Consequently, new strategies that can mitigate these adverse effects represent an 
important unmet need.  Two potential strategies in this group of patients are a) to utilize a highly 
active second generation androgen receptor (AR) inhibitor as monotherapy and b) to add a highly 
active second generation AR inhibitor to conventional LHRHa IADT.  The first approach is 
predicated on the expectation that AR inhibitor monotherapy will have fewer adverse events, 
while the second approach is based on the expectation that more effective combination therapy 
will result in greater anti-cancer activity, and consequently, after a finite period of therapy, allow 
a longer period of time off ADT (and hence improved QOL) as part of an intermittent ADT 
approach. 
The proposed clinical trial will study the effects of 12 months of therapy with ARN-509 alone, or 
in combination with an LHRHa, each compared with LHRHa alone, in men with a rapidly rising 
serum PSA after prior definitive local therapy for prostate cancer.  Endpoints selected reflect 
measurable short term effects of ADT, including quality of life and several metabolic 
parameters.  In addition, the relative effect of each treatment strategy on PSA suppression as well 
as testosterone recovery (and subsequent PSA progression) after 12 months of therapy will be 
evaluated.  Favorable results suggesting an improvement in QOL for either strategy will provide 
justification for larger definitive trials of second generation AR inhibitors as a treatment 
alternative or addition to LHRHa therapy in the BCR disease population. 
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2 HYPOTHESIS AND STUDY OBJECTIVES 
2.1 HYPOTHESIS #1:  
For men with non-metastatic, non-castrate prostate cancer who have rapidly rising PSA levels 
after definitive local therapy, treatment with 12 months of ARN-509 monotherapy compared 
with 12 months of ADT in the form of LHRHa monotherapy will result in better preservation of 
QOL as measured by the FACT-P scale. Parallel and exploratory findings demonstrating 
comparable PSA suppression, and less negative impact on the metabolic profile (including 
measurements of fasting lipid profiles, insulin resistance, and bone mineral density) of subjects 
who receive ARN-509 monotherapy as opposed to therapy with an LHRHa would form the 
preliminary basis for further definitive study of ARN-509 monotherapy in biochemically 
relapsed prostate cancer. 
2.2 HYPOTHESIS #2:  
For men with non-metastatic, non-castrate prostate cancer who have rapidly rising PSA levels 
after definitive local therapy, treatment with 12 months of therapy with the combination of 
ARN-509 + LHRHa, compared with 12 months of therapy with LHRHa alone, will not be 
associated with a clinically significant worsening of QOL as measured by the FACT-P scale. 
Parallel, exploratory findings suggesting more durable PSA suppression coupled with adequate 
serum testosterone recovery, favorable PSA modulation with respect to PSA nadir and time to 
PSA progression, along with acceptable safety data, would form the preliminary basis for larger 
clinical trials testing the combination of ARN-509 plus LHRHa vs. LHRHa alone in the hormone 
sensitive prostate cancer disease setting. 
2.3 STUDY OBJECTIVES 
2.3.1 Primary Objectives 
• 
To compare the mean change from baseline in QOL as measured by total FACT-P score 
over a period of 12 months of therapy with ARN-509 monotherapy vs. LHRHa 
monotherapy in men with BCR to test for superiority with ARN-509 monotherapy. 
• 
To compare the mean change from baseline in QOL as measured by total FACT-P score 
over a period of 12 months of therapy with ARN-509 + LHRHa vs. LHRHa monotherapy in 
men with BCR to test for non-inferiority with ARN-509 + LHRHa. 
2.3.2 Secondary Objectives 
• 
To compare (a) ARN-509 monotherapy vs. LHRHa monotherapy and (b) ARN-509 + 
LHRHa vs. LHRHa monotherapy with regards to change over time in QOL as measured by 
other QOL measurements. 
• 
To compare (a) ARN-509 monotherapy vs. LHRHa monotherapy and (b) ARN-509 + 
LHRHa vs. LHRHa monotherapy with regards to PSA modulation. 
• 
To compare (a) ARN-509 monotherapy vs. LHRHa monotherapy and (b) ARN-509 + 
LHRHa vs. LHRHa monotherapy with regards to metabolic and hormonal effects. 
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• 
To characterize the safety profile of ARN-509 monotherapy and in combination with 
LHRHa. 
• 
Biomarker analyses will be conducted on formalin-fixed paraffin-embedded (FFPE) blocks 
or slides, plasma, and whole blood samples collected from consented subjects to assess 
ARF876L mutation and other resistance markers from all 3 treatment groups.  
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3 STUDY DESIGN  
3.1 OVERALL STUDY CHARACTERISTICS 
This is a Phase 2, randomized, open-label 3-arm multicenter study evaluating 12 months of 
treatment with an LHRHa monotherapy, ARN-509 monotherapy, or the combination in men with 
non-metastatic biochemically relapsed prostate cancer with rapidly increasing PSA levels after 
prior definitive therapy for localized prostate cancer.  The two experimental arms (ARN-509 
monotherapy; ARN-509 + LHRHa) will each be compared with a control arm of standard 
androgen deprivation (LHRHa monotherapy).  Subjects will be stratified by PSADT (< 6 months 
vs. 6-12 months) and age (≤ 70 vs. greater than 70) and randomized with equal probability (1:1:1 
ratio) from within each of the four strata to one of the 3 study arms.  
There will be 2 treatment periods of 12 months each (24 months): 
(1) On-therapy Period lasting 12 months, during which time subjects receive randomly 
assigned protocol therapy 
(2) Off-therapy Observation Period from months 13 through 24  
Subjects who develop progressive disease (either by serum PSA or radiographic progression) at 
any time during the 2 study periods will be removed from the study and will be treated as per 
individual investigator discretion. Subjects who discontinue before completion of the On-therapy 
Period in the absence of progressive disease will enter the Off-therapy Observation Period of the 
study.  If subjects do not have evidence of PSA or radiographic progression at the end of 24 
months, they will remain on study, enter a Follow-up Period, and be followed until PSA or 
radiographic progression or initiation of non-protocol therapy. Non-protocol therapy is defined 
as re-initiation of hormonal therapy or initiation of other anti-cancer therapy.  The total study 
duration is 6 years from the date of first subject enrolled once the Off-therapy Observation 
Period has been completed. Subjects in the Follow-up Period will be discontinued at the time of 
the final clinical cutoff as described in Section 11.2.2. 
3.2 STUDY ENDPOINTS 
3.2.1 Primary Endpoint: 
The mean change from baseline in total FACT-P score at 12 months  
3.2.2 Secondary Endpoints: 
A) Quality of Life:  
 Mean change from baseline in total FACT-P score over time 
 Mean change from baseline in EORTC QLQ-C30/PR25 score over time 
 Mean change from baseline in SHIM score over time 
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B) PSA Modulation: 
 Time to PSA progression. PSA progression will be defined as a rise to greater than 50% 
of the baseline serum PSA or rise of 2 ng/mL or more above the nadir, whichever is 
higher, confirmed by repeat measurement at least 2 weeks later. 
 Proportion of subjects without evidence of PSA or radiographic progression during the 
24-month treatment period and with recovery of serum testosterone at 24 months. 
Testosterone recovery will be defined as a serum testosterone > 150 ng/dL 
 Proportion of subjects with a PSA less than 0.2 ng/mL after 7 months of protocol therapy 
C) Metabolic and Hormonal 
 Mean change from baseline in markers of insulin resistance (including body mass index, 
fasting glucose/insulin, and hemoglobin A1C), fasting lipid profile, and bone mineral 
density as measured at the femoral neck, and lumbar spine by DEXA scan over time  
 For subjects randomized to the LHRHa-based treatment arms: the time to testosterone 
recovery to greater than 50 ng/dL (non-castrate) and > 150 ng/dL during the Off-therapy 
Observation Period 
 The mean change from baseline in serum DHT and estradiol levels over time 
D) Safety: 
 Incidence and severity of adverse events. 
 Abnormal findings in physical exams and laboratory tests 
E) Correlative Studies 
• 
Frequency of subjects emerging with ARF876L mutation at the end of treatment and 
progression.  
• 
Frequency of subjects expressing various RNA markers previously demonstrated 
to confer resistance ARN-509 at baseline, end of treatment, and progression 
  
 
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3.3 STUDY SCHEMA 
 
3.4 STUDY TIMELINES 
3.4.1 Primary Completion: 
With estimated accrual duration of 12 months, the data-cutoff for analysis of primary and 
secondary endpoints will be at 36 months from the time the study opens to accrual. 
3.4.2 Study Completion: 
The study is estimated to reach completion 5 years from the time the study opens to accrual.  
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4 STUDY POPULATION 
4.1 STUDY POPULATION 
Ninety men, with a rising serum PSA after prior definitive therapy including radical 
prostatectomy or radiation therapy with curative intent, who have a PSADT ≤12 months, will be 
enrolled across multiple academic centers in the United States. 
4.2 INCLUSION CRITERIA 
1. Histologic confirmation of adenocarcinoma of the prostate 
2. Rising PSA after prior definitive therapy for localized prostate cancer, including radical 
prostatectomy, external beam radiation therapy, brachytherapy, or combination of radical 
prostatectomy and radiotherapy  
3. Prior primary or salvage radiation or not a candidate for localized salvage radiation due to 
subject preference or clinical assessment based upon disease characteristics and/or 
subject co-morbidities. 
4. Minimum PSA: 
o 1.0 ng/mL if prior radical prostatectomy with or without adjuvant or salvage 
radiation 
o Nadir plus 2.0 ng/mL if prior definitive radiation therapy alone without prior 
radical prostatectomy  
5. Criterion modified per amendment 
o 5.1 PSADT of less than or equal to 12 months: 
 PSADT calculation must include all recorded PSA values over the past 
6 months prior to randomization, with a minimum of 3 values spaced at 
least 2 weeks apart, with each included value preferably measured at the 
same laboratory. PSA values obtained prior to localized therapy will be 
excluded. 
 The calculation of PSADT is based on the natural log of PSA. 
 Actual calculation of the PSADT can be obtained from the following 
online calculator: 
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx 
6. Criterion modified per amendment 
o 6.1 Criterion modified per amendment 
o 6.2 No evidence of metastatic disease on imaging by whole body bone scan and 
CT or MRI of the abdomen/pelvis within 6 weeks prior to randomization   
 Abdominal or pelvic lymph nodes measuring ≤2 cm in short axis are 
allowed. 
7. Serum testosterone level ≥150 ng/dL 
8. Criterion modified per amendment 
o 8.1 Criterion modified per amendment 
o 8.2 Prior ADT allowed if last dose was >6 months prior to randomization  
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9. Laboratory criteria include WBC > 3,000/mm³, hemoglobin > 7.0 g/dL, platelets 
> 70,000/mm³, total bilirubin < 2.0 mg/dL, AST less than 2.5 times the upper limit of 
normal 
10.  Criterion modified per amendment  
o 10.1 QTc ≤480 msec  
11. Estimated life expectancy >5 years 
12. ECOG performance status of 0 or 1 
13. Criterion modified per amendment 
o 13.1 Age ≥18 years 
14. Ability to sign written informed consent 
15. Criterion modified per amendment  
o 15.1 Ability to swallow study drug whole as a tablet 
16. Criterion modified per amendment 
o 16.1 Prior chemotherapy is allowed only in the (neo) adjuvant setting, and if last 
dose was >6 months prior to randomization 
17. Criterion modified per amendment 
o 17.1 To avoid risk of drug exposure through the ejaculate (even men with 
vasectomies), subjects must use a condom during sexual activity while on study 
drug and for 3 months following the last dose of study drug. Donation of sperm is 
not allowed while on study drug and for 3 months following the last dose of study 
drug. 
4.3 EXCLUSION CRITERIA 
1. Criterion modified per amendment 
o 1.1 Criterion modified per amendment 
o 1.2 Use of 5-alpha reductase antagonist (ie, finasteride, dutasteride) within 
6 weeks prior to randomization 
2. Criterion modified per amendment 
o 2.1 Criterion modified per amendment 
o 2.2 Use of antiandrogen (eg, flutamide, nilutamide, bicalutamide) within 6 weeks 
prior to randomization  
3. Prior bilateral orchiectomy 
4. Criterion modified per amendment 
o 4.1 Criterion modified per amendment 
o 4.2 Prior treatment with ADT for biochemically relapsed prostate cancer. Prior 
ADT as neo-adjuvant, concurrent, and/or adjuvant treatment following salvage 
radiation therapy or prostatectomy for biochemically relapsed disease is allowed 
provided last dose of ADT is >6 months prior to randomization and the screening 
serum testosterone level is ≥150 ng/dL.  
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5. Criterion modified per amendment 
o 5.1 Use of systemic steroids at an equivalent dose of prednisone 5 mg/day or 
higher at randomization 
6. Criterion modified per amendment 
o 6.1 Use of other medications that are known to potentially lower serum PSA (ie, 
herbal medicines, nutritional supplements) within 6 weeks prior to randomization  
7. Criterion modified per amendment  
o 7.1 Use of investigational agent within 6 weeks prior to randomization 
8. Criterion modified per amendment 
o 8.1 Criterion modified per amendment 
o 8.2 Prior use of bone modifying agent(s) within 3 months prior to randomization  
9.  Any history of seizures or medical condition, which lowers seizure threshold 
10. Prior pathologic findings consistent with small cell carcinoma, transitional cell 
carcinoma, or prostate cancer with neuroendocrine features 
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5 PROHIBITIONS AND RESTRICTIONS 
During study treatment, the following prohibitions and restrictions apply: 
If the subject is engaged in sexual activity with a woman of childbearing potential, a condom is 
required along with another effective contraceptive method consistent with local regulations 
regarding the use of birth control methods for subjects participating in clinical studies and their 
partners. Highly effective forms of contraception include:  
 established use of oral, injected or implanted hormonal methods of contraception; 
placement of an intrauterine device (IUD) or intrauterine (IUS) system; 
 barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository; 
 vasectomy; 
 true abstinence (an option when this is in line with the preferred and usual lifestyle of the 
subject). 
These restrictions must continue during treatment with study drug and for 3 months after the last 
dose of study drug.  
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6 STUDY RATIONALE  
6.1 RATIONALE FOR THE STUDY POPULATION 
Subjects with a PSADT of less than or equal to 12 months will be enrolled in an attempt to 
include as many subjects as possible while insuring that included subjects remain at sufficiently 
high risk to warrant ADT.  Subjects will be stratified by PSADT of < 6 months vs. 6-12 months, 
as those with PSADT < 6 months have a shorter time to progression in prior studies [5].  
Subjects will be additionally stratified by age (≤ 70 vs. > 70 at the time of study enrollment), as 
older age is associated with a longer time to testosterone recovery after cessation of ADT.  The 
minimum PSA required for study entry follows commonly used guidelines to define biochemical 
recurrence while also allowing for accurate measurement of PSADT (greater than 1.0 ng/mL 
post-RP and nadir + 2 ng/mL post-RT) [43]. 
Prior ADT used in combination with RT will be permitted, as neoadjuvant, concurrent and 
adjuvant ADT is the standard of care for high-risk localized prostate cancer patients undergoing 
definitive radiation therapy.  Prior ADT used in the context of RT will be permitted, provided the 
last effective ADT was > 6 months prior to randomization, and if serum testosterone has 
recovered to > 150 ng/dL prior to randomization.  Due to relatively small sample size per study 
arm, PSADT and age will be the 2 stratification factors.  Nevertheless, prior hormonal therapy 
will be a demographic variable compared between study arms.  Time from definitive therapy to 
biochemical relapse, as well as Gleason grade at the time of diagnosis are 2 other validated 
prognostic factors in BCR patients, which will also be measured at baseline and compared 
between study arms [44, 45]. 
6.2 RATIONALE FOR TREATMENT ARMS  
6.2.1 LHRHa Monotherapy as Control Arm 
There is no universally accepted standard of care for patients with BCR and short PSADT.  
While randomized trials demonstrating an overall survival benefit of early vs. deferred ADT are 
lacking, treatment with an LHRHa is a commonly used practice.  The decision to add a short 
course or prolonged treatment with a first generation antiandrogen such as bicalutamide to the 
LHRHa is quite variable across clinical practice, with no randomized data available to guide 
decision-making.  In the metastatic setting, a first generation antiandrogen is often added 
concurrently or prior to initiation of ADT, to prevent a testosterone “flare” with initiation of 
ADT which can worsen pain and other symptoms from transient growth of cancer metastases.  
For this study population, with an absence of radiographically detectable metastases, this is less 
of a concern.  Treatment with LHRHa monotherapy without a short course of a first generation 
antiandrogen is an acceptable treatment approach and will therefore be used as the shared control 
arm in this study.  LHRH antagonists will not be permitted, as their relative efficacy in this 
setting is largely untested, and would introduce a potential confounder given the difference in 
rates of testosterone and PSA decline upon treatment initiation with this agent as compared with 
LHRH agonist therapy [46]. 
6.2.2 ARN-509 Monotherapy  
Prior trials of monotherapy with a first generation AR inhibitor, bicalutamide, suggest that 
relative to LHRH therapy this approach may improve bone density, reduce the increase in fat 
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mass and diminish fatigue, loss of sexual interest and vasomotor flushing [29].  The question of 
whether 12 months of monotherapy with a highly potent, second generation, pure AR antagonist 
such as ARN-509, when compared with standard LHRHa therapy, can better preserve QOL, 
lessen impact on metabolic parameters such as fasting lipid profile, bone mineral density, and 
insulin resistance, while demonstrating comparable clinical efficacy with respect to changes in 
serum PSA has not previously been tested.  In addition to preclinical data demonstrating the 
superiority of second generation AR antagonists, the clinical non-cross resistance of second 
generation AR antagonists with first generation AR antagonists provides a strong rationale to test 
these agents in this setting.  Results from the proposed study, if favorable, would form the basis 
and justification for larger trials comparing ARN-509 monotherapy to ADT in BCR prostate 
cancer with both efficacy and safety/QOL endpoints. 
6.2.3 ARN-509 + LHRHa  
The combination of a second generation antiandrogen with an LHRHa has not previously been 
tested in BCR prostate cancer patients.  The proposed study will test the hypothesis that the 
addition of ARN-509 to an LHRHa will not be associated with a clinically significant worsening 
of QOL compared with the LHRHa alone as measured by the FACT-P scale after 12 months of 
treatment.  The addition of a highly potent, pure AR antagonist to standard LHRHa therapy will 
also generate preliminary data assessing whether treatment with the combination for a finite 
period of time (12 months), in a low tumor burden, non-AR amplified disease state, results in 
greater anti-cancer activity (as demonstrated by more durable PSA suppression), and 
consequently, allows a longer period of time off therapy.  As discussed below, parallel, 
exploratory studies will compare the kinetics of testosterone recovery and PSA modulation.  
Findings suggesting adequate serum testosterone recovery, favorable PSA kinetics, along with 
acceptable QOL and safety data, would form the preliminary basis for larger clinical trials testing 
the combination of ARN-509 plus LHRHa vs. LHRHa alone.  
6.3 RATIONALE FOR STUDY TREATMENT SCHEDULE 
The study design utilizes the backbone of an intermittent therapy approach. Intermittent 
androgen deprivation therapy (IADT) has become an acceptable method of minimizing the 
toxicity of long term continuous ADT. IADT programs generally refer to “cycles” of treatment, 
with each cycle being comprised of an On -therapy Period followed by an Off-therapy 
Observation Period. In previously published IADT studies, in general, the initial induction 
On-therapy Period ranged between 8-12 months [47, 48].  The Off-therapy Observation Period is 
generally driven by PSA, with re-institution of ADT at a pre-determined PSA level.  The first 
Off-therapy Observation Period can often equal or even exceed 12 months; however subsequent 
off-therapy intervals tend to become progressively shorter with each successive cycle of 
intermittent therapy [47-49].  Numerous Phase 2 and 3 trials comparing IADT to continuous 
ADT, though not adequately powered for non-inferiority, have shown comparable overall and 
prostate-cancer specific survival and improved QOL [22-25].  As discussed above, more 
recently, a randomized Phase 3, non-inferiority trial of continuous vs. intermittent ADT in 
1,386 patients with BCR after prior definitive radiation treatment was conducted by the NCIC.  
There was no difference in overall survival after a median follow up of 6.9 years (HR = 1.02, 
95% CI:  0.86, 1.21) and significantly better QOL with IADT [26].  The results of this trial 
provide further justification for the use of intermittent therapy in the trial design of the current 
study protocol. 
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The study plan for the proposed protocol consists of 2 periods.  The first period is the On-therapy 
Period consisting of 12 months of randomly assigned protocol therapy to 1 of the 3 treatment 
arms.  After 12 months of protocol therapy, if there is no evidence of PSA or radiographic 
progression, subjects will enter the Off-therapy Observation Period where they are followed by 
serial clinic visits and serum PSA and testosterone measurements without initiation of any 
subsequent therapy until the time of PSA or other progression. Data obtained from this clinical 
trial will form the basis of a larger, randomized Phase 3 trial that follows subjects through 
multiple periods of therapy. 
6.4 RATIONALE FOR THE SELECTION OF STUDY EVALUATIONS 
6.4.1 Primary Endpoint 
The FACT-P scale has been chosen as the primary measure of QOL based on its prior validation 
and widespread use in clinical trials of men with advanced prostate cancer [33].  The generalized 
FACT-G scale together with the prostate cancer subscale contain items which encompass the 
clinical experience of men with prostate cancer, including general items addressing fatigue, side 
effects from therapy, physical function, emotional well-being, as well as those more specific to 
prostate cancer patients such as erectile dysfunction [see Appendix 1].  
6.4.2 Secondary Endpoints 
A number of additional endpoints will be evaluated to assess the overall impact of the assigned 
therapy.  These endpoints fall under 3 categories: 1) further measures of QOL, 2) metabolic 
markers, including bone mineral density, and 3) PSA modulation and hormone levels. 
6.4.2.1 
Other QOL Endpoints 
Other QOL instruments will be administered and will be used to complement the FACT-P scale.  
The EORTC QLQ-C30, along with the prostate cancer subscale EORTC QLQ-PR25, are 
validated scales that have been used widely in prior trials of prostate cancer patients across a 
spectrum of disease stages [34, 35].  Specifically, the EORTC QLQ-PR25 contains multiple 
items pertaining to the use of ADT, including development of hot flushes, fatigue, weight gain, 
decreased libido, painful gynecomastia, and decreased sexual function [see Appendix 2], and 
thus can serve as a particularly useful measure of QOL during hormonal therapy for prostate 
cancer. Additionally, the SHIM scale will be used to assess sexual function, as erectile 
dysfunction can often be among the most troubling side effects of androgen deprivation therapy 
and therefore have a significant impact on QOL and tolerability of treatment [see Appendix 3]. 
6.4.2.2 
Metabolic Markers 
Although the proposed study is not designed to detect differences in study arms in the incidence 
of diabetes, cardiovascular events, or osteoporotic fractures, risk factors for these conditions will 
be measured on a regular basis during protocol therapy.  These include intermediate markers of 
insulin resistance, including fasting serum glucose and insulin, body mass index, and 
hemoglobin A1C, fasting lipid panel, as well as bone mineral density as measured by DEXA 
scan. 
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6.4.2.3 
PSA Modulation and Hormone Levels 
The extent to which a therapeutic intervention modulates PSA levels has not been extensively 
evaluated as an intermediate marker of outcome in patients with BCR prostate cancer.  In the 
proposed trial, three different aspects of PSA modulation will be evaluated: PSA nadir level, 
time to PSA progression, and PSA non-progression in the face of normal testosterone levels.  In 
addition, the effect of the therapeutic interventions on relevant hormonal levels such as 
testosterone, DHT and estradiol will be evaluated. 
PSA Nadir: In a prior clinical trial of men with metastatic hormone sensitive prostate cancer, 
after 7 months of induction ADT, men with a nadir PSA level of less than 0.2 ng/mL vs. 0.2 thru 
4.0 vs. > 4.0 had a progressively shorter overall survival, declining from a median of 75 to 44 to 
13 months, respectively [52].  Further, recommendations for trial design in BCR disease by the 
PSA Working Group [50] suggest that PSA decline can form the basis for larger trials using 
primary endpoints such as metastasis-free or overall survival.  Whether the PSA nadir data 
observed in patients with metastatic disease is relevant to patients with BCR is not known.  
Nevertheless, as an exploratory secondary endpoint, the proportion of men achieving a PSA 
nadir after 7 months of protocol therapy of less than 0.2 ng/mL will be measured in the proposed 
trial.  Validation of nadir PSA as a potential intermediate endpoint of metastasis-free or overall 
survival, however, will require confirmation in large prospective trials in this disease setting. 
Time to PSA Progression: There is no consensus or standardized definition of PSA progression 
in the BCR disease setting. Various PSA thresholds have been used as a “trigger” to initiate 
treatment in prior trials of IADT, ranging from < 1.0 ng/mL to 20 ng/mL [47].  The recently 
reported NCIC-PR7 international trial of continuous vs. intermittent ADT used a PSA threshold 
of 10 ng/mL to restart ADT in the intermittent treatment arm [26], although this relatively high 
PSA value would be unlikely to be accepted by patients in the United States, who are 
accustomed to taking action based on much lower PSA values. 
The PSA Working Group guidelines suggest that the mechanism of the investigative agent be 
taken into account when setting a PSA level to define recurrence [50].  For example, the addition 
of a cytotoxic chemotherapeutic agent to hormonal therapy, in which the treatment goal is to 
eradicate residual disease and achieve long term remission, any detectable PSA might be an 
appropriate level to define disease recurrence.  For hormonal therapy, particularly when 
intermittent therapy is being considered, efforts have been made to individualize the PSA at 
which therapy is re-initiated, in order to reflect the fact that there is a broad range of baseline 
PSA values at which patients are first treated.  Thus, in some IADT series, PSA recurrence has 
been defined as a rise in serum PSA to more than 50% of baseline level [51].  In patients 
previously treated with RT, progression has been defined as a serum PSA increase to greater than 
2 ng/mL above the serum PSA nadir, reflecting the ASTRO guidelines for defining biochemical 
recurrence after prior definitive RT for localized prostate cancer [43]. 
For the purposes of this study, PSA progression during either the On-therapy Period or 
Off-therapy Observation Period will be arbitrarily defined as an increase in serum PSA to 50% 
or greater compared with baseline, or an absolute increase in 2 ng/mL or more above the nadir, 
whichever is higher, confirmed by repeat serum PSA measurement at least 2 weeks later.  This 
definition in part draws on ASTRO guidelines defining biochemical recurrence after prior 
definitive radiation therapy, and in part reflects current clinical practice in which the patient’s 
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baseline serum PSA level prior to starting treatment is taken into account when making treatment 
decisions regarding the re-initiation of therapy during the observational phase of IADT.  The 
definition of PSA progression in the proposed trial, as in all trials of IADT to date, is arbitrary, 
but will be uniformly applied to all enrolled patients. 
The PSA working group has suggested that duration of clinical activity is a key intermediate 
endpoint in initial Phase 2 trials of agents conducted in the BCR disease population [50].  Indeed, 
in an exploratory analysis of a trial of IADT in BCR patients, Yu and colleagues demonstrated 
that in patients who completed the first cycle of IADT, a shorter duration of the first “off 
treatment” interval was associated with a shorter time to developing castrate resistant prostate 
cancer and shorter overall survival [53].  In the proposed trial, the time to PSA progression from 
the initiation of protocol therapy (ie, Day 1 of On-therapy Period) will be evaluated for each of 
the 3 treatment arms.  This analysis is exploratory in nature, both because the definition of “PSA 
progression” and the consequent resumption of therapy on an intermittent program is arbitrary, 
and because this endpoint requires a sufficient number of patients and duration of follow-up to 
record enough PSA progression events to have adequate statistical power to detect a difference 
between study arms. Nevertheless, data suggesting that the time to PSA progression was similar 
with ARN-509 monotherapy or with LHRHa monotherapy, or alternatively, suggesting a longer 
time to PSA progression when ARN-509 was added to LHRHa monotherapy would be 
provocative, and serve as the potential basis for launching a more definitive Phase 3 trial. 
PSA Suppression with Normal Testosterone Levels: In BCR prostate cancer patients, minimizing 
toxicity while preserving clinical efficacy is a central goal of treatment.  Much of the toxicity of 
ADT results from its induction of a hypogonadal state.  Treatment alternatives to continuous 
ADT, such as IADT, seek to minimize decrements in quality of life and metabolic parameters 
induced by medical castration by increasing the percentage of time that patients spend in a 
eugonadal state.  Thus, preservation of, or a return to, normal testosterone level, while 
maintaining a durable effect on serum PSA, is a potentially clinically relevant endpoint that 
could be measured utilizing the proposed study design, which incorporates intermittent therapy.  
In the proposed trial, this is an exploratory endpoint, since cessation of therapy does not 
necessarily equate to a return to eugonadal state, and there is a considerable variability in the 
time to serum testosterone recovery in prior studies of short-term ADT or IADT.  For example, 
in a randomized trial of IADT with 6 months of induction ADT followed by randomization to 
either thalidomide vs. placebo, Gulley and colleagues demonstrated that the median time to low 
testosterone (defined as > 50, but < 212 ng/dL) or normal testosterone (defined as > 212 ng/dL) 
recovery was 12.9 and 16.6 weeks, respectively [54].  However, there was considerable 
variability with some patients taking up to 40 weeks to achieve a testosterone level > 50 ng/dL.  
Advanced age and low baseline serum testosterone level (< 212 ng/dL) were associated with a 
delay in time to testosterone recovery in this study.  Twenty percent of men older than 66 years 
did not achieve normal testosterone levels by 44 weeks after cessation of ADT.  In another report 
by Pickles and colleagues, in 267 patients treated with ADT for 3 months to 3 years in duration, 
the median time to testosterone recovery after cessation of ADT (defined as testosterone 
> 10 nmol/L or 288 ng/dL) was approximately 10 months [55].  Again there was considerable 
variability in the time to recovery; both older age and low baseline serum testosterone were 
associated with a longer time to testosterone recovery.  Despite these limitations, assessment of 
serum testosterone recovery is an important parameter to be measured in studies of BCR men 
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receiving novel treatments or treatment strategies that incorporate ADT into the study treatment 
plan. 
Thus, in the proposed study, the proportion of subjects who completed 24 months (12 months of 
treatment followed by 12 months of observation) and who have recovered serum testosterone to 
> 150 ng/dL while remaining PSA progression and metastasis-free will be calculated as an 
exploratory secondary endpoint.  Using a cutoff of serum testosterone greater than 150 ng/dL is 
acknowledged to be somewhat arbitrary, as prior clinical studies measuring the time to 
testosterone recovery have used a range of serum testosterone thresholds ranging from 
150-300 ng/dL.  Nevertheless, treatment strategies that achieve durable PSA suppression with a 
finite period of treatment, while either avoiding castration altogether or allowing serum 
testosterone recovery during Off-therapy Observation Period, would be worthy of further 
investigation in Phase 3 trials. 
Hormone Levels: The androgen receptor is activated by various androgenic ligands besides 
testosterone, including dihydrotestosterone (DHT), which is produced from testosterone by the 
enzyme 5-alpha reductase.  In hormone-sensitive prostate cancer patients treated with traditional 
ADT, serum levels of DHT decrease with treatment.  For example, in a prior study of 69 patients 
treated with ADT for a period of 6 months, serum DHT levels decreased by an average of 92.5% 
compared with pretreatment serum levels [56].  Furthermore, bicalutamide monotherapy 
increases serum concentrations of testosterone and estradiol [29]. Because estradiol plays an 
important role in skeletal homeostasis in normal men, this may be the mechanism by which 
bicalutamide monotherapy lacks the adverse skeletal effects of LHRHa.  A significant caveat, 
however, is that serum androgen levels may not reflect tissue hormone levels.  Indeed, in the 
previously mentioned study above, though serum DHT levels decreased by 93% after 6 months 
of ADT, tissue DHT levels decreased by only 75%, and there was only a weak correlation 
between serum and tissue DHT levels (r = 0.229; p = 0.025) [57]. Nevertheless, the ready 
availability of serum hormone levels and their potential utility as intermediate outcome markers 
warrants their assessment in an exploratory fashion. 
In summary, the proposed trial will evaluate the effects of 12 months of therapy with a highly 
potent AR inhibitor (ARN-509) alone, or in combination with an LHRHa, each compared with 
LHRHa alone on a number of short-term markers, including quality of life, metabolic 
parameters, and PSA modulation.  The anticipated results from this trial may provide 
justification for larger definitive trials of second generation AR inhibitors as a treatment 
alternative to LHRHa monotherapy in patients with BCR. 
6.4.2.4 
Correlative studies: Exploratory Biomarkers:  
• 
For consenting subjects, archived tumor samples FFPE blocks or slides will be collected 
any time after enrollment to gain understanding of biology and identify  markers 
associated with response or resistance to complete androgen annihilation compared with 
apalutamide or LHRH alone 
• 
For consenting subjects whole blood will be collected at baseline (predose on Day 1 of 
study treatment) and end of treatment or progression in PAXgene tubes for RNA testing 
for markers previously demonstrated to confer resistance to ARN-509 (see Section 7.1). 
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These include androgen receptor anomalies (eg: AR amplification, ARv3/7, and 
ARv567), AR axis genes, and other compensatory pathway markers. 
• 
Previous studies with metastatic CPRC subjects provide evidence that an acquired 
mutation in the androgen receptor (ARF876L) may be associated with resistance to 
ARN-509 treatment [60]. Plasma-based circulating DNA will be used to assess the 
presence of the ARF876L mutation at progression 
.
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7 STUDY ACTIVITIES 
7.1 STUDY SCHEDULE: ON- THERAPY PERIOD (DAY 1 – MONTH 12) 
 
Pre-Study1 
Day 11 
Therapy 
End of 
each 
month2 ,5 
 
End of 
Month 
33,5 
 
End of 
Month 63, 5 
 
End of 
Month 93, 5 
 
End of 
Month  
123, 5 
Progression Visit 
(PSA or  
radiographic) 
(if before End of 
Month 12)4 
LHRH agonist (in 2 of the 3 
treatment arms) 
 
 
X5 
X5 
 
 
 
 
 
 
ARN-509 (in 2 of the 
3 treatment arms) 
 
X5 
X5 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
History/Physical Exam6 
X 
X 
 
X 
 
 
 
 
X 
Safety Assessment7 
X7 
X 
 
X 
 
 
 
 
X 
Concomitant Medications 
 
 
 
X8 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight/BMI 
X 
X 
 
X 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
X 
 
 
 
 
X 
CT or MRI of abd/pelvis 
X9 
 
 
 
 
 
 
 
X9 
Whole body bone scan 
X9 
 
 
 
 
 
 
 
X9 
FACT-P, EORTC QLQ-C30/QLQ-
PR25, SHIM 
X 
 
 
 
X 
 
 
X 
X10 
DEXA scan (BMD measured at 
femoral neck and lumbar 
spine)11 
X12 
 
 
 
 
 
 
X 
X12 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
CBC w/diff and platelets 
X 
 
 
 
X 
X 
X 
X 
X 
ALT, AST, AlkP, total bilirubin 
X 
 
 
 
X 
X 
X 
X 
X 
TSH 
X 
 
 
 
X 
X 
X 
X 
X 
PSA13 
X 
X 
 
X 
 
 
 
 
X 
Fasting glucose, lipids, HgbA1C 
X 
 
 
 
X 
X 
X 
X 
X 
Serum testosterone, Estradiol, 
DHT, and fasting insulin 14 
X 
 
 
 
X 
X 
X 
X 
X 
Plasma/Serum/Urine for 
banking (optional)15 
 
X 
 
 
X 
X 
X 
X 
X 
PBMCs for banking (optional)15 
 
X 
 
 
 
 
 
 
 
Whole blood RNA testing 
(optional)16 
 
X 
 
 
 
 
 
X 
X 
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Pre-Study1 
Day 11 
Therapy 
End of 
each 
month2 ,5 
 
End of 
Month 
33,5 
 
End of 
Month 63, 5 
 
End of 
Month 93, 5 
 
End of 
Month  
123, 5 
Progression Visit 
(PSA or  
radiographic) 
(if before End of 
Month 12)4 
Plasma for biomarker testing 
(optional)17 
 
 
 
 
 
 
 
X 
X 
Archival FFPE tumor blocks 
or slides for biomarker 
assessments (optional) 
 
X18 
 
 
 
 
 
 
 
abd = abdomen; ALT = alanine aminotransferase; AST = aspartate aminotransferase; AlkP = alkaline phosphatase;; BMD = bone mineral density; BMI = body 
mass index; CBC = complete blood count; CT = computed tomography; DEXA = dual energy x-ray absorptiometry; DHT = dihydrotestosterone; ECOG = 
Eastern Cooperative Oncology Group; eCRF=electronic case report form; EORTC = European Organization for Research and Treatment of Cancer; 
FACT-P = Functional Assessment of Cancer Therapy-Prostate scale; FFPE=formalin-fixed paraffin-embedded; HgbA1C = hemoglobin A1C; ICF = informed 
consent form; LHRHa = luteinizing hormone releasing hormone agonist; MRI = magnetic resonance imaging; PBMCs = peripheral blood mononuclear cells; 
PSA = prostate-specific antigen; SHIM = Sexual Health Inventory of Men Index; TSH=thyroid stimulating hormone; 
 
1Pre-study assessments need to be completed within 14 days prior to randomization. Day 1 must occur within 5 calendar days of randomization.  
2Subjects who discontinue during the On-therapy Period in the absence of progressive disease will enter the Off-therapy Observation Period of the study (see 
schedule below). If at any time a subject initiates a non-protocol therapy, the subject will be removed from study and treated as per individual investigator 
discretion. 
3 In addition to the end of each month visit assessments. Window for all visits is during treatment is ±2 days. Window for laboratory assessments before study 
visits is -7 days. 
4 Complete these assessments if a subject develops PSA or radiographic progression before the end of Month 12. The subject will then be removed from study 
and treated as per individual investigator discretion  
5 Choice of LHRHa is per investigator’s discretion. The first dose of ARN-509 or LHRHa will be on Day 1. ARN-509 will be administered daily with or without 
food.  All subjects should be following a 28-day, 28-day, 35-day schedule for their monthly visit (i.e., the 1st post-Day 1 visit is scheduled for 28 days later, the 
2nd post-Day 1 visit is scheduled for 28+28 days later, the 3rd post-Day 1 visit is scheduled for 28+28+35 days later, the 4th post-Day 1 visit is scheduled for 
28+28+35+28 days later, etc).  If a subject does not receive a scheduled LHRHa injection within ±7 days of the scheduled due date for injection, he will be 
removed from study 
6 Physical exam changes will not be collected in the eCRF, any change in physical exam from baseline needs to be recorded on the adverse event page 
7 Adverse event collection starts from signing the ICF. For subjects who discontinue therapy and do not proceed to the Off-therapy Period, AEs must be recorded 
up to 30 days after the last dose of study medication.  
8 See Section 7.5.4.  
9 Scans need to be done within 6 weeks prior to randomization. At the Progression Visit, scans may be omitted if already done within the prior 1 month. 
10 At the Progression Visit, may be omitted if already done with the prior 1 month. 
11 For reference, see, https://www.shef.ac.uk/FRAX/tool.aspx?country=9. DEXA scan is also to be used for osteoporosis assessment. 
12 DEXA scan needs to be done within 12 weeks prior to randomization. At Progression Visit, scans may be omitted if already done within the prior 1 month. 
13 PSA laboratory evaluations should preferably be performed by the same laboratory using an ultrasensitive assay. Serum PSA sample on Day 1 should be taken 
predose.  
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14 See Appendix 6 for details on collection, processing, and shipping of peripheral blood samples collected for measurement of testosterone, DHT, estradiol, and 
fasting insulin. 
15 The banking of plasma, serum, urine, and PBMCs is optional (see Appendix 6 for collection, processing, and shipping instructions). Samples should be 
collected predose on Day 1.  
16 Whole blood to be collected in PAXgene tubes (2.5 ml) (optional) (see Appendix 6 for collection, processing, and shipping instructions). Samples should be 
collected predose on Day 1. 
17 Plasma to be collected in EDTA tubes (10 mL) (optional) (see Appendix 6 for collection, processing, and shipping instructions).  
18The FFPE tumor blocks or slides may be collected anytime during or after enrollment. 
 
 
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7.2 STUDY SCHEDULE: OFF-THERAPY OBSERVATION PERIOD 
(MONTHS 13-24) AND FOLLOW-UP PERIOD (MONTH 25+) 
 
End of every 
2 months 
End of  
Month 182 
End of 
Month 242 
Progression 
Visit (PSA or 
radiographic) 
(if occurs 
before  
End of  
Month 24) 
Follow-up 
Period 
(Month 25+)3 
History/Physical 
Exam1 
X 
 
 
X 
X 
Safety Assessment 
X 
 
 
X 
 
Weight/BMI 
X 
 
 
 
 
CT or MRI 
abd/pelvis 
 
 
 
X 
 
Whole body bone 
scan 
 
 
 
X 
 
FACT-P, EORTC 
QLQ-C30/PR25, 
SHIM 
 
 
X 
X6 
 
PSA4 
X 
 
 
X 
X 
Serum 
testosterone5 
X 
 
 
X 
X 
Fasting glucose, 
lipids, serum 
insulin5, HbA1C 
 
X 
X 
X 
 
Whole blood RNA 
testing (optional)5 
 
 
 
X 
X7 
Plasma for 
biomarker testing 
(optional)5 
 
 
 
X 
X7 
abd = abdomen; BMI = body mass index; CT = computed tomography; eCRF=electronic case report form; 
EORTC = European Organization for Research and Treatment of Cancer; FACT-P = Functional Assessment of 
Cancer Therapy-Prostate scale; HgbA1C = hemoglobin A1C; MRI = magnetic resonance imaging; PSA = prostate-
specific antigen; SHIM = Sexual Health Inventory of Men Index 
 
1 Physical exam changes will not be collected in eCRF, any change in physical exam from baseline needs to be 
recorded on the adverse event page.  
2 In addition to the end of every 2-month visit assessments, visit window is ±7 days.  
3 Visit to occur every 3 months (±7 days). Subjects who develop PSA or radiographic progression, or initiate 
non-protocol therapy will be removed from study and treated as per individual investigator discretion. 
4 Preferably measured at the same laboratory using an ultrasensitive assay.  
5 See Appendix 6 for details on collection, processing, and shipping of peripheral blood for measurement of 
testosterone, fasting insulin, plasma DNA, and whole blood for RNA testing.  
6 May be omitted if already done within the prior 1 month. 
7 If no progressive disease occurred during Month 1-24, whole blood RNA and plasma for biomarker testing only 
need to be collected during the Follow-up Period when progressive disease occurs. (see Appendix 6 for collection, 
processing and shipping instructions).  
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7.3 SCREENING PERIOD/PRE-STUDY EVALUATION 
All subjects must sign a written informed consent form before study specific-screening 
procedures are performed.  Screening procedures to evaluate subject eligibility will be conducted 
within 14 days prior to randomization. The measurements collected at screening will be 
considered the baseline values except for PSA. Serum PSA measurements at Day 1 will be 
considered as baseline for PSA endpoints. 
7.3.1 Clinical Assessments 
 Complete history and physical examination 
 Baseline demographics 
 Height, weight, body mass index  
 ECOG Performance Status (see Appendix 4) 
 FACT-P (see Appendix 1), EORTC QLQ-C30/EORTC QLQ-PR25 (see  
Appendix 2), and Sexual Health Inventory for Men (SHIM) (see Appendix 3)  
 Electrocardiogram 
7.3.2 Laboratory Assessments 
 Complete blood count including differential and platelet count 
 Total bilirubin, alkaline phosphatase, AST, ALT 
 Thyroid stimulating hormone (TSH) 
 Serum PSA level measured by ultrasensitive assay  
 Calculation of PSA doubling time, using all known PSA levels within the past 6 months 
including screening PSA level (but not Day 1 PSA).  There must be a minimum of 
3 values spaced at a minimum of 2 weeks apart, with each included value measured at the 
same laboratory (preferably). PSA values obtained prior to localized therapy will be 
excluded.  The PSA doubling time can be calculated from the website: 
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx 
 Fasting glucose, fasting lipid panel (total cholesterol, LDL, HDL, triglyceride), and 
hemoglobin A1C  
 Peripheral blood collection for measurement of serum testosterone, DHT, estradiol, and 
fasting serum insulin levels (see Appendix 6 for collection, processing, and shipping 
instructions). 
7.3.3 Radiographic Studies  
Once the subject has given written informed consent and is eligible for the study as per the 
laboratory/clinical parameters outlined above, the following radiographic information will be 
collected.  
 Radionuclide bone scan  
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 Cross-sectional imaging of the abdomen and pelvis with IV contrast per investigator 
discretion (CT or MRI). Subjects who are intolerant of IV CT contrast agents may have 
CT scans performed with oral contrast or without any contrast, as long as method is 
identical each time new scans are done.  
 DEXA bone densitometry scan with measured bone mineral density at the femoral neck, 
and lumbar spine (see https://www.shef.ac.uk/FRAX/tool.aspx?country=9).   
Radionuclide bone scans and CT/MRI images must have been done within 6 weeks prior to 
randomization.  There will be no central reading of the scans and radiographic progression is 
based on investigator assessment. The DEXA bone densitometry scan must have been taken 
within 12 weeks prior to randomization. 
7.4 RANDOMIZATION: 
Once eligibility is confirmed, subjects will be stratified according to their pre-study PSADT 
(<6 months vs. 6 – 12 months) and age at study entry (≤ 70 vs. > 70).  They will be randomized 
with equal probability to 1 of the 3 treatment arms from within each of the 4 strata.  Balance in 
treatment assignment will be achieved using a randomized block design.  Randomization will be 
carried out via computer generated random assignment.  All subjects must commence treatment 
within (5 calendar days) of randomization.  Study sites will email the Eligibility Checklist to the 
sponsor in order to obtain the subject’s treatment assignment.  Once subject eligibility is 
confirmed by the sponsor, an email with the treatment assignment number will be provided to the 
study site.   
7.5 STUDY PERIOD I: ON-THERAPY PERIOD (MONTHS 1 TO 12) 
The 24-month study treatment period will be divided into two 12-month periods: the On-therapy 
Period during which subjects receive protocol therapy (ARN-509 monotherapy, ARN-509 + 
LHRHa, or LHRHa monotherapy).  Subjects will commence protocol therapy on Day 1 of the 
On-therapy Period. The study timeline is defined as Day 1 = first dose of study treatment. 
Subsequent study time points will be defined based on study calendar, irrespective of subsequent 
dose delays/interruptions (see Section 9 for discussion of dose delays due to toxicity). 
Subjects will be treated with protocol therapy for 12 months, or until disease progression (either 
by PSA or radiographic), unacceptable toxicity, subject/physician withdrawal, or initiation of 
non-protocol therapy.  PSA progression is defined as an increase in PSA to > 50% of the 
baseline value or an increase of > 2 ng/mL above the nadir, whichever is higher confirmed by 
repeat measurement at least 2 weeks later.  Radiographic progression is defined as the detection 
of new metastasis on either bone scan or cross-sectional imaging (CT or MRI) [61].  If subjects 
develop progressive disease (either by PSA or radiographic) while receiving protocol therapy, 
they will discontinue protocol therapy, have a Progression Visit, and be treated as per individual 
investigator discretion.   
If there is no evidence of disease progression (by serum PSA or radiographically) after 
12 months of protocol therapy or if subject discontinues treatment before 12 months of protocol 
therapy for reasons other than disease progression, subjects will enter the 12-month Off-therapy 
Observation Period. Continuation of hormone therapy or initiation of any form of anti-cancer 
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therapy in the absence of PSA or radiographic progression will be considered non-protocol 
therapy and will result in study removal. 
Efforts will be made to ensure that subjects who develop progressive disease before 12 months 
of therapy still complete QOL scales at 3 and 12 months. 
7.5.1 Day 1 of Study Treatment 
Subjects will return to study site for a history and physical exam including weight, measurement 
of serum PSA, and dispensing of study drug(s), including the first injection of LHRHa and 
1 month supply of ARN-509 for subjects randomized to those arms. Collection of optional 
samples (samples for banking, archival FFPE blocks or slides for transcriptome profiling 
(RNAseq), whole blood for RNA testing, and plasma for biomarker testing) should occur before 
predose.  
7.5.2 LHRH Agonist 
For subjects randomized to either the LHRHa monotherapy or the LHRHa + ARN-509 
combination treatment arms, the choice and schedule of LHRHa will be up to individual 
investigator’s discretion and will be administered for a total of 12 months of therapy in the 
absence of disease progression or unacceptable toxicity.  No change in dosing schedule of 
LHRHa will be permitted once the subject has commenced protocol therapy.  For example, the 
use of an every 3 month subcutaneously injected LHRHa would be administered on Day 1 and 
on Months 3, 6, and 9.  The use of LHRH antagonists (ie, degarelix) will not be permitted as 
outlined in Section 6.2.1. No dose reductions or interruptions of LHRHa will be permitted (see 
Section 9.3).  If a subject does not receive a scheduled LHRHa injection within ±7 days of the 
scheduled due date for injection, he will be removed from study.  Subjects on the LHRHa 
monotherapy arm will not be allowed to crossover to receive ARN-509. 
7.5.3 ARN-509 
Subjects randomized to either of the two ARN-509-containing arms will receive ARN-509 dosed 
orally on a daily basis with or without food. The starting dose of ARN-509 is 240 mg/day.  With 
Amendment 7 (Version 8.0), subjects who are receiving the softgel capsules will switch to the 
tablet formulation. Ongoing subjects on a reduced dose of capsules should continue with that 
dose with lowest allowed dose being 120 mg (see Section 8). Dose delays and dose reductions 
will be permitted as per guidelines outlined in Section 9.2.  
7.5.4 Concomitant Medications 
Concomitant medications will be recorded at each monthly clinic visit. Subjects are 
recommended to take calcium 1000 mg/day and vitamin D (cholecalciferol) 800 IU/day in 
divided doses.  Phosphodiesterase inhibitors such as sildenafil used to treat erectile dysfunction 
may be initiated or continued as per individual investigator discretion.  Breast irradiation and/or 
tamoxifen to prevent and/or treat painful gynecomastia will also be permitted per individual 
investigator discretion.  Subjects who require the initiation of bisphosphonate or other bone-
targeted therapy (eg, those sustaining an osteoporotic fracture) while on study will be permitted 
to do so and remain on study, but subjects who have used a bone-modifying agent within 
3 months prior to randomization will be excluded (see Section 4).  
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7.5.4.1 
Prohibited Medications 
No concomitant use of any anti-cancer therapy will be permitted.  This will include surgery, 
radiation therapy, and other secondary hormonal therapies including first generation 
antiandrogens, 5-alpha reductase inhibitors (i.e. finasteride, dutasteride), megestrol acetate, 
immunotherapy, chemotherapy, or other investigational agents while on study [see Appendix 5 
for list of prohibited treatments while on study]. Start of any of these therapies will result in 
discontinuation from the study, see Section 7.8. Nutritional supplements containing saw palmetto 
or pomegranate are also specifically prohibited.   
7.5.4.2 
ARN-509: Prohibited Medications: 
As a class effect, androgen receptor antagonists have been associated with seizures due to an 
off-target mechanism of action (GABAA inhibition).  To date, no subjects receiving ARN-509 
have experienced seizures, however, in preclinical experiments, at very high doses, dogs treated 
with ARN-509 had tremors and generalized seizures.  Subjects will be closely monitored for 
seizures, but as a precautionary measure, the following drugs known to decrease the seizure 
threshold or cause seizure will be prohibited. 
• Aminophylline, theophylline  
• Atypical anti-psychotic drugs: clozapine, olanzapine, ziprasidone, bupropion 
• Phenothiazine anti-psychotic drugs: chlorpromazine, mesoridazine, thioridazine 
• Tricyclic and tetracyclic anti-depressants: amitriptyline, desipramine, doxipine, 
imipramine, maprotiline, mirtazapine (Remeron) 
• Lithium 
• Meperidine (Demerol) and pethidine 
7.5.4.3 
ARN-509: Restricted Medications: 
If it is absolutely necessary for the well-being of the subject and alternative therapies are not 
available, these drugs should be used with caution and after discussion with Dr. Aggarwal and 
the Sponsor’s Medical Monitor.  The list of medications that are prohibited or restricted while 
taking ARN-509, is provided in Appendix 5.  
7.5.5 Safety Assessment 
Subjects will be assessed for adverse events at each monthly clinic visit during the On-therapy 
Period.  Adverse event collection starts with the signing of the ICF (see Section 7.1). Adverse 
events will be graded according to the National Cancer Institute (NCI)-Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03 (available at http://ctep.cancer.gov).  See 
Section 12.1.4 for attribution of adverse events.  Dose modifications (interruptions, reductions or 
both) for ARN-509, will be allowed as per guidelines outlined in Section 9.2.   
7.5.6 QOL 
The FACT-P, EORTC QLQ-C30/QLQ-PR25, and SHIM questionnaires will be completed at the 
end of Month 3 and Month 12 or at the time of PSA or radiographic progression (if occurs before 
Month 12, every effort will be made to obtain the 12-month questionnaires for those who 
discontinue before 12 months). 
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7.5.7 Laboratory Assessments 
Subjects who experience disease progression (PSA or radiographically) before the end of 
12 months should complete laboratory assessments at the Progression Visit as outlined in the 
Study Schedule. During treatment, laboratory assessments include the following:  
 Serum PSA level measured by ultrasensitive assay at the end of each month 
 Complete blood count including differential and platelet count at the end of Months 3, 6, 
9, and 12 of protocol therapy.  
 Total bilirubin, alkaline phosphatase, AST, ALT at the end of Months 3, 6, 9, and 12. 
 TSH at the end of Months 3, 6, 9, and 12. 
 Fasting glucose, fasting lipid panel (total cholesterol, LDL, HDL, triglyceride), and 
hemoglobin A1C at the end of Months 3, 6, 9, and 12.  
 Peripheral blood collection for measurement of serum testosterone, DHT, estradiol, and 
fasting serum insulin levels at the end of Months 3, 6, 9, and 12 ( see Appendix 6 for 
collection, processing, and shipping instructions).  
 Peripheral blood and urine collection for banking of, serum, plasma, and urine at the end 
of Months 3, 6, 9, and 12 of protocol therapy (optional). See Appendix 6 for procedures 
to ensure subject confidentiality and instructions on collection, processing, shipping of 
samples. 
 Whole blood collected for PAXgene analysis (optional) on Day 1 and end of Month 12  
7.5.8 Radiographic Assessments 
A whole body nuclear bone scan, along with cross-sectional imaging of the abdomen/pelvis (CT 
or MRI) will be obtained as prompted by signs and symptoms of metastatic disease and at the 
time of PSA progression.  DEXA scan measuring BMD at the femoral neck, and lumbar spine 
will be obtained after 12 months of protocol therapy or at the time of PSA or radiographic 
progression (if occurs before Month 12, see Progression Visit in Study Schedule).  
Subjects who are intolerant of IV CT contrast agents may have CT scans performed with oral 
contrast or without, as long as method is identical each time new scans are done. 
There will be no central reading of the scans and radiographic progression will be based upon 
investigator assessment. 
7.6 STUDY PERIOD II: OFF-THERAPY OBSERVATION PERIOD (MONTHS 
13 TO 24) 
Subjects without progressive disease (by PSA or radiographic) after 12 months of protocol 
therapy will stop protocol therapy and enter the Off-therapy Observation Period from Month 13 
to Month 24. Continuation of hormonal therapy or initiation of any other of anti-cancer therapy 
in the absence of PSA or radiographic progression will be considered non-protocol therapy and 
will result in study removal. Use of concomitant medications, which may affect serum PSA will 
not be permitted (see Section 7.5.4).  
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Subjects who develop either PSA or radiographic progression during the Off-therapy 
Observation Period will have a Progression Visit, and be treated as per individual investigator 
discretion.  Efforts will be made to ensure that subjects who develop progressive disease (PSA or 
radiographic) or discontinue in the absence of progressive disease before 24 months still 
complete QOL scales after 24 months as prespecified in the study protocol.  
7.6.1 Safety Assessment  
Subjects will be assessed for adverse events at clinic visits at the end of every 2 months during 
the Off-therapy Observation Period.  
7.6.2 QOL 
The FACT-P, EORTC QLQ-C30/QLQ-PR25, and SHIM questionnaires will be completed at the 
time of progression (PSA or radiographic) or after 24 months.  
7.6.3 Laboratory Assessments 
Subjects who experience disease progression (PSA or radiographic) before the end of 24 months 
should complete laboratory assessments at the Progression Visit as outlined in the Study 
Schedule. During the Off-therapy Follow up Period laboratory assessments include the 
following:  
 Serum PSA level at the end of every 2 months (see Section 10.6).  
 Peripheral blood collection for measurement of serum testosterone levels at the end of 
every 2 months (see Appendix 6 for collection, processing, and shipping instructions).  
 Fasting glucose, fasting lipid panel (total cholesterol, LDL, HDL, triglyceride), and 
hemoglobin A1C at the end of Months 18 and 24.  
 Peripheral blood collection for measurement of fasting serum insulin at the end of 
Months 18 and 24 (see Appendix 6).  
7.6.4 Radiographic Assessment 
A whole body nuclear bone scan, along with cross-sectional imaging of the abdomen/pelvis (CT 
or MRI; with IV contrast per individual investigator discretion), will be obtained as prompted by 
signs and symptoms of metastatic disease and at the time of PSA progression. 
Subjects who are intolerant of IV CT contrast agents may have CT scans performed with oral 
contrast or without, as long as method is identical each time new scans are done 
There will be no central reading of the scans and radiographic progression will be based upon 
investigator assessment. 
7.7 FOLLOW UP PERIOD (MONTH 25+) 
Subjects without progressive disease (PSA or radiographic) at end of 24 months will enter a 
Follow-up Period.  During this period, subjects will be followed by history and physical exam, 
serum PSA, and testosterone levels every 3 months.  Subjects who develop PSA or radiographic 
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progression, or initiate non-protocol therapy will be removed from study and treated as per 
individual investigator discretion. 
If no progressive disease occurred during Months 1 to 24 and it occurs during the Follow-up 
Period, whole blood RNA and plasma sample collections for biomarker testing should be 
collected from subjects who consented to this optional sample collection (see Section 7.2, 
Appendix 6).  
 
7.8 REASONS FOR STUDY DISCONTINUATION 
Subjects will discontinue study protocol treatment for the following reasons, whichever comes 
soonest: 
• PSA progression, defined as an increase in PSA to > 50% of the baseline value or an 
increase of > 2 ng/mL above the nadir, whichever is higher, confirmed by repeat 
measurement at least 2 weeks later.  
• Radiographic progression, defined as the detection of new metastasis on either bone 
scan or cross-sectional imaging (CT or MRI). 
• Subject or treating physician decision  
• Unacceptable toxicity  
• Non-protocol therapy  
Efforts will be made to ensure that subjects who discontinue in the absence of progressive 
disease (PSA or radiographic) enter the Off-therapy Observation Period or the Follow-up Period 
(see also Sections 7.5, 7.6 and 7.7).  
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8 STUDY DRUG INFORMATION 
8.1 ARN-509 
Drug Substance: ARN-509 drug substance is an almost white to slightly brown powder  
Chemical Name: (4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-
diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide) 
Molecular Formula:  C21H15F4N5O2S 
Molecular Weight:   477.44 
Formulation: The ARN-509 tablet supplied for this study contains 60 mg of JNJ-56021927. It 
will be manufactured and provided under the responsibility of the Sponsor. Refer to the 
Investigator's Brochure for a list of excipients.  
Packaging, Storage, and Labeling: The ARN-509 60-mg tablets will packaged in 120-count, 
160 cc high-density polyethylene (HDPE) bottles with child-resistant caps. Study drug labels will 
contain information to meet the applicable regulatory requirements 
Dose and Administration 
ARN-509 will be administered orally on a continuous daily dosing regimen at a dose of 240 mg 
per day (4 x 60-mg tablets) with or without food.   
The switch to tablets for subjects who are receiving softgel capsules will occur at the start of the 
next cycle (onsite visit). Each softgel capsule contains 30 mg of active drug, and each tablet 
contains 60 mg of active drug. The conversion from the softgel capsules to the tablet formulation 
is 2:1 (Table 1). 
 
Table 1 
Softgel Capsule to Tablet Conversion 
Dose 
Number of Softgel Capsules 
Number of Tablets 
240 mg 
8 
4 
180 mg 
6 
3 
120 mg 
4 
2 
Drug Supply: Study drug will be provided free of charge to subjects enrolled on this study by 
the company Sponsor.  ARN-509 is to be ordered directly from a designee indicated by the study 
Sponsor.  
Dispensing of Drug: Sufficient study drug for the next cycle of therapy will be provided to 
subjects randomized to one of the two ARN-509 treatment arms at each monthly study visit.  
Inventory and Control: The ARN-509 used for this study must be maintained under adequate 
security and stored in the pharmacy at the study site until dispensing or their destruction at each 
study site’s investigational pharmacy. Investigators may not supply study medication to any 
person not enrolled in this study or to any person not named as a sub-investigator. In addition, 
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the investigator must maintain an accurate, running inventory of all drug supplies received and 
dispensed during conduct of the study.  
Return of Clinical Supplies: Upon completion or termination of the study, all used and unused 
original study drug bottles, whether empty or containing study drug, should be destroyed at each 
study site’s investigational pharmacy (or site’s authorized destruction unit) following their 
site-specific procedure on drug destruction after the study Sponsor approves the drug destruction 
policy at the site. Any return shipments must provide proof of delivery, and will be accompanied 
by the Drug Accountability Form and a memo noting the number of bottles and quantity of study 
drug being returned in the site’s drug accountability records. Drug will not be returned to the 
Sponsor. 
8.2 LHRH AGONIST 
Choice of specific LHRHa to be used in this study will be per investigator discretion/site practice 
guidelines. Options include Eligard®, Lupron Depot®, Zoladex®, or Trelstar®.  Dosing schedule 
will be per individual investigator discretion. 
Route of Administration: The LHRHa injections will be delivered either subcutaneously 
(Eligard®, Zoladex®) or intramuscularly (Lupron Depot® or Trelstar®) by a trained health care 
provider while on protocol therapy. 
Drug Supply: The use of LHRHa in this disease setting is considered standard of care and as 
such will be billed to the subject’s medical insurance.  
Dispensing of Drug: Subjects will receive a LHRHa injection either subcutaneously or 
intramuscularly depending on the specific drug formulation. 
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9 DOSAGE MODIFICATIONS/TOXICITY 
9.1 TOXICITY 
Toxicities and Adverse Events will be assessed during each monthly clinic visit using the 
NCI-CTCAE Version 4.03.  Because CTEP has standardized the CTCAE, the NCI does not 
require the inclusion of the CTCAE within this protocol document.  However, all appropriate 
treatment areas will have access to a copy of the CTCAE Version 4.03. A copy can be 
downloaded from the CTEP home page: http://ctep.cancer.gov 
9.2 DOSE MODIFICATIONS FOR ARN-509 
Intrapatient dose interruptions or reductions will be permitted provided that study 
discontinuation criteria have not been met (Section 7.8). 
 Subjects experiencing seizure of any grade or Grade 4 neurotoxicity will have protocol 
therapy permanently discontinued. 
 For subjects experiencing Grades 1-2 treatment-related adverse events, short treatment 
breaks can be instituted as per the discretion of the Investigator until the severity of the 
toxicity decreases to Grade 1 or returns to baseline.  If toxicity recurs, dose reductions to 
the next lower dose level will be allowed as per the discretion of the Investigator. 
 For subjects experiencing Grade ≥ 3 treatment-related adverse events other than seizure, 
Grade 4 neurotoxicity or life threatening toxicity, study drug should be held until the 
severity of the toxicity decreases to Grade 1 or returns to baseline.  If toxicity recurs at 
Grade 3 or higher, the dose of ARN-509 should be reduced to the next lower dose level.  
A maximum of 2 dose level reductions will be allowed (Table 2). 
 Any subject requiring > 28 days delay in treatment due to AEs may meet one of the 
criteria for study treatment discontinuation (see Section 7.8), which must be discussed 
with Sponsor.   
 
Table 2 
ARN-509 Dose Levels 
Total Daily Dose 
Number of 60-mg Tablets (QD) 
240 mg 
4 
180 mg 
3 
120 mg 
2 
 
Doses reduced for study treatment-related toxicities should generally not be re-escalated, 
however, re-escalation back to the previous dose level may be permitted in consultation with the 
Sponsor.   
9.3 DOSE MODIFICATIONS FOR LHRHA 
There will be no mandated dose reductions or delays for LHRHa therapy due to adverse events 
that are typically attributed to ADT, including anemia, hot flashes, gynecomastia, fatigue, mood 
changes, decreased libido, erectile dysfunction, and weight gain.  Unanticipated adverse events 
that are not included in the above list, that the investigator attributes to LHRHa therapy will be 
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recorded, and if Grade 3 or higher in severity for a duration of more than 4 weeks, will lead to 
study discontinuation due to unacceptable toxicity and treatment as per individual investigator 
discretion.  
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10 ASSESSMENT OF INVESTIGATIONAL PRODUCT 
10.1 
FACT-P SCALE 
The FACT-P scale [version 4.0] is a well validated metric [33] developed by Cella and 
colleagues, which includes a 27-item “core” quality of life measure (FACT-G) grouped into 4 
subscales: physical well-being, social/family well-being, emotional well-being, and functional 
well-being.  There are an additional 12 items specific to prostate cancer; 10 of which are prostate 
cancer specific physical problems.  Items are rated on a 5-item Likert scale, from 0, “not at all”, 
to 4, “very much” (see Appendix 1).  The total range of scores is from 0 – 156.  Higher scores 
indicate higher degree of functioning and better quality of life. Internal consistency of the 
prostate cancer specific subscale ranged from 0.65 to 0.69, with coefficients for FACT-G 
subscales and aggregated scores ranging from 0.61 to 0.90.  Concurrent validity was confirmed 
by the ability to discriminate subjects by disease stage, performance status, and baseline prostate-
specific antigen (PSA) level.  Sensitivity to change in performance status and PSA score over a 
2-month period suggested that some subscales of the FACT-P are sensitive to meaningful 
clinical change [33].  Prior clinical trials have established that minimally important differences 
that are clinically significant and may impact treatment decisions range from 5 to 8 points 
depending on tumor subtype [57]. 
As per standard scoring guidelines for the FACT-P scale, if a subject does not answer specific 
items of from a subscale of the FACT-P, the weighted average of the remaining answered items 
will be used for scoring purposes, as long as > 50% of items are answered for that particular 
subscale.  If there are less than 50% of items answered in a given subscale, or less than 80% of 
items answered overall, the FACT-P score for that particular subject will be excluded from the 
statistical analysis.  
10.2 
EORTC QLQ-C30/QLQ-PR25 
The EORTC QLQ-C30 [version 3] is a well validated [34], and widely used measure of health-
related quality of life among cancer patients.  The EORTC QLQ-C30 consists of 30 items, which 
list the functioning and symptoms of cancer patients.  Five multi-item function scales are scored: 
physical function (PF), role function (RF), emotional function (EF), social function (SF), and 
global health status/quality of life.  Furthermore, nine single-item scales (symptoms) are scored, 
including fatigue, pain, dyspnea, and gastrointestinal problems.  The scales are, according to the 
EORTC guidelines, linearly transformed: all scales range from 0 to 100, in which a higher scale 
score represents a higher level of functioning.  With respect to the single-item scale, a higher 
score indicates more symptoms or problems; scores of these items will be inverted for the 
purposes of statistical analysis.  In addition, a subscale related to prostate cancer (EORTC QLQ-
PR25) will also be administered, consisting of 25 items, with the same linear transformation to a 
scale ranging from 0 to 100 (see Appendix 2).  
10.3 
SEXUAL HEALTH INVENTORY FOR MEN (SHIM) 
The Sexual Health Inventory for Men (SHIM) is a well validated [38] abridged 5-item of the 
15-item International Index of Erectile Function, which has been extensively studied in men with 
erectile dysfunction due to various etiologies, including prostate cancer-related therapies.  It 
consists of 5 items pertaining to sexual functioning, with scores ranging from 0-5 for most items. 
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Higher scores indicate higher level of sexual function and less erectile dysfunction (see 
Appendix 3).  
10.4 
ADMINISTRATION OF QOL QUESTIONNAIRES 
The aforementioned questionnaires (FACT-P, EORTC QLQ-C30/QLQ-PC25 and SHIM) will be 
administered to each subject according to the study schedules (see Sections 7.1 and 7.2).  The 
questionnaires should take approximately 20-30 minutes to complete.  A designated clinical 
research coordinator will ensure that subjects complete the questionnaires during their study 
visit.  If a subject stops protocol therapy due to unacceptable toxicity or progressive disease, 
effort will be made to ensure that subjects continue to complete QOL questionnaires according to 
the study schedule. 
10.5 
 METABOLIC PARAMETERS 
Subjects experiencing disease progression (PSA or radiographic) during either the On-therapy 
Period or the Off-therapy Observation Period should complete assessments required at the 
Progression Visit (see Study Schedules for details).  
10.5.1 Markers of Insulin Resistance 
Fasting plasma glucose, fasting serum insulin, body mass index, and hemoglobin A1C will be 
measured according to the study schedules (See Sections 7.1 and 7.2).  Subjects must be fasting 
for at least 12 hours prior to collection of blood for fasting glucose and insulin measurement.  If 
the subject is not in a fasting state at the particular time point, the fasting glucose and insulin 
tests will be omitted from the analysis.  
Peripheral blood for fasting serum insulin level determination will be collected, shipped and 
banked as per instructions outlined in Appendix 6. 
10.5.2 Fasting Lipid Panel 
The fasting lipid panel (total cholesterol, LDL, HDL, and triglycerides) will be measured at 
according to the study schedules (see Sections 7.1 and 7.2).  Subjects must be fasting for at least 
12 hours prior to collection of blood for accurate measure of fasting lipid panel.  If the subject is 
not in a fasting state at a particular study time point, the lipid panel will not be collected on that 
date and omitted from these exploratory statistical analyses.  
10.5.3 Bone Mineral Density 
DEXA scans will be completed during the On-therapy Period according to the study schedule 
(see Section 7.1)  The mean percent change in bone mineral density as measured at the femoral 
neck, and lumbar spine will be compared between experimental ARN-509 containing arms and 
control LHRHa monotherapy arm.  
10.5.4 Serum Hormone Levels 
Peripheral blood for measurement of serum hormone levels, including testosterone, estradiol, and 
dihydrotestosterone, will be collected, banked, and shipped as outlined in Appendix 6. See study 
schedules for timing of sample collection (Sections 7.1 and 7.2).  
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10.6 
PSA MEASUREMENT 
Serum PSA will be measured using local CLIA-certified laboratory using an ultrasensitive assay. 
It is preferable that each subject has serial laboratory measurements of PSA at the same 
laboratory while on study. 
10.7 
OPTIONAL SAMPLE COLLECTION FOR BANKING, RNA, AND 
BIOMARKER ANALYSIS 
Optional samples of peripheral blood will be collected for banking of plasma, serum, and 
PBMCs. Archival FFPE blocks or slides, whole blood for RNA testing, and biomarker collection 
are also optional.  Please see Appendix 6 for collection, processing, and shipping instructions).  
Archival FFPE blocks are preferred however slides will also be accepted. Whole blood will be 
collected in PAXgene tubes for RNA testing for markers previously confer resistance to 
ARN-509 or enzalutamide. These include androgen receptor anomalies (eg: AR amplification, 
ARv3/7, and ARv567), AR axis genes, and other compensatory pathway markers. See Study 
Schedules (Section 7) for timing of optional sample collections. 
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
adequate sample material. Therefore, some analyses may be deferred or not done if, for any 
reason, the analysis will have no scientific value. Biomarker data from this study may be 
compared with or combined with data obtained from prior studies.   
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11 PLANNED STATISTICAL METHODS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used in analyzing the data is outlined in the protocol. 
Details will be provided in the Statistical Analysis Plan (SAP). 
11.1 
DETERMINATION OF SAMPLE SIZE AND STUDY POWER 
The expected mean decline in FACT-P score and within group standard deviation for the control 
arm treated with 12 months of LHRHa monotherapy is 4-8 and 8-12 points, respectively, based 
on prior studies of measuring QOL using FACT-P among men treated with ADT [32, 58, 59]. A 
change in total FACT score that is clinically meaningful and impacts treatment in prior studies 
ranges from 5-8 points depending on cancer subtype [56].  Approximately 30 subjects will be 
randomized to each of the 3 treatment arms for this comparison.  Accounting for a 
dropout/questionnaire non-completion rate of 10%, this will allow for 27 evaluable subjects per 
study arm.  For the comparison of the mean change in FACT-P score between ARN-509 
monotherapy and LHRHa monotherapy, this sample size has 80% power to detect an effect size 
of at least 0.86, corresponding to a difference of 7.5 points in mean 12 month change in FACT-P 
score between treatment groups with a common standard deviation for the change in each arm of 
8.7 which is similar to the reported standard deviation for LHRHa monotherapy.  This is based 
upon a 2 group t test, using a bidirectional level of significance of 0.025 (adjusted for 
2 comparisons).  To test for non-inferiority in QOL with ARN-509 + LHRHa compared with 
LHRHa monotherapy, inferior QOL is defined as a greater than 7 point difference in mean 
change in FACT-P score between the treatment groups and the common standard deviation is 
again assumed to be 8.7.  This sample size has 82% power to reject the null hypothesis of a 
difference in mean score  and accept the alternative hypothesis of non-inferiority with an effect 
size of at least 0.81, using a 2 group t-test with 2-sided α of 0.025.   
11.2 
CLINICAL CUTOFFS 
11.2.1 Interim Analysis 
No interim analysis will be planned for efficacy due to the expected rate of accrual, the primary 
endpoint being analyzed, and total sample size. 
An interim safety review will be performed after 20 subjects have completed at least 1 month of 
therapy with either ARN-509 monotherapy or ARN-509 + LHRHa.  If there are more than 
5 subjects with Grade 3 or higher toxicities not related to ADT (anemia, fatigue, gynecomastia, 
hot flushes, decreased libido, erectile dysfunction, mood changes, and weight gain), that the 
study investigator deems as possibly, probably, or definitely treatment-related, the study will be 
terminated.  This indicates that at least 30% of the subjects had unacceptable toxicities.  If 
accrual is completed and all 60 subjects were treated with ARN-509 (with or without LHRHa) 
and if unacceptable toxicity is > 30%, then the exact 95% lower bound for unacceptable toxicity 
of 30% would be 20.4%.  Study enrollment will continue during the interim safety review.  
11.2.2 Final Clinical Cutoff 
The Sponsor will establish a final clinical cutoff date after all subjects have completed the Month 
24 Visit. Data collection will cease at this time. The final clinical study report will be written 
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based on these data. Any subjects who continue in the Follow-up Period will be discontinued 
from the study. 
11.3 
ANALYSIS POPULATIONS 
Subject disposition, quality of life, metabolic, and PSA suppression endpoints will be assessed 
using data from the intent-to-treat (ITT) population.  All subjects randomized into the study will 
be classified according to their assigned treatment group, regardless of the actual treatment 
received.  Safety analyses will be performed using all subjects who received at least 1 dose of 
study drug, with treatment assignments designated according to actual study treatment.  
11.4 
METHODS FOR ANALYSIS 
11.4.1 Analytic Plan for the Primary Endpoint 
Change from baseline in FACT-P total scale will be analyzed using a mixed-model for repeated 
measures (MMRM). The model will include baseline scale, treatment, month (categorical), and 
treatment-by-month interaction as covariates. An unstructured variance-covariance matrix will 
be used to model within-subject errors, but simpler structures (eg, compound symmetry) may be 
used to ensure estimation convergence. Change from baseline will be estimated using least-
squares means with factor levels weighted according to overall baseline sample means. Data up 
to 12 months will be included in the analysis and the primary time point of interest will be at 12 
months.  
Contrasts will be set up to compare ARN-509 monotherapy vs. LHRHa monotherapy and ARN-
509 + LHRHa vs. LHRHa monotherapy. To test for non-inferiority with respect to ARN-509 + 
LHRHa compared with LHRHa monotherapy, inferior boundary is defined as a greater than 
7 point difference in mean change in FACT-P total score. 
The estimated least-squares mean (+/- SE) over time will be presented using a line plot. 
11.4.2 Analytic Plan for the Secondary Endpoints 
The secondary QOL endpoints will be analyzed using a similar approach as for the primary 
endpoint. Data up to 24 months will be included in the analysis.   
PSA Modulation: 
The proportion of subjects without PSA or radiographic progression and who have recovered 
serum testosterone to greater than 150 ng/dL at 24 months from Day 1 will be compared for 
subjects treated ARN-509 monotherapy vs. LHRHa monotherapy and for ARN-509 + LHRHa 
vs. LHRHa monotherapy.  The proportions by treatment will be compared using the chi-square 
test or Fisher’s exact test as appropriate. Results will be summarized at 24 months from Day 1 
with 95% confidence intervals for each treatment arm. Subjects who withdraw from the study 
prior to 24 months after Day 1 will not be included in this analysis. Details can be found in the 
statistical analysis plan (SAP). 
The proportion of subjects with a PSA less than 0.2 ng/mL after 7 months of protocol therapy 
will be analyzed using similar approaches for proportion of subjects without evidence of PSA or 
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radiographic progression during the 24-month treatment period and with recovery of serum 
testosterone at 24 months.  
The probability distributions by treatment group of the time to PSA progression will be estimated 
using the Kaplan-Meier method. Durations will be measured from Day 1 of study treatment to 
the first date of PSA progression. The log-rank test will be used to compare the distribution of 
time to PSA progression.  
Metabolic and Hormonal Parameters: 
The mean change from baseline for markers of insulin resistance (including fasting glucose, 
insulin, body mass index, and hemoglobin A1C), fasting lipid panel (including total cholesterol, 
LDL, HDL, and serum triglycerides), and hormone levels (including DHT and estradiol) 
analyzed using a similar approach as for the primary endpoint.  
The mean change in bone mineral density at the femoral neck, and lumbar spine as measured by 
DEXA scan will be compared for ARN-509 monotherapy vs. LHRHa monotherapy and 
ARN-509 + LHRHa vs. LHRHa monotherapy using an analysis of covariance (ANCOVA) that 
controls for baseline values of the corresponding measurement.  
The time to serum testosterone recovery to > 50 ng/dL and > 150 ng/dL after the cessation of 
protocol therapy at 12 months will be compared for ARN-509 + LHRHa vs. LHRHa 
monotherapy. The probability distributions by treatment group of the time to testosterone 
recovery will be estimated using the Kaplan-Meier method. The log-rank test will be used to 
compare the distribution of time to testosterone recovery. Subjects who discontinue study drug 
prior to 12 months for disease progression, unacceptable toxicity, or study withdrawal, as well as 
subjects who continue hormonal therapy after 12 months or receive non-protocol therapy, will 
not be included in the analysis of this exploratory endpoint.  
No adjustment for multiple comparisons will be made for the analysis of the secondary and 
correlative endpoints. Some correlative analyses may be deferred or not done if, for any reason, 
the analysis will have no scientific value.  
Safety Analysis:  
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify 
adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Toxicities will be graded for severity according to 
NCI-CTCAE Version 4.03 (see Section 12.1.5). All reported adverse events with onset during 
the On-therapy Period up to 30 days after the last dose of study medication will be included in 
the analysis.  
Specifically, the following adverse events will be summarized: 
• 
All adverse events 
• 
Grade 3 or higher adverse events 
• 
Serious adverse events 
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• 
Adverse events leading to discontinuation of treatment 
• 
Adverse events leading to death 
Summaries, listings, or subject narratives may be provided, as appropriate, for those subjects 
who died, who discontinue treatment due to an adverse event, or who experience a ≥Grade 3 or 
higher or a serious adverse event.   
In addition, abnormal findings in physical exams and laboratory tests will be summarized.  
Biomarker analysis 
Biomarker analyses will be conducted on archival FFPE blocks or slides, plasma and whole 
blood samples collected from subjects who consented to participate in biomarker analysis to 
assess ARF876L mutation and other resistance markers from all 3 treatment groups.  
Further association may be made with clinical endpoints with:  
• Markers identified from RNAseq analysis of archival tumor samples 
• Plasma DNA at progression or end of treatment will be used to assess the frequency of 
ARF876L mutation 
• Whole blood samples collected at baseline and end of treatment or progression will be used 
to identify the type and frequency of AR anomalies or other RNA based markers associated 
with ARN-509 treatment resistance or response 
The association of the rest of the biomarkers with clinical response or relevant survival endpoints 
may be assessed using appropriate statistical methods (eg, analysis of variance [ANOVA], 
categorical or survival models), depending on the endpoints. Analyses may be performed within 
and between each treatment group. Other clinical covariates (such as baseline tumor 
characteristics and subject demographics) may also be included in the model. Correlation of 
baseline biomarker expression levels with clinical response or relevant time-to-event endpoints 
may be performed to identify responsive (or resistant) subgroups.  
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
adequate subject material. Therefore, some analyses may be deferred or not done if, for any 
reason, the analysis will have no scientific value. Biomarker data from this study may be 
compared with or combined with data obtained from prior studies. 
 
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12 REPORTING AND DOCUMENTATION OF ADVERSE EVENTS 
12.1 
DEFINITIONS OF ADVERSE EVENTS  
12.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse event does 
not necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) product. 
(Definition per International Conference on Harmonisation [ICH]). 
Note: Adverse event collection starts with the signing of the ICF.  
Examples of adverse events include but are not limited to: 
 Abnormal test findings 
 Clinically significant signs and symptoms 
 Changes in physical examination findings  
 Worsening of signs and symptoms of the malignancy under study.  Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods should 
not be reported as an adverse event. 
 Signs or symptoms resulting from dose overdose, dependency, withdrawal, abuse, and/or 
misuse 
 Drug interactions 
 Exposure in utero (pregnancy) 
For laboratory abnormalities, the criteria for determining whether an abnormal test finding 
should be reported as an adverse event are as follows: 
 Test result is associated with accompanying symptoms, and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
 Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy, and/or 
 Test result is considered to be an adverse event by the Investigator 
12.1.2 Serious Adverse Event (SAE) 
A serious adverse event (SAE) based on ICH and European Union (EU) Guidelines on 
Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence 
that at any dose:  
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 Results in death.  If the malignancy under study has a fatal outcome during the study or 
within the safety reporting period, the event leading to death should be reported as a 
Grade 5 SAE; death is an outcome and not the adverse event in itself. 
 Is life-threatening (ie, immediate risk of death from the reaction as it occurred).  It does 
not include a reaction which hypothetically might have caused death had it occurred in a 
more severe form. 
 Requires or prolongs inpatient hospitalization (ie, the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay).  
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (eg, surgery performed earlier than planned) 
 Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions 
 Results in a congenital anomaly or birth defect 
 Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse 
Events not considered to be SAEs are hospitalizations for: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 Elective or pre-planned treatment for a pre-existing condition that did not worsen 
 Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 Respite care or social admissions 
12.1.3 Expectedness 
An adverse event or suspected adverse reaction for ARN-509 is considered “unexpected” if it is 
not listed in the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed.  For LHRHa with a marketing authorization, the expectedness of an AE will be 
determined based on whether or not it is listed in the applicable package insert or summary of 
product characteristics. 
12.1.4 Attribution 
A suspected adverse reaction means any adverse event for which there is reasonable possibility 
that the study drug caused the adverse event.  For the purposes of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal relationship between the 
drug and the adverse event.   
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The Investigator will assign attribution of the possible association of the event with the study 
drug using the following definitions: 
Not Related 
An adverse event that is not related to the use of the drug. 
Unlikely (doubtful) 
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. 
Possible 
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded. 
Probable 
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s). 
Definitely (Very Likely) 
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge). 
12.1.5 Severity 
Signs or symptoms should be graded and recorded by the Investigator according to the 
NCI-CTCAE (Version 4.03).  
Any adverse event not listed in the CTCAE will be graded as follows: 
Grade 1, Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities. 
Grade 2, Moderate: Sufficient discomfort is present to cause interference with normal activity. 
Grade 3, Severe: Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. 
Grade 4, Life-threatening: Urgent intervention indicated. 
Grade 5, Death: Death. 
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities). 
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12.2 
SPECIAL REPORTING SITUATIONS 
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• 
Overdose of a sponsor study drug 
• 
Suspected abuse/misuse of a sponsor study drug 
• 
Inadvertent or accidental exposure to a sponsor study drug 
• 
Medication error involving a sponsor product (with or without subject/patient exposure to 
the sponsor study drug, eg, name confusion) 
 
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF. 
12.3 
PROCEDURES 
12.3.1 All Adverse Events 
All adverse events and special reporting situations, whether serious or non-serious, will be 
reported from the signing of the ICF until completion of the subject's last study-related procedure 
(may include contact for follow-up of safety). Serious adverse events, including those 
spontaneously reported to the investigator within 30 days after the last dose of study drug, must 
be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol. 
 
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments. 
 
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, 
must be recorded using medical terminology in the source document and the eCRF, using the 
NCI- CTCAE V4.03. Whenever possible, diagnoses should be given when signs and symptoms 
are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection"). Investigators must record in the eCRF their 
opinion concerning the relationship of the adverse event to study therapy. All measures required 
for adverse event management must be recorded in the source document and reported according 
to sponsor instructions. 
 
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) 
that approved the protocol unless otherwise required and documented by the IEC/IRB.  
12.3.2 Serious Adverse Events 
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 24 hours of their knowledge of the event. 
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Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a physician from the study site, 
and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a serious 
adverse event should be made by facsimile (fax). 
 
SAE fax: 1-908 450-1334 
 
Explicitly state any specific serious adverse event follow-up that is required to be recorded on 
the eCRF; this will ensure that a placeholder is included on the eCRF and the follow-up will 
occur. 
 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
 
Suspected transmission of an infectious agent by a medicinal product will be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject's participation in a study must be reported as a serious 
adverse event, except hospitalizations for the following: 
 
• 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons 
such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation of the 
originally planned hospitalization is to be reported as a new serious adverse event. 
 
Disease progression should not be recorded as an adverse event or serious adverse event term; 
instead, signs and symptoms of clinical sequelae resulting from disease progression/lack of 
efficacy will be reported if they fulfill the serious adverse event definition. 
12.3.3  Pregnancy 
Because the effect of the blinded study drug on sperm is unknown, pregnancies in partners of 
male subjects included in the study will be reported by the investigational staff within 24 hours 
of their knowledge of the event using the appropriate pregnancy notification form. 
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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant may be collected. 
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13 PRODUCT QUALITY COMPLAINT HANDLING 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The Sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all studies conducted by the sponsor or its affiliates 
will be conducted in accordance with those procedures. 
13.1 
PROCEDURES 
All initial PQCs must be reported to the Sponsor (or designee) by the study-site personnel within 
24 hours after being made aware of the event. If the defect is combined with a serious adverse 
event, the study-site personnel must report the PQC to the sponsor according to the serious 
adverse event reporting timelines (refer to Section 12.3.2). A sample of the suspected product 
should be maintained for further investigation if requested by the Sponsor. 
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14 DATA COLLECTION, RETENTION AND MONITORING 
14.1 
DATA COLLECTION INSTRUMENTS 
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.   
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, and transmitted in a secure 
manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF. 
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. All subjective measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.  
The Clinical Research Coordinator (CRC) or designated study site personnel will complete the 
eCRFs within 5 days following a subject visit and queries are to be addressed within 5 days from 
the date issued. The Investigator will review and approve the completed eCRFs.   Subjects will 
not be identified by name in the study database or on any study documents to be collected by the 
Sponsor (or designee), but will be identified by a site number, subject number. 
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating eCRF data and creates an electronic audit trail.   
If corrections to an eCRF are needed after removal of the original eCRF copy from the 
investigational site, a data correction form (DCF) will be used. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
3 different ways: 
• Site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool) 
• Site manager can generate a query for resolution by the investigational staff 
• Clinical data manager can generate a query for resolution by the investigational staff  
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug.  The 
information collected on eCRFs shall be identical to that appearing in original source documents.  
Source documents will be found in the subject’s medical records maintained by study site 
personnel.  All source documentation should be kept in separate research folders for each 
subject. 
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In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto eCRFs.  Each eCRF must be 
reviewed for accuracy by the Investigator, corrected as necessary, and then approved.  
Alternatively, the Investigator may sign individual, printed eCRFs.  These signatures attest that 
the information contained on the eCRFs is true and accurate.  A copy of the eCRF will remain at 
the Investigator’s site at the completion of the study. 
At study completion, when the database has been declared to be complete and accurate, the 
database will be locked.  Any changes to the database after that time can only be made by joint 
written agreement among Aragon Pharmaceuticals, the Study Chair, the Trial Statistician, and 
the Protocol Project Manager at UCSF. 
14.2 
DATA QUALITY CONTROL AND REPORTING 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. The sponsor will 
review eCRFs for accuracy and completeness during on-site monitoring visits and after 
transmission to the sponsor; any discrepancies will be resolved with the investigator or designee, 
as appropriate. After upload of the data into the clinical study database they will be verified for 
accuracy and consistency with the data sources. Queries are entered, tracked, and resolved 
through the eDC system directly.  The study database will be updated in accordance with the 
resolved queries.  All changes to the study database will be documented. 
14.3 
ARCHIVAL OF DATA 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim and final reports), data for 
analysis is locked and cleaned per established procedures. 
14.4 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., eCRFs and hospital records), all original signed informed consent forms, 
copies of all eCRFs, safety reporting forms, source documents, and detailed records of treatment 
disposition, and adequate documentation of relevant correspondence (e.g., letters, meeting 
minutes, telephone calls reports).  The records should be retained by the Investigator according 
to ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever is longer, 
but at a minimum, all study documentation must be retained for 2 years after the last marketing 
application approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of ARN-509. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), the Sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
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investigator, another institution, or to the Sponsor itself.  The Investigator must obtain the 
Sponsor’s written permission before disposing of any records, even if retention requirements 
have been met. 
14.5 
MONITORING 
Monitoring visits will be conducted by representatives of the Sponsor according to the US CFR 
Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the 
Investigator grants permission to the Sponsor (or designee), and appropriate regulatory 
authorities to conduct on-site monitoring and/or auditing of all appropriate study documentation. 
14.6 
SUBJECT CONFIDENTIALITY 
In order to maintain subject confidentiality, only a site number and subject number will identify 
all study subjects on eCRFs and other documentation submitted to the Sponsor.  Additional 
subject confidentiality issues (if applicable) are covered in the Clinical Trial Agreement. 
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15 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according in accordance with the US FDA regulations, the 
International Conference on Harmonisation (ICH) E6 Guidelines for GCP, and applicable local, 
state, and federal laws.  
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number.  All study records will be kept in a locked file cabinet and 
code sheets linking a subject’s name to a subject identification number will be stored separately 
in another locked file cabinet.  Clinical information will not be released without written 
permission of the subject, except as necessary for monitoring by the FDA.  The Investigator must 
also comply with all applicable privacy regulations (e.g., Health Insurance Portability and 
Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
15.1 
PROTOCOL AMENDMENTS 
Any amendment to the protocol will be written in collaboration by UCSF with the Sponsor.  
Protocol amendments cannot be implemented without prior written IRB/IEC approval except as 
necessary to eliminate immediate safety hazards to subjects.  A protocol amendment intended to 
eliminate an apparent immediate hazard to subjects may be implemented immediately, provided 
the IRB/IECs are notified within five working days. 
15.2 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS 
COMMITTEES 
The protocol, Investigator’s Brochure, the consent forms, any information to be given to the 
subject (including subject recruitment materials) and relevant supporting information must be 
submitted to the IRB/IEC by the Investigator for review and approval before the study is 
initiated.  Any member of the IRB/IEC who is directly affiliated with this study as an 
Investigator or as site personnel must abstain from the IRB/IEC vote on the approval of the 
protocol.  The IRB/IECs unconditional approval statement will be transmitted by the Investigator 
to the Sponsor (or designee) prior to the shipment of study supplies to the site.  This approval 
must refer to the study by exact protocol title and number and should identify the documents 
reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the subjects 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification 
was submitted and subsequently approved should be obtained.   
Investigators are required to promptly report to their respective IRB/IEC all unanticipated 
problems involving risk to human subjects.  Some IRBs/IECs may want prompt notification of 
all SAEs, whereas others require notification only about events that are serious, assessed to be 
related to study treatment, and are unexpected.  Investigators may receive written IND safety 
reports or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with regulatory 
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requirements and with the policies and procedures established by their IRB/IEC and archived in 
the site’s study file.  
Finally, the Investigator will keep the IRB/IEC informed as to the progress of the study, 
revisions to documents originally submitted for review, annual updates and/or request for re-
approvals, and when the study has been completed.  
15.3 
INFORMED CONSENT FORM 
Informed consent will be obtained in accordance with the ICH GCP, US Code of Federal 
Regulations for Protection of Human Subjects (21 CFR 50.25[a, b], CFR 50.27, and CFR Part 
56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), 
and local regulations. 
The Sponsor’s master ICF will be provided to each site.  Sponsor or its designee must review and 
approve any proposed deviations from the master ICF or any alternate consent forms proposed 
by the site before IRB/IEC submission.  Subjects must be re-consented to the most current 
version of the consent forms during their participation in the study.  The final IRB/IEC-approved 
consent forms must be provided to Sponsor for regulatory purposes. 
The consent forms must be signed by the subject or the subject’s legal representative before his 
participation in the study.  The case history for each subject shall document the informed consent 
process and that written informed consent was obtained prior to participation in the study. A 
copy of each signed consent form must be provided to the subject or the subject’s legal 
representative.  If applicable, it will be provided in a certified translation of the local language. 
All signed and dated consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 
The ICF should be revised whenever there are changes to procedures outlined in the informed 
consent or when new information becomes available that may affect the willingness of the 
subject to participate. 
For any updated or revised consent forms, the case history for each subject shall document the 
informed consent process and that written informed consent was obtained for the updated/revised 
consent form for continued participation in the study.  The final revised IRB/IEC-approved ICF 
must be provided to Sponsor for regulatory purposes. 
15.4 
REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES OF THE 
PROTOCOL OR ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority in any area of the World, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
product, the Sponsor should be informed immediately.   
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of. 
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15.5 
SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, drug safety problems, or at the discretion of the Sponsor.  In addition, 
the Sponsor retains the right to discontinue development of ARN-509 at any time. 
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator.  After notification, the Investigator must notify the respective IRB/IEC, and contact 
all participating subjects and the hospital pharmacy (if applicable) within a 4-week time period.  
As directed by the Sponsor, all study materials must be collected and all eCRFs completed to the 
greatest extent possible. 
15.6 
 USE OF INFORMATION AND PUBLICATION  
All information, including but not limited to information regarding ARN-509 or the Sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the Sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the Sponsor's prior 
written consent. 
The investigator understands that the information developed in the study will be used by the 
Sponsor in connection with the continued development of ARN-509, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information 
derived from the clinical studies to be used, the investigator is obligated to provide the Sponsor 
with all data obtained in the study. 
The results of the study will be reported in a Clinical Study Report generated by the Sponsor and 
will contain eCRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the Sponsor's database]. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory biomarkerr 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the Sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the Sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the Sponsor in 
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writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the Sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study 
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the Sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version. 
Registration of Clinical Studies and Disclosure of Results 
The Sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law. 
 
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30. Clegg N, Wongvipat J, Joseph J, et al. Discovery and development of ARN 509, a novel anti-
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31. Tran T, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for 
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33. Esper P, Mo F, Chodak G, et al. Measuring the quality of life in men with prostate cancer 
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38. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Peña BM.Development and evaluation of an 
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39. Menon M, Kaul S, Bhandari A, et al. Potency following robotic radical prostatectomy: A 
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40. Cauley JA, Hochberg MC, Lui LY, et al. Long-term risk of incident vertebral fractures. 
JAMA 2007; 298(23):2761-2767. 
41. Lee H, McGovern K, Finkelstein JS, et al. Changes in bone mineral density and body 
composition during initial and long-term gonadotropin-releasing hormone agonist treatment 
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42. Shahinian VB, Kuo YF, Freeman JL, and Goodwin JS. Risk of fracture after androgen 
deprivation for prostate cancer. New Engl J of Medicine 2005; 352(2):154-164. 
43. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following 
radiotherapy with or without hormonal therapy in men with clinically localized prostate 
cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat 
Oncol Biol Phys. 2006; 65(4):965-74. 
44. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality 
following biochemical recurrence after radical prostatectomy. JAMA 2005; 294(4):433–439. 
45. Antonarakis ES, Trock BJ, Feng Z, et al. The natural history of metastatic progression in men 
with PSA-recurrent prostate cancer after radical prostatectomy: 25-year follow-up. J Clin 
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46. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, 
comparative, randomized, open-label, parallel-group phase III study in patients with prostate 
cancer. BJUI 2008; 102(11):1531-1538. 
47. Boccon-Gibod L, Hammerer P, Madersbachert S, et al. The role of intermittent androgen 
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49. Grossfeld GD, Chaudhary UB, Reese DM, et al. Intermittent androgen deprivation: update of 
cycling characteristics in patients without clinically apparent metastatic prostate cancer. J of 
Urology 2001; 58(2):240-245. 
50. Scher HI, Eisenberger M, D’Amico AV, et al. Eligibility and outcomes reporting guidelines 
for clinical trials for patients in the state of a rising prostate-specific antigen: 
recommendations from the Prostate-Specific Antigen Working Group. Journal of Clinical 
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51. Grossfeld GD, Small EJ, and Carroll PR. Intermittent androgen deprivation for clinically 
localized prostate cancer: initial experience. J of Urology 1998; 51:137-144. 
52. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after 
androgen deprivation is a strong independent predictor of survival in new metastatic prostate 
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53. Yu EY, Gulati R, Telesca D, et al. Duration of first off-treatment interval is prognostic for 
time to castration resistance and death in men with biochemical relapse of prostate cancer 
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54. Gulley JL, Figg WD, Steinberg SM, et al. A prospective analysis of the time to normalization 
of serum androgens following 6 months of androgen deprivation therapy in patients on a 
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55. Pickles T, Agranovich A, Berthelet E, et al. Testosterone recovery following prolonged 
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56. Nishiyama T, Hashimoto Y, and Takahashi K. The influence of androgen deprivation therapy 
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57. Webster K, Cella D, and Yost K.  The Functional Assessment of Chronic Illness Therapy 
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58. Segal RJ, Reid RD, Courneya KS, et al. Resistance exercise in men receiving androgen 
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59. Potosky AL, Knopf K, Clegg LX, et al. Quality-of-life outcomes after primary androgen 
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Appendix 1. FACT-P 
Below is a list of statements that other people with your illness have said are important.  Please 
circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
PHYSICAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy ............................................
0 
1 
2 
3 
4 
GP2 
I have nausea ...........................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family ..............................
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ...............................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment ..............
0 
1 
2 
3 
4 
GP6 
I feel ill ....................................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed .............................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends .........................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family .................
0 
1 
2 
3 
4 
GS3 
I get support from my friends ..................................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .........................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about 
my illness.................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is 
my main support) ....................................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, 
please answer the following question. If you prefer 
not to answer it, please mark this box           and go to 
the next section
 
 
 
 
 
GS7 
I am satisfied with my sex life ................................
0 
1 
2 
3 
4 
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Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad .....................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness ..........................................................................
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .........
0 
1 
2 
3 
4 
GE4 
I feel nervous ..............................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ....................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ...................
0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GF1 
I am able to work (include work at home) .................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ............
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ..........................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ......................................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun .............
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now.....
0 
1 
2 
3 
4 
 
 
 
 
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Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
C2 
I am losing weight ...................................................
0 
1 
2 
3 
4 
C6 
I have a good appetite..............................................
0 
1 
2 
3 
4 
P1 
I have aches and pains that bother me .....................
0 
1 
2 
3 
4 
P2 
I have certain parts of my body where I 
experience pain ........................................................
0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to do ..
0 
1 
2 
3 
4 
P4 
I am satisfied with my present comfort level ..........
0 
1 
2 
 
4 
P5 
I am able to feel like a man .....................................
0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels ...........................
0 
1 
2 
3 
4 
P7 
I have difficulty urinating ........................................
0 
1 
2 
3 
4 
BL2 
I urinate more frequently than usual .......................
0 
1 
2 
3 
4 
P8 
My problems with urinating limit my activities ......
0 
1 
2 
3 
4 
BL5 
I am able to have and maintain an erection .............
0 
1 
2 
3 
4 
 
  
 
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Appendix 2. EORTC QLQ-C30/QLQ-PR25 
 
 
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Appendix 3. Sexual Health Inventory for Men (SHIM) 
 
 
 
 
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Appendix 4. ECOG Performance Status Scale 
Performance Status Score Conversion3 
 
ECOG (Zubrod)1 
Karnofsky2 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on 
all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or 
sedentary nature, e.g., light 
housework, office work. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
 
70 
Cares for self, unable to carry 
on normal activity or do normal 
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. 
60 
Requires occasional  
assistance, but is able to care 
for most of his/her needs. 
 
50 
Requires considerable 
assistance and frequent medical 
care. 
 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care 
and assistance. 
 
30 
Severely disabled, 
hospitalization indicated.  
Death not imminent. 
 
4 
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. 
Death not imminent. 
 
10 
Moribund, fatal processes 
progressing rapidly. 
 
 
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1. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
2. Karnofsky, D. A., Abelmann, W. H., Craver, L. F., and Burchenal:.The use of nitrogen mustards in the 
palliative treatment of cancer. Cancer 1:634-656, 1948. 
 
3. National Cancer Institute – Cancer Therapy Evaluation Program: Clinical Data Update System (CDUS), 
Instructions and Guidelines. Version 3.0 release 5, 11 January, 2011. 
 
 
 
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Appendix 5. List of Medications and Supplements Either Prohibited Or Not 
Recommended While On Study: 
 
Medications/Supplements Which Are PROHIBITED While On Study: 
 
Aldactone 
Aminophylline 
Amitriptyline 
Bicalutamide 
Buproprion 
Chemotherapy 
Chlorpromazine 
Clozapine 
Cyproterone acetate 
Diethylstilbesterol 
Degarelix 
Desipramine 
Doxipine 
Dutasteride  
Estrogens 
Finasteride 
Fluconazole 
Flutamide 
Imipramine 
Immunotherapy 
Itraconazole 
Ketoconazole 
Lithium 
Maprotiline  
Megestrol 
Meperidine 
Mesoridazine 
Milk thistle 
Mirtazapine 
Nilutamide 
Olanzapine  
Other investigational agents 
PC-SPES 
Pethidine 
Pomegranate extract 
Pomegranate juice 
Progesterones 
Radiotherapy other than prevention/treatment of painful gynecomastia 
Saw palmetto 
Spironolactone  
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Steroids at an equivalent dose of prednisone 5 mg per day or higher 
Theophylline 
Thioridazine 
Ziprasidone 
 
 
Medications/Supplements Which Are RESTRICTED While on Study 
(Monitor for Increased Toxicity/Potential Drug Interactions): 
 
Drug Interactions: In vitro, CYP3A4 and CYP2C8 are the enzymes primarily responsible for 
the metabolism of ARN-509. Co-administration of a strong CYP3A4 inhibitor (itraconazole) had 
no clinically meaningful effect on the PK of ARN-509 and its active metabolite ARN00308.  
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the AUC of ARN-509 
by 68% but decreased the AUC of ARN00308 by 15%.  The effects of CYP3A4 inducers or 
CYP2C8 inducers on the PK of ARN-509 have not been evaluated in vivo. Co-administration of 
ARN-509 with the following drugs that can induce CYP3A4 or CYP2C8 should be avoided as 
co-administration with any of these agents may decrease ARN-509 plasma concentrations. 
Alternative therapies should be used when available.  
• Strong CYP3A4 inducers: phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, efavirenz, tipranivir, St. John's wort 
• CYP2C8 inducers: rifampin 
 
 
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Appendix 6. Peripheral Blood Collection, Processing, and Shipping 
Instructions 
 
Peripheral blood for measurement of serum testosterone, dihydrotestosterone, estradiol, and 
fasting insulin levels will be collected at each site according to the instructions outlined below, 
and shipped to a central laboratory for analysis. Specimens should be shipped within 1 month of 
date of collection. 
 
Peripheral blood and urine collection for banking of peripheral blood mononuclear cells 
(PBMC), plasma, serum, and urine is optional. Specimens will be banked at a central laboratory. 
 
I. Subject Confidentiality 
 
Prior to the date of collection of each sample to be shipped to a central laboratory, the local CRC 
should notify the lead center CRC that specimen is to be collected at the subject’s next visit.  The 
lead center CRC will then assign unique specimen log numbers to be written on the specimen 
vials; this will ensure subject confidentiality.   
 
A central laboratory will serve as a repository for banking human samples. The samples will 
receive a subject-insensitive identifier and the link to subject identity will be kept in a locked file 
with access only by the director of the Tissue Bank. Other investigators will have access to the 
samples only through established Tissue Core procedures. That is, investigators must submit a 
written request to use the stored samples as part of a CHR-approved protocol that is reviewed by 
the Tissue Core committee. This review limits the testing that can be done on these samples. 
Subjects have the right at any time to request that all remaining samples be destroyed. The 
subject or relatives may be contacted about future, additional research on stored samples, if 
necessary. Additional written consent will be required if additional samples are to be taken. 
 
II. Serum Hormone Measurements 
 
At baseline, after month 3, 6, 9, and 12, fifteen mL of whole blood will be collected in two red 
top tubes (no gel) and centrifuged at 3000 rpm for 10 minutes. The serum will be decanted into 
three 2mL polypropylene screw cap (leak-proof) vials that have been properly labeled with the 
unique specimen log numbers provided and stored at -80°C until shipment to a central 
laboratory.  
 
After month 14, 16, 18, 20, 22, and 24, five mL of whole blood will be collected in one red top 
tube (no gel) and centrifuged at 3000 rpm for 10 minutes. The serum will be decanted into one 2 
mL polypropylene screw cap (leak-proof) vial with the proper label and stored at -80°C until 
shipment to a central laboratory. 
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Serum testosterone, estradiol, and dihydrotestosterone levels will be measured in batched 
samples using liquid chromatography/tandem mass spectrometry (LC/MS/MS).  
 
III. Fasting Plasma Insulin Measurement  
 
At baseline, after month 3, 6, 9, 12, 18, and 24, five mL of whole blood will be collected in one 
red top tube (no gel) and centrifuged at 3000 rpm for 10 minutes. The serum will be decanted 
into one 2 mL polypropylene screw cap (leak-proof) vial that has been properly labeled with the 
unique specimen log numbers provided at stored at -80°C until shipment to a central laboratory. 
 
IV. Banking of Peripheral Blood, Plasma, and Serum (Optional) 
 
At baseline, after month 3, 6, 9, and 12, twenty mL of whole blood will be collected in one 
tigertop tube (serum) and one lavender top tube (plasma) and centrifuged at 3000 rpm for 10 
minutes. The serum and plasma will be decanted into two 2mL polypropylene screw cap (leak-
proof) vials (four total vials) that have been properly labeled with the unique specimen log 
numbers provided and stored at –80°C until shipment to a central laboratory.  
 
At baseline, after month 3, 6, 9, and 12, urine should be collected and decanted into two 2mL 
polypropylene screw cap (leak-proof) vials labeled with the assigned specimen log numbers and 
stored in refrigerator until shipment to a central laboratory.  
 
At baseline, twelve mL of whole blood in 2 plastic EDTA tubes will also collected and freshly 
frozen at -80°C until shipment to a central laboratory. 
 
V. Archival FFPE Blocks or Slides, Plasma and Whole Blood for Biomarker 
Testing (Optional) 
Archival FFPE blocks or slides will be collected from consented subjects any time after enrolling 
into the study. Ship Archival FFPE blocks or slides ambient to a central laboratory. Whole blood 
samples will be collected at baseline end of treatment and progression. Blood (2.5ml) will be 
collected in PAXgene™ Blood RNA tube. PAXgene tube should be at room temperature (18-
25°C) prior to use. To prevent backflow, place donor’s arm in a downward position. Hold tube in 
a vertical position, below the donor’s arm during blood collection. Release tourniquet as soon as 
blood starts to flow into tube. Make sure tube additives do not touch stopper or end of the needle 
during venipuncture. Ensure that blood has stopped flowing into the PAXgene tube before 
removing the tube from the holder (at least 10 seconds). Gently invert the PAXgene tube 8-10 
times. Always leave the PAXgene tube as the FINAL TUBE to draw. If the PAXgene tube is the 
only tube required, collect blood into a 2 mL discard tube prior to collecting the PAXgene tube. 
The discard tube must be filled with at least 2 mL of blood to flush the air from the tubing. 
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Be sure to follow complete PAXgene collection and sample handling instructions, which are 
provided with the tubes. Label tube with unique specimen identification numbers, which will be 
provided. Store samples at –80°C until shipped to a central laboratory. 
Peripheral blood (10 ml) will be collected in K2EDTA tubes at end of treatment and progression. 
Centrifuge at room temperature for 10 minutes at 1600 (±150) g. After centrifugation, transfer 
supernatant of the EDTA tube (using a disposable pipette) to one fresh 15 ml labeled centrifuge 
tube. Centrifuge the plasma in the 15 ml centrifuge tube at room temperature for 10 min at 3000 
(±150) g. After centrifugation, transfer supernatant to a fresh 15 ml centrifuge tube without 
disturbing the cellular layer using a disposable pipette. Be sure to pre-label this transfer tube. 
After transferring the plasma to a new 15 ml centrifuge tube as described, gently mix plasma. 
Transfer 1ml plasma each into (2) 2ml labeled cryovials provided. 
Place cryo tubes into a storage box and freeze upright. Store samples at -80°C until shipped to a 
central laboratory. Ship both aliquots (primary and back-up) together in your shipment. 
VI. Shipping Instructions 
 
Specimens may be batch-shipped on dry ice by overnight delivery Mondays-Thursdays.  For 
specimens to be shipped to a central laboratory, the local coordinator should notify the lead 
center coordinator at the central laboratory prior to specimen shipment.  As for the specimens to 
be shipped to a central laboratory (archival FFPE blocks or slides, plasma and whole blood for 
biomarker testing [optional samples]), please refer to the Central Laboratory Manual for the 
shipping instructions. 
 
 
 
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SAP_001.pdf: 
1
Approved, Date: 26 March 2019
Janssen Research & Development *
Statistical Analysis Plan
The Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in Men with 
Biochemically Relapsed Hormone Sensitive Prostate Cancer
Protocol ARN-509-002; Phase 2
JNJ-56021927 (apalutamide)
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Aragon Pharmaceuticals Inc, Janssen Biotech, Inc.; Janssen 
Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious 
Diseases BVBA; Janssen R&D Ireland; or Janssen Research & Development, LLC. The term “sponsor” 
is used throughout the protocol to represent these various legal entities; the sponsor is identified on the 
Contact Information page that accompanies the protocol.
Status:
Approved  
Date:
26 March 2019
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-182843967, 1.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY ............................................................................................................................ 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION ................................................................................................................................ 6
1.1
Trial objectives................................................................................................................................... 6
1.1.1
Primary Objective(s)........................................................................................................................ 6
1.1.2
Secondary Objectives ...................................................................................................................... 6
1.1.3
Other Objectives ............................................................................................................................. 6
1.2
Trial Design ....................................................................................................................................... 6
1.3
Statistical Hypotheses for Trial Objectives............................................................................................ 7
1.3.1
Hypothesis 1................................................................................................................................... 7
1.3.2
Hypothesis 2................................................................................................................................... 7
1.4
Sample Size Justification..................................................................................................................... 7
1.5
Randomization and Blinding................................................................................................................ 8
1.5.1
Randomization................................................................................................................................ 8
1.5.2
Blinding ......................................................................................................................................... 8
2.
GENERAL ANALYSIS DEFINITIONS ............................................................................................... 8
2.1
Analysis Sets...................................................................................................................................... 9
2.2
Study Period I: On-therapy Period (Months 1-12).................................................................................. 9
2.2.1
Day 1 of Study Treatment .............................................................................................................. 10
2.2.2
LHRH Agonist.............................................................................................................................. 10
2.2.3
Apalutamide ................................................................................................................................. 10
2.2.4
Safety Assessment......................................................................................................................... 10
2.2.5
Quality of Life .............................................................................................................................. 11
2.2.6
Laboratory Assessments ................................................................................................................ 11
2.2.7
Radiographic Assessments ............................................................................................................. 11
2.3
Study Period II: Off-therapy Observation Period (Months 13-24) ......................................................... 11
2.3.1
Safety Assessment......................................................................................................................... 12
2.3.2
Quality of Life .............................................................................................................................. 12
2.3.3
Laboratory Assessments ................................................................................................................ 12
2.3.4
Radiographic Assessment .............................................................................................................. 12
2.4
Follow Up Period (Month 25+).......................................................................................................... 12
3.
INTERIM ANALYSIS........................................................................................................................ 13
4.
SUBJECT INFORMATION ............................................................................................................... 13
4.1
Demographics and Baseline Characteristics ........................................................................................ 13
4.2
Disposition Information .................................................................................................................... 13
4.3
Treatment Compliance and Extent of Exposure ................................................................................... 14
4.4
Protocol Deviations........................................................................................................................... 14
4.5
Pre-study and Concomitant Therapy................................................................................................... 14
4.6
Prohibited Medications ..................................................................................................................... 15
4.7
Reasons for Study Discontinuation..................................................................................................... 15
5.
EFFICACY......................................................................................................................................... 16
5.1
Analysis Specification....................................................................................................................... 16
5.1.1
Level of Significance..................................................................................................................... 16
5.1.2
Data Handling Rules...................................................................................................................... 17
5.2
Primary Endpoint.............................................................................................................................. 17
5.2.1
Analytic Plan for the Primary Endpoint........................................................................................... 17
5.3
Secondary Endpoints ........................................................................................................................ 17
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5.3.1
Analytic Plan for the Secondary Endpoints...................................................................................... 18
5.3.1.1
Quality of Life ........................................................................................................................... 18
5.3.1.2
PSA Modulation ........................................................................................................................ 18
5.3.1.3
Metabolic and Hormonal Parameters ........................................................................................... 18
5.3.2
Other Evaluations.......................................................................................................................... 19
5.4
QOL Scales...................................................................................................................................... 20
5.4.1
FACT-P........................................................................................................................................ 20
5.4.2
EORTC QLQ-C30......................................................................................................................... 20
5.4.3
Sexual Health Inventory for Men (SHIM)........................................................................................ 20
6.
SAFETY............................................................................................................................................. 21
6.1
Adverse Events................................................................................................................................. 21
6.1.1
Clinical Laboratory Tests .................................................................................................................. 23
6.1.2
Vital Signs ....................................................................................................................................... 23
6.1.3
Electrocardiogram ............................................................................................................................ 23
7.
PHARMACOKINETICS.................................................................................................................... 24
8.
BIOMARKERS .................................................................................................................................. 24
9.
MEDICAL RESOURCE UTILIZATION ........................................................................................... 24
10.
REFERENCES................................................................................................................................... 25
11.
APPENDIX......................................................................................................................................... 26
11.1
Appendix 1: FACT-P........................................................................................................................ 26
11.2
Appendix 2: EORTC QLQ-C30/QLQ-PR25 ....................................................................................... 33
11.3
Appendix 3: SEXUAL HEALTH INVENTORY FOR MEN (SHIM) ................................................... 37
LIST OF TABLES
Table 1:
Key censoring rules .................................................................................................................................19
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AMENDMENT HISTORY
None
ABBREVIATIONS
ADT
androgen deprivation therapy
AlkP
alkaline phosphatase
ALT
alanine aminotransferase
AR
androgen receptor
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ASTRO
American Society for Therapeutic Radiology and Oncology
BCR
biochemical relapse
BMD
bone mineral density 
BMI
body mass index
CAB
combined androgen blockade
CBC
complete blood count
CI
confidence interval
eCRF
electronic case report form
CRPC
castrate-resistant prostate cancer
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAO
data as observed
DEXA
dual energy x-ray absorptiometry
DHT
dihydrotestosterone
DLT
dose-limiting toxicity
ECOG
Eastern Cooperative Oncology Group
eDC
electronic data capture
EORTC
European Organization for Research and Treatment of Cancer
FACT-P
Functional Assessment of Cancer Therapy – Prostate
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
HDL
high-density lipoprotein
HR
hazard ratio
IADT
intermittent androgen deprivation therapy
ITT
intent-to-treat
mITT
modified intent-to-treat
LDL
low-density lipoprotein
LHRH
luteinizing hormone-releasing hormone
LHRHa
LHRH agonist
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NCIC
National Cancer Institute of Canada
OS
overall survival
PAB
peripheral androgen blockade
PBMC
peripheral blood mononuclear cells
PQC
product quality complaint
PSA
prostate-specific antigen
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PSADT
PSA doubling time
QOL
quality of life
RT
radiation therapy
RTOG
Radiation Therapy Oncology Group
TSH
thyroid stimulating hormone
SHIM
Sexual Health Inventory for Men
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1.
INTRODUCTION
This document describes the planned statistical analyses for study protocol ARN-509-002 (The 
Role of Highly Selective Androgen Receptor (AR) Targeted Therapy in Men with Biochemically 
Relapsed (BCR) Hormone Sensitive Prostate Cancer).  This statistical analysis plan (SAP) is 
meant to supplement the study protocol.  Any deviations from this analysis plan will be 
described in the clinical study report.  
1.1
Trial objectives
1.1.1
Primary Objective(s)

To test for superiority of apalutamide monotherapy vs. LHRHa monotherapy in prostate 
cancer patients with BCR by comparing the mean change from baseline in quality of life 
(QOL) as measured by total FACT-P score over a period of 12 months of therapy.

To test for non-inferiority of the combination apalutamide + LHRHa vs. LHRHa 
monotherapy in prostate cancer patients with BCR by comparing the mean change from 
baseline in QOL as measured by total FACT-P score over a period of 12 months of therapy.
1.1.2
Secondary Objectives

To compare (a) apalutamide monotherapy vs. LHRHa monotherapy and (b) combination 
apalutamide + LHRHa vs. LHRHa monotherapy with regards to change over time in QOL 
as measured by EORTC QLQ-C30 and SHIM.

To compare (a) apalutamide monotherapy vs. LHRHa monotherapy and (b) combination 
apalutamide + LHRHa vs. LHRHa monotherapy with regards to PSA modulation.

To compare (a) APALUTAMIDE monotherapy vs. LHRHa monotherapy and (b) 
combination apalutamide + LHRHa vs. LHRHa monotherapy with regards to metabolic and 
hormonal effects.
1.1.3
Other Objectives

To characterize the safety profile of apalutamide monotherapy and in combination with 
LHRHa.

To conduct biomarker analyses from all 3 treatment groups.
1.2
Trial Design
This is a randomized, multicenter, open-label, 3-arm phase 2 clinical trial evaluating 12 months 
of treatment with luteinizing hormone releasing hormone agonist (LHRHa) monotherapy, 
apalutamide monotherapy, or the combination of apalutamide and LHRHa, in men with non-
metastatic BCR prostate cancer with rapidly rising PSA levels after prior definitive therapy for 
localized prostate cancer. Enrollment of approximately 90 subjects (30 per arm) is planned for 
this study. Patients will be followed for safety and efficacy as per the schedule of assessments 
and will remain on study treatment until the time of PSA or radiographic progression or initiation 
of non-protocol therapy or subject/physician withdrawal from the study, whichever occurs first. 
Subjects will be stratified by PSADT (< 6 months vs. 6-12 months) and age (≤70 vs. > 70).  
There will be 2 periods of 12 months each in the 24-month-long treatment period: 1) an on-
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therapy period lasting 12 months, during which time subjects receive randomly assigned protocol 
therapy, and 2) an off-therapy observation period also lasting 12 months. If there is no evidence 
of PSA or radiographic progression after 24 months from Day 1 of the on-treatment period, 
subjects will enter a follow-up period.  Subjects will remain on study until the time of PSA or 
radiographic progression or initiation of non-protocol therapy or subject/physician withdrawal 
from the study, whichever occurs first. Patients who discontinue before completion of the on-
therapy period in the absence of progressive disease will enter the off-therapy observation period 
of the study.
1.3
Statistical Hypotheses for Trial Objectives
1.3.1
Hypothesis 1
For men with non-metastatic, non-castrate prostate cancer who have rapidly rising PSA levels 
after definitive local therapy, treatment with 12 months of apalutamide monotherapy compared 
with 12 months of ADT in the form of LHRHa monotherapy will result in better preservation of 
QOL as measured by the FACT-P scale. Parallel and exploratory findings demonstrating 
comparable PSA suppression, and less negative impact on the metabolic profile (including 
measurements of fasting lipid profiles, insulin resistance, and bone mineral density) of subjects 
who receive apalutamide monotherapy as opposed to therapy with an LHRHa would form the 
preliminary basis for further definitive study of apalutamide monotherapy in biochemically 
relapsed prostate cancer.
1.3.2
Hypothesis 2
For men with non-metastatic, non-castrate prostate cancer who have rapidly rising PSA levels 
after definitive local therapy, treatment with 12 months of therapy with the combination of 
apalutamide + LHRHa, compared with 12 months of therapy with LHRHa alone, will not be 
associated with a clinically significant worsening of QOL as measured by the FACT-P scale. 
Parallel, exploratory findings suggesting more durable PSA suppression coupled with adequate 
serum testosterone recovery, favorable PSA modulation with respect to PSA nadir and time to 
PSA progression, along with acceptable safety data, would form the preliminary basis for larger 
clinical trials testing the combination of apalutamide plus LHRHa vs. LHRHa alone in the 
hormone sensitive prostate cancer disease setting.
1.4
Sample Size Justification
The expected mean decline in FACT-P score and within group standard deviation for the control 
arm treated with 12 months of LHRHa monotherapy are 4-8 and 8-12 points, respectively, based 
on prior studies of measuring QOL using FACT-P among men treated with ADT [1, 2, 3]. A 
change in total FACT-P score that is clinically meaningful and impacts treatment in prior studies 
ranges from 5-8 points depending on cancer subtype [4].  Approximately 30 subjects will be 
randomized to each of the 3 treatment arms for this comparison.  Accounting for a 
dropout/questionnaire non-completion rate of 10%, this will allow for 27 evaluable subjects per 
study arm.  For the comparison of the mean change in FACT-P score between apalutamide
monotherapy and LHRHa monotherapy, this sample size has 80% power to detect an effect size 
of at least 0.86, corresponding to a difference of 7.5 points in mean 12 month change in FACT-P 
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score between treatment groups with a common standard deviation for the change in each arm of 
8.7 which is similar to the reported standard deviation for LHRHa monotherapy.  This is based 
upon a 2-group t test, using a bi-directional level of significance of 0.025 (adjusted for 
2 comparisons).  To test for non-inferiority in QOL with apalutamide + LHRHa compared with 
LHRHa monotherapy, inferior QOL is defined as a greater than 7-point difference in mean 
change in FACT-P score between the treatment groups and the common standard deviation is 
again assumed to be 8.7.  This sample size has 82% power to reject the null hypothesis of a 
difference in mean score and accept the alternative hypothesis of non-inferiority with an effect 
size of at least 0.81, using a 2-group t-test with 2-sided α of 0.025.
1.5
Randomization and Blinding
1.5.1
Randomization
Upon verification of inclusion and exclusion criteria, eligible patients will be centrally 
randomized in a 1:1:1 ratio to apalutamide monotherapy, apalutamide + LHRHa, or LHRHa 
monotherapy.  The randomization will be stratified as follows:

PSADT (< 6 months vs. 6-12 months)

Age at study entry (≤70 years vs. > 70 years)
Balance in treatment assignment will be achieved using a randomized block design.  
Randomization will be carried out via computer generated random assignment.  All subjects 
must commence treatment within (5 calendar days) of randomization.  Study sites will email the 
Eligibility Checklist to the sponsor to obtain the subject’s treatment assignment. Once subject 
eligibility is confirmed by the sponsor, an email with the treatment assignment number will be 
provided to the study site.
1.5.2
Blinding
This is an open-label study.
2.
GENERAL ANALYSIS DEFINITIONS
Study Day: For safety, study day will be calculated in reference to the date of first dose. Study 
Day 1 corresponds to the date the subject receives first dose of study drug. For efficacy analysis, 
Study Day will be calculated in reference to the date of randomization. 
Cycle: For the purpose of the study, a treatment cycle is defined as 28 days. Subjects will begin 
taking study drug on Day 1 of Cycle 1.  All subjects should be following a 28-day, 28-day, 35-
day schedule for their monthly visit (i.e., the 1st post-Day 1 visit is scheduled for 28 days later, 
the 2nd post-Day 1 visit is scheduled for 28+28 days later, the 3rd post-Day 1 visit is scheduled 
for 28+28+35 days later, the 4th post-Day 1 visit is scheduled for 28+28+35+28 days later, etc).
Baseline Value: Unless otherwise specified, the baseline value will be defined as the closest 
measurement prior to or on the day of the first dose of study drug. Change from baseline will be 
defined as (post-baseline value – baseline value).
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Treatment Duration: Treatment duration will be defined as the duration of time from the date 
of the first dose of study drug to the date of last dose of study drug.
Time to event: Time to event calculations will be defined as the time from randomization to the 
date of the event of interest. Time to event or duration of event endpoints will be based on the 
actual date of the event, not visit number or visit label.
2.1
Analysis Sets
The following analysis sets will be used for this study:
Intent-to-Treat (ITT) Population: The ITT population includes all randomized subjects and 
will be classified according to their assigned treatment group, regardless of the actual treatment 
received. Subject disposition and efficacy analyses will be performed on data from the ITT 
population.
Safety Population: The safety population includes all subjects who received at least 1 dose of 
study drug as actually treated.
Modified Intent-to-Treat Population (mITT): For outcomes related to testosterone recovery, 
subjects who withdrew from the study prior to 24 months after day 1 will be excluded from the 
analysis.
2.2
Study Period I: On-therapy Period (Months 1-12)
The 24-month study treatment period will be divided into two 12-month periods: the on-therapy 
period during which subjects receive protocol therapy (apalutamide monotherapy, apalutamide + 
LHRHa, or LHRHa monotherapy).  Subjects will commence protocol therapy on Day 1 of the 
on-therapy period. The study timeline is defined as Day 1 = first dose of study treatment. 
Subsequent study time points will be defined based on study calendar, irrespective of subsequent 
dose delays/interruptions.
Subjects will be treated with protocol therapy for 12 months, or until disease progression (either 
by PSA or radiographic), unacceptable toxicity, subject/physician withdrawal, or initiation of 
non-protocol therapy.  PSA progression is defined as an increase in PSA to > 50% of the 
baseline value or an increase of > 2 ng/mL above the nadir, whichever is higher confirmed by 
repeat measurement at least 2 weeks later.  Radiographic progression is defined as the detection 
of new metastasis on either bone scan or cross-sectional imaging (CT or MRI) [5].  If subjects 
develop progressive disease (either by PSA or radiographic) while receiving protocol therapy, 
they will discontinue protocol therapy, have a Progression Visit, and be treated as per individual 
investigator discretion.  
If there is no evidence of disease progression (by serum PSA or radiographically) after 
12 months of protocol therapy or if subject discontinues treatment before 12 months of protocol 
therapy for reasons other than disease progression, subjects will enter the 12-month Off-therapy 
Observation Period. Continuation of hormone therapy or initiation of any form of anti-cancer 
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therapy in the absence of PSA or radiographic progression will be considered non-protocol 
therapy and will result in study removal.
Efforts will be made to ensure that subjects who develop progressive disease before 12 months 
of therapy still complete QOL scales at 3 and 12 months.
2.2.1
Day 1 of Study Treatment
Patients will return to study site for a history and physical exam including weight, measurement 
of serum PSA, and dispensing of study drug(s), including the first injection of LHRHa and 1-
month supply of apalutamide for subjects randomized to those arms. Collection of optional 
samples (samples for banking, archival FFPE blocks or slides for transcriptome profiling 
(RNAseq), whole blood for RNA testing, and plasma for biomarker testing) should occur before 
pre-dose. 
2.2.2
LHRH Agonist
For subjects randomized to either the LHRHa monotherapy or the LHRHa + apalutamide
combination treatment arms, the choice and schedule of LHRHa will be up to individual 
investigator’s discretion and will be administered for a total of 12 months of therapy in the 
absence of disease progression or unacceptable toxicity.  No change in dosing schedule of 
LHRHa will be permitted once the subject has commenced protocol therapy.  For example, the 
use of every 3 month subcutaneously injected LHRHa would be administered on Day 1 and on 
Months 3, 6, and 9.  The use of LHRH antagonists (ie, degarelix) will not be permitted. No dose 
reductions or interruptions of LHRHa will be permitted. If a subject does not receive a scheduled 
LHRHa injection within ±7 days of the scheduled due date for injection, he will be removed 
from study.  Subjects on the LHRHa monotherapy arm will not be allowed to crossover to 
receive apalutamide.
2.2.3
Apalutamide
Subjects randomized to either of the two apalutamide-containing arms will receive apalutamide
dosed orally on a daily basis with or without food. The starting dose of apalutamide is 240 
mg/day.  With Amendment 7 (Version 8.0), subjects who are receiving the soft gel capsules will 
switch to the tablet formulation. Ongoing subjects on a reduced dose of capsules should continue 
with that dose with lowest allowed dose being 120 mg. Dose delays and dose reductions will be 
permitted as per guidelines outlined in the study protocol/
2.2.4
Safety Assessment
Subjects will be assessed for adverse events at each monthly clinic visit during the On-therapy 
Period.  Adverse event collection starts with the signing of the ICF. Adverse events will be 
graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03 (available at http://ctep.cancer.gov).  See the study 
protocol for attribution of adverse events.  Dose modifications (interruptions, reductions or both) 
for apalutamide, will be allowed as per guidelines outlined in the study protocol.
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2.2.5
Quality of Life
The FACT-P, EORTC QLQ-C30/QLQ-PR25, and SHIM questionnaires will be completed at the
end of Month 3 and Month 12 or at the time of PSA or radiographic progression (if occurs before 
Month 12, every effort will be made to obtain the 12-month questionnaires for those who 
discontinue before 12 months).
2.2.6
Laboratory Assessments
Subjects who experience disease progression (PSA or radiographically) before the end of 
12 months should complete laboratory assessments at the Progression Visit as outlined in the 
Study Schedule. During treatment, laboratory assessments include the following: 

Serum PSA level measured by ultrasensitive assay at the end of each month

Complete blood count including differential and platelet count at the end of Months 3, 6, 9, 
and 12 of protocol therapy. 

Total bilirubin, alkaline phosphatase, AST, ALT at the end of Months 3, 6, 9, and 12.

TSH at the end of Months 3, 6, 9, and 12.

Fasting glucose, fasting lipid panel (total cholesterol, LDL, HDL, triglyceride), and 
hemoglobin A1C at the end of Months 3, 6, 9, and 12. 

Peripheral blood collection for measurement of serum testosterone, DHT, estradiol, and 
fasting serum insulin levels at the end of Months 3, 6, 9, and 12.  

Peripheral blood and urine collection for banking of, serum, plasma, and urine at the end of 
Months 3, 6, 9, and 12 of protocol therapy (optional). 

Whole blood collected for PAXgene analysis (optional) on Day 1 and end of Month 12 
2.2.7
Radiographic Assessments
A whole-body nuclear bone scan, along with cross-sectional imaging of the abdomen/pelvis (CT 
or MRI) will be obtained as prompted by signs and symptoms of metastatic disease and at the 
time of PSA progression.  DEXA scan measuring BMD at the femoral neck, and lumbar spine 
will be obtained after 12 months of protocol therapy or at the time of PSA or radiographic 
progression (if occurs before Month 12, see Progression Visit in Study Schedule). 
Subjects who are intolerant of IV CT contrast agents may have CT scans performed with oral 
contrast or without, if method is identical each time new scans are done. There will be no central 
reading of the scans and radiographic progression will be based upon investigator assessment.
2.3
Study Period II: Off-therapy Observation Period (Months 13-24)
Subjects without progressive disease (by PSA or radiographic) after 12 months of protocol 
therapy will stop protocol therapy and enter the Off-therapy Observation Period from Month 13 
to Month 24. Continuation of hormonal therapy or initiation of any other of anti-cancer therapy 
in the absence of PSA or radiographic progression will be considered non-protocol therapy and 
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will result in study removal. Use of concomitant medications, which may affect serum PSA will 
not be permitted. 
Subjects who develop either PSA or radiographic progression during the Off-therapy 
Observation Period will have a Progression Visit and be treated as per individual investigator 
discretion.  Efforts will be made to ensure that subjects who develop progressive disease (PSA or 
radiographic) or discontinue in the absence of progressive disease before 24 months still 
complete QOL scales after 24 months as prespecified in the study protocol. 
2.3.1
Safety Assessment 
Subjects will be assessed for adverse events at clinic visits at the end of every 2 months during 
the Off-therapy Observation Period. 
2.3.2
Quality of Life
The FACT-P, EORTC QLQ-C30/QLQ-PR25, and SHIM questionnaires will be completed at the 
time of progression (PSA or radiographic) or after 24 months. 
2.3.3
Laboratory Assessments
Subjects who experience disease progression (PSA or radiographic) before the end of 24 months 
should complete laboratory assessments at the Progression Visit as outlined in the Study 
Schedule. During the Off-therapy Follow up Period laboratory assessments include the 
following: 

Serum PSA level at the end of every 2 months. 

Peripheral blood collection for measurement of serum testosterone levels at the end of every 
2 months.

Fasting glucose, fasting lipid panel (total cholesterol, LDL, HDL, triglyceride), and 
hemoglobin A1C at the end of Months 18 and 24. 

Peripheral blood collection for measurement of fasting serum insulin at the end of Months 
18 and 24.
2.3.4
Radiographic Assessment
A whole-body nuclear bone scan, along with cross-sectional imaging of the abdomen/pelvis (CT 
or MRI; with IV contrast per individual investigator discretion), will be obtained as prompted by 
signs and symptoms of metastatic disease and at the time of PSA progression. Subjects who are 
intolerant of IV CT contrast agents may have CT scans performed with oral contrast or without, 
as long as method is identical each time new scans are done There will be no central reading of 
the scans and radiographic progression will be based upon investigator assessment.
2.4
Follow Up Period (Month 25+)
Subjects without progressive disease (PSA or radiographic) at end of 24 months will enter a 
Follow-up Period.  During this period, subjects will be followed by history and physical exam, 
serum PSA, and testosterone levels every 3 months.  Subjects who develop PSA or radiographic 
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progression or initiate non-protocol therapy will be removed from study and treated as per 
individual investigator discretion. If no progressive disease occurred during Months 1 to 24 and
it occurs during the Follow-up Period, whole blood RNA and plasma sample collections for 
biomarker testing should be collected from subjects who consented to this optional sample 
collection.
3.
INTERIM ANALYSIS
No interim analysis will be planned for efficacy due to the expected rate of accrual, the primary 
endpoint being analyzed, and total sample size. An interim safety review will be performed after 
20 subjects have completed at least 1 month of therapy with either apalutamide monotherapy or 
apalutamide + LHRHa.  If there are more than 5 subjects with Grade 3 or higher toxicities not 
related to ADT (anemia, fatigue, gynecomastia, hot flushes, decreased libido, erectile 
dysfunction, mood changes, and weight gain), that the study investigator deems as possibly, 
probably, or definitely treatment-related, the study will be terminated.  This indicates that at least 
30% of the subjects had unacceptable toxicities.  If accrual is completed and all 60 subjects were 
treated with apalutamide (with or without LHRHa) and if unacceptable toxicity is > 30%, then 
the exact 95% lower bound for unacceptable toxicity of 30% would be 20.4%.  Study enrollment 
will continue during the interim safety review.
4.
SUBJECT INFORMATION
4.1
Demographics and Baseline Characteristics
The following will be summarized by treatment group and overall using the ITT population:

Age, race, ethnicity, height, and weight.

Baseline ECOG performance status

Baseline PSA value

Number of years since diagnosis of prostate cancer

Gleason grade/clinical stage/pathologic stage (if prior prostatectomy)/PSA at the time of 
diagnosis

Fasting glucose, fasting lipid panel (total cholesterol, LDL, HDL, triglyceride), and 
hemoglobin A1C

Use of (neo) adjuvant ADT and time interval since prior ADT (if applicable)

Type and date(s) of definitive local therapy (radical prostatectomy and/or radiation therapy)

Time interval from definitive therapy to biochemical relapse to study entry

PSA doubling time at the time of study entry

QOL as measured by FACT-P, EORTC QLQ-C30/QLQ-PR25, and SHIM scores at study 
entry
4.2
Disposition Information
Subject enrollment and disposition will be summarized by treatment group. The summary of 
subject disposition will display the number of subjects randomized, and the numbers of subjects 
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in ITT, safety. The summary will also include the number and percent of subjects who completed 
the study and who discontinued from the study and study treatment, respectively, and reason for 
discontinuation as documented in the subject status case report form.
4.3
Treatment Compliance and Extent of Exposure
The safety population will be used to summarize drug exposure, treatment compliance, and dose 
modifications by treatment group.
Treatment duration will be defined as the duration from the date of the first dose of study drug to 
the date of last dose of study drug. The number of tablets taken will be calculated based on the 
number of tablets dispensed at the study visits minus the number of returned tablets.
For apalutamide, the overall percent treatment compliance will be defined as the number of 
tablets taken during the study divided by the expected number of tablets, multiplied by 100. Each 
subject should be taking a maximum of 4 x 60-mg tablets of study drug per day while on the 
study. A subject’s expected number of tablets will be calculated as the number of assigned
tablets per day multiplied by treatment duration. 
Choice of specific LHRHa to be used in this study will be per investigator discretion/site practice 
guidelines.  Options include Eligard®, Lupron Depot®, Zoladex®, or Trelstar®.  Dosing schedule 
will be per individual investigator discretion. The use of LHRH antagonists (e.g. degarelix) will 
not be permitted. The LHRHa injections will be delivered either subcutaneously (Eligard®, 
Zoladex®) or intramuscularly (Lupron Depot®, Trelstar®) by a trained health care provider while 
on protocol therapy. Subjects with at least one dose modification and the reason for the dose 
modification will be summarized by treatment group.
4.4
Protocol Deviations
Protocol deviations and eligibility deviations will also be summarized by treatment group. 
Protocol deviations will be reviewed on a case-by-case basis and assessed if they are considered 
major deviations for this study. The final list will be compiled before database lock. Examples of 
major protocol deviations may include, but are not limited to, the following:

Deviation from inclusion/exclusion criteria that may affect efficacy endpoints

Major study drug dosing errors or dose modifications that are not within the protocol 
specifications that may compromise subject safety or efficacy assessments.

Administration of prohibited concomitant medication during the course of the study 
treatment period

Any other deviation that impacts subject safety 
4.5
Pre-study and Concomitant Therapy
Concomitant medications, other than study treatment, and medications taken prior to starting 
study treatment will be summarized for all subjects using the Safety population analysis set by 
treatment group. Concomitant medications will be recorded at each monthly clinic visit. Subjects 
are recommended to take calcium 1000 mg/day and vitamin D (cholecalciferol) 800 IU/day in 
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divided doses.  Phosphodiesterase inhibitors such as sildenafil used to treat erectile dysfunction 
may be initiated or continued as per individual investigator discretion.  Breast irradiation and/or 
tamoxifen to prevent and/or treat painful gynecomastia will also be permitted per individual 
investigator discretion. Subjects who require the initiation of bisphosphonate or other bone-
targeted therapy (eg, those sustaining an osteoporotic fracture) while on study will be permitted 
to do so and remain on study, but subjects who have used a bone-modifying agent within 
3 months prior to randomization will be excluded.
4.6
Prohibited Medications
No concomitant use of any anti-cancer therapy will be permitted.  This will include surgery, 
radiation therapy, and other secondary hormonal therapies including first generation 
antiandrogens, 5-alpha reductase inhibitors (i.e. finasteride, dutasteride), megestrol acetate, 
immunotherapy, chemotherapy, or other investigational agents while on study. Start of any of 
these therapies will result in discontinuation from the study. Nutritional supplements containing 
saw palmetto or pomegranate are also specifically prohibited.  
As a class effect, androgen receptor antagonists have been associated with seizures due to an 
off-target mechanism of action (GABAA inhibition).  To date, no subjects receiving apalutamide
have experienced seizures, however, in preclinical experiments, at very high doses, dogs treated 
with apalutamide had tremors and generalized seizures.  Subjects will be closely monitored for 
seizures, but as a precautionary measure, the following drugs known to decrease the seizure 
threshold or cause seizure will be prohibited.

Aminophylline, theophylline 

Atypical anti-psychotic drugs: clozapine, olanzapine, ziprasidone, bupropion

Phenothiazine anti-psychotic drugs: chlorpromazine, mesoridazine, thioridazine

Tricyclic and tetracyclic anti-depressants: amitriptyline, desipramine, doxipine, imipramine, 
maprotiline, mirtazapine (Remeron)

Lithium

Meperidine (Demerol) and pethidine
4.7
Reasons for Study Discontinuation
Subjects will discontinue study protocol treatment for the following reasons, whichever comes 
soonest:

PSA progression

Radiographic progression, defined as the detection of new metastasis on either bone scan or 
cross-sectional imaging (CT or MRI).

Subject or treating physician decision 

Unacceptable toxicity 

Non-protocol therapy 
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5.
EFFICACY
This section outlines the planned analyses of the primary, secondary, and other efficacy 
endpoints of the study.
Efficacy analyses will be performed in the ITT population, incorporating the randomization 
stratification factors. All continuous variables will be summarized using number of subjects (n), 
mean, standard deviation (SD), median, minimum, and maximum. Categorical variables will be 
summarized with count and percentage.
Time-to-event endpoints will be summarized using the Kaplan-Meier method [6] and displayed 
graphically where appropriate. Median event times and two-sided 95% confidence interval (CI) 
for each treatment group will be provided. Stratified Cox proportional-hazard models will be 
used to estimate the hazard ratio (HR) and its 95% CI. The stratification factors to be used in the 
analysis are PSADT (< 6 months vs. 6-12 months), and age at study entry (≤70 years vs. > 70 
years).
The testing for the time-to-event endpoints will be based on the stratified log rank test; non-
stratified log rank test will be performed as a sensitivity analysis, as appropriate. Multivariate 
Cox regression analysis, adjusting for important selected prognostic factors.
The proportional hazard assumption will be assessed graphically by plotting log (-log [estimated 
survival distribution function]) against log (survival time). The resulting graphs should have 
approximately parallel lines when the assumption holds. If the proportional hazards assumption 
is reasonably met, then the HR will be used as an estimate of treatment effect. If the proportional 
hazards assumption is violated, then the inference remains statistically valid for testing equality 
in survival distributions, but treatment effect will only be estimated using the median time to 
event in each treatment group.
Endpoints with binary outcome will be summarized by descriptive statistics (count and 
percentage) by the treatment group. The risk ratio or risk difference (treatment: control) will be 
reported along with the corresponding two-sided 95% CI. The two treatment groups will be 
compared by using the chi-square test; Fisher’s exact test may be used if the expected counts in 
some of the cells are less than 5.
5.1
Analysis Specification
5.1.1
Level of Significance
In general, a two-sided significance level of α = 0.05 will be used for all hypothesis testing and 
all CIs will be calculated on the two-sided 95% confidence level, unless otherwise specified. 
Since this is a three-arm study testing two simultaneous hypotheses, α/2 = 0.025 level of 
significance will be used to test each.
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5.1.2
Data Handling Rules
In general, no imputation method is planned for handling missing or incomplete data. Sensitivity 
analyses with censoring rules may be conducted if warranted and will be documented in the 
clinical study report.
5.2
Primary Endpoint
The primary efficacy endpoint is the mean change from baseline in total FACT-P score at 12 
months. The FACT-P scale is described in section 5.4.1.
5.2.1
Analytic Plan for the Primary Endpoint
Change from baseline in FACT-P total scale will be analyzed using a mixed-model for repeated 
measures. The model will include baseline scale, treatment, month (categorical), and treatment-
by-month interaction as covariates. An unstructured variance-covariance matrix will be used to 
model within-subject errors, but simpler structures (eg, compound symmetry) may be used to 
ensure estimation convergence. Change from baseline will be estimated using least-squares 
means with factor levels weighted according to overall baseline sample means. Data up to 12 
months will be included in the analysis and the primary time point of interest will be at 12 
months. Contrasts will be set up to compare apalutamide monotherapy vs. LHRHa monotherapy
and apalutamide + LHRHa vs. LHRHa monotherapy. To test for non-inferiority with respect to 
apalutamide + LHRHa compared with LHRHa monotherapy, inferior boundary is defined as a 
greater than 7-point difference in mean change in FACT-P total score. The estimated least-
squares mean (+/- SE) over time will be presented using a line plot. A sensitivity analysis will be 
conducted by including data up to 24 months.
5.3
Secondary Endpoints
The following secondary endpoints will be analyzed:
A) Quality of Life: 

Mean change from baseline in total FACT-P score over time

Mean change from baseline in EORTC QLQ-C30/PR25 score over time

Mean change from baseline in SHIM score over time
B) PSA Modulation:

Time to PSA progression, which is defined as a rise to greater than 50% of the baseline 
serum PSA or rise of 2 ng/mL or more above the nadir, whichever is higher, confirmed by 
repeat measurement at least 2 weeks later (see Table 1 for the censoring rules).

Proportion of subjects without evidence of PSA or radiographic progression during the 24-
month treatment period and with recovery of serum testosterone at 24 months. Testosterone 
recovery will be defined as a serum testosterone greater than 150 ng/dL.

Proportion of subjects with a PSA less than 0.2 ng/mL after 7 months of protocol therapy
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C) Metabolic and Hormonal

Mean change from baseline in markers of insulin resistance (including body mass index, 
fasting glucose/insulin, and hemoglobin A1C), fasting lipid profile, and bone mineral 
density as measured at the femoral neck, and lumbar spine by DEXA scan over time 

Time to testosterone recovery to greater than 50 ng/dL (non-castrate) and greater 
than 150 ng/dL during the off-therapy observation period for subjects randomized to the 
LHRHa-based treatment arms (see Table 1 for the censoring rules)

The mean change from baseline in serum DHT and estradiol levels over time
5.3.1
Analytic Plan for the Secondary Endpoints
5.3.1.1
Quality of Life
The secondary QOL endpoints will be analyzed using a mixed-model for repeated measures like
the primary endpoint. The model will include baseline scale, treatment, month (categorical), and 
treatment-by-month interaction as covariates. FACT-P, EORTC QLQ-C30/PR25, and SHIM 
scales are described in sections 5.4.1, 5.4.2, and 5.4.3, respectively. 
5.3.1.2
PSA Modulation
The proportion of subjects without PSA or radiographic progression and who have recovered 
serum testosterone to greater than 150 ng/dL at 24 months from Day 1 will be compared for 
subjects treated apalutamide monotherapy vs. LHRHa monotherapy and for apalutamide + 
LHRHa vs. LHRHa monotherapy.  The proportions by treatment will be compared using the 
chi-square test or Fisher’s exact test as appropriate and summarized using either risk ratio or risk 
difference and corresponding 95% confidence interval. Results will be summarized at 24 months 
from Day 1 with 95% confidence intervals for each treatment arm. Subjects who withdraw from 
the study prior to 24 months after Day 1 will not be included and this analysis will be conducted 
as modified intent-to-treat (mITT).
The proportion of subjects with a PSA less than 0.2 ng/mL after 7 months of protocol therapy 
will be analyzed using similar approaches for proportion of subjects without evidence of PSA or 
radiographic progression during the 24-month treatment period and with recovery of serum 
testosterone at 24 months. 
The probability distributions by treatment group of the time to PSA progression will be estimated 
using the Kaplan-Meier method. Durations will be measured from Day 1 of study treatment to 
the first date of PSA progression. The log-rank test will be used to compare the distribution of 
time to PSA progression. 
5.3.1.3
Metabolic and Hormonal Parameters
The mean change from baseline for markers of insulin resistance (including fasting glucose, 
insulin, body mass index, and hemoglobin A1C), fasting lipid panel (including total cholesterol, 
LDL, HDL, and serum triglycerides), and hormone levels (including DHT and estradiol) 
analyzed using a similar approach as for the primary endpoint. 
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The mean change in bone mineral density at the femoral neck, and lumbar spine as measured by 
DEXA scan will be compared for apalutamide monotherapy vs. LHRHa monotherapy and 
apalutamide + LHRHa vs. LHRHa monotherapy using an analysis of covariance that controls for 
baseline values of the corresponding measurement. 
The time to serum testosterone recovery to > 50 ng/dL and > 150 ng/dL after the cessation of 
protocol therapy at 12 months will be compared for apalutamide + LHRHa vs. LHRHa 
monotherapy. The probability distributions by treatment group of the time to testosterone 
recovery will be estimated using the Kaplan-Meier method. The log-rank test will be used to 
compare the distribution of time to testosterone recovery. Subjects who discontinue study drug 
prior to 12 months for disease progression, unacceptable toxicity, or study withdrawal, as well as 
subjects who continue hormonal therapy after 12 months or receive non-protocol therapy, will 
not be included in the analysis of this exploratory endpoint. 
No adjustment for multiple comparisons will be made for the analysis of the secondary and 
correlative endpoints. 
Table 1:
Key censoring rules
Scenario
Censoring rule
Time to PSA Progression

Any increase in PSA to > 50% of the baseline value or an increase of ≥2 
ng/mL above the nadir, whichever is higher, and confirmed by repeat 
measurement at least 2 weeks later is considered an event.

Subjects who have no PSA progression at the time of analysis will be 
censored at the last known date of PSA assessment.

Subjects without a baseline PSA or without any post baseline values will 
be censored at randomization date.
Time to Serum Testosterone 
Recovery

Any testosterone value between 12 months to 24 months that is greater 
than 150 ng/dL (or 50 ng/dL as the case may be) is considered an event.

If a subject had testosterone recovery (between 12 and 24 months) that 
happened after hormonal or subsequent therapy started, then the subject 
is censored at the hormonal or subsequent therapy start date.

If a subject had testosterone recovery (between 12 and 24 months) that 
happened before hormonal or subsequent therapy started, then the 
recovery is considered as an event.

Subjects who were not treated will be censored at randomization date.

Subjects who do not fall under any of the above-mentioned category will 
be censored at the end of on-therapy period or off-therapy period (if the 
subject is in the off-therapy period).
5.3.2
Other Evaluations
A) Safety:

Incidence and severity of adverse events.

Abnormal findings in physical exams and laboratory tests
B) Correlative Studies
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
Frequency of subjects emerging with ARF876L mutation at the end of treatment and 
progression. 

Frequency of subjects expressing various RNA markers previously demonstrated to confer 
resistance apalutamide at baseline, end of treatment, and progression
5.4
QOL Scales
5.4.1
FACT-P
The FACT-P scale [version 4.0] is a well validated metric [7] developed by Cella and colleagues, 
which includes a 27-item “core” quality of life measure (FACT-G) grouped into 4 subscales: 
physical well-being, social/family well-being, emotional well-being, and functional well-being.  
There are an additional 12 items specific to prostate cancer; 10 of which are prostate cancer 
specific physical problems.  Items are rated on a 5-item Likert scale, from 0, “not at all”, to 4, 
“very much” (see Section 11.1).  The total range of scores is from 0 – 156.  Higher scores 
indicate higher degree of functioning and better quality of life. Concurrent validity was 
confirmed by the ability to discriminate subjects by disease stage, performance status, and 
baseline prostate-specific antigen (PSA) level.  Prior clinical trials have established that 
minimally important differences that are clinically significant and may impact treatment 
decisions range from 5 to 8 points depending on tumor subtype [8].
5.4.2
EORTC QLQ-C30
The EORTC QLQ-C30 [Version 3] is a well validated [9], and widely used measure of health-
related quality of life among cancer patients.  The EORTC QLQ-C30 consists of 30 items, which 
list the functioning and symptoms of cancer patients.  Five multi-item function scales are scored: 
physical function (PF), role function (RF), emotional function (EF), social function (SF), and 
global health status/quality of life.  Furthermore, nine single-item scales (symptoms) are scored, 
including fatigue, pain, dyspnea, and gastrointestinal problems.  The scales are, according to the 
EORTC guidelines, linearly transformed: all scales range from 0 to 100, in which a higher scale 
score represents a higher level of functioning.  With respect to the single-item scale, a higher 
score indicates more symptoms or problems; scores of these items will be inverted for the 
purposes of statistical analysis.  In addition, a subscale related to prostate cancer (EORTC QLQ-
PR25) will also be administered, consisting of 25 items, with the same linear transformation to a 
scale ranging from 0 to 100 (see Section 11.2).
5.4.3
Sexual Health Inventory for Men (SHIM)
The Sexual Health Inventory for Men (SHIM) is a well validated [10] abridged 5-item of the 
15-item International Index of Erectile Function, which has been extensively studied in men with 
erectile dysfunction due to various etiologies, including prostate cancer-related therapies.  It 
consists of 5 items pertaining to sexual functioning, with scores ranging from 0-5 for most items. 
Higher scores indicate higher level of sexual function and less erectile dysfunction (see Section 
11.3). 
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6.
SAFETY
6.1
Adverse Events
The verbatim terms used in the electronic case report form (eCRF) by investigators to identify 
adverse events will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Toxicities will be graded for severity according to 
NCI-CTCAE Version 4.03. All reported adverse events with onset during the On-therapy Period 
up to 30 days after the last dose of study medication will be included in the analysis. 
Specifically, the following adverse events will be summarized:

All adverse events

Grade 3 or higher adverse events

Serious adverse events

Adverse events leading to discontinuation of treatment

Adverse events leading to death
Summaries, listings, or subject narratives may be provided, as appropriate, for those subjects 
who died, who discontinue treatment due to an adverse event, or who experience a ≥Grade 3 or 
higher or a serious adverse event.
In addition, abnormal findings in physical exams and laboratory tests will be summarized. 
All AEs reported during the AE reporting period (inclusive of the 30-day post last dose of study 
drug period) will be considered as treatment-emergent adverse events and will be summarized by 
treatment group as treated using all subjects in the safety population.
For each treatment group, AE incidence rates will be summarized with frequency and percentage 
by SOC and preferred term, with all subjects treated in that treatment group as the denominator, 
unless otherwise specified. In addition, AE incidence rates will also be summarized by severity 
and relationship to study drug. Treatment-related AEs are those judged by the Investigator to be 
at least possibly related to the blinded study drug. Subjects with multiple occurrences of events 
will only be counted once at the maximum severity to study drug for each preferred team, SOC, 
and overall. Deaths that occur within 30 days after the last dose of study drug are defined as on-
study deaths.
AE onset date will not be imputed if it’s completely missing. Partial AE onset date will be 
imputed as follows:

If the AE onset date is missing day only, it will be set to:

the first day of the month that the AE occurred, if the month/year of the onset of AE is 
different from the month/year of the study treatment start.
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
the day of the study treatment start, if the month/year of the onset of AE is the same as 
month/year of the study treatment start but different from the month/year of the AE 
resolution date.

the day of the study treatment start or the day of AE resolution date, whichever is earlier 
if the month/year of the onset of AE and month/year of the study treatment start and 
month/year of the AE resolution date are same.

If the AE onset date is missing both day and month, it will be set to the earliest of:

January 1 of the year of onset, as long as this date is after the study treatment start

the day and month of the study treatment start, if this date is the same year as that the 
AE occurred.

the AE resolution date.
Summary tables of the following AEs will be provided:

Overall summary of AEs: the number and percentage of subjects who experienced any AE, 
any serious adverse event (SAE), any treatment-related AE, any treatment-related SAE, any 
discontinuations due to an AE, and any deaths  

All AEs by SOC and preferred term All AEs by SOC, preferred term, and toxicity grade

Grades 3 or 4 AEs by SOC and preferred term

Treatment-related AEs by SOC and preferred term

Treatment-related AEs by SOC, preferred term, and toxicity grade

Treatment-related Grades 3 or 4 AEs by SOC and preferred term 

AEs that led to study drug discontinuation by SOC and preferred term. Study drug 
discontinuation will be determined from the treatment disposition CRF (where reason for 
discontinuation is “Adverse Event”) and the specific AE will be determined from the AE 
CRF page (where action taken is “Drug withdrawn”)

AEs that led to study drug discontinuation by SOC, preferred term, and toxicity grade

AEs that led to dose modification by SOC, preferred term, and toxicity grade

All SAEs by SOC and preferred term

All SAEs by SOC, preferred term, and toxicity grade

Deaths will be summarized by time period (on-study vs. during follow-up) and cause of 
death. 
Subject listings of all AEs by toxicity grade, Grades 3 or 4 AEs, all SAEs, AEs that led to study 
drug discontinuation, dose modification, and all deaths will be provided as well.
Narratives will be written for the following subjects in the final clinical study report:

Subjects who die ≤ 30 days after the last dose of study drug

Subjects who discontinue study drug due to treatment-emergent AE 
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
Subjects who experience a treatment-emergent SAE 

Subjects who experience seizure, 

Subjects who experience other Grade 3 or higher treatment-emergent adverse events of 
special interest
6.1.1
Clinical Laboratory Tests
Lab data collected centrally by UCSF and by local labs will be summarized. Normal ranges will 
be used to identify values that are outside the normal ranges and abnormal laboratory results will 
be graded according to the NCI-CTCAE Version 4.03. 
Descriptive statistics will be provided for each test result and for the change from baseline by 
visit. A shift summary of baseline grade by maximum post baseline NCI-CTCAE toxicity grade 
will be presented, as appropriate for selected parameters. For each laboratory parameter, the 
baseline laboratory value will be defined as the last laboratory value collected on or prior to the 
date of the first dose of study drug. A listing of subjects who develop toxicities of Grade ≥3 will 
be provided for each lab type. Liver function test data will be summarized based on eDISH and 
Hy’s Law criteria [11]. Listings will be provided for subjects who meet the eDISH criteria and 
Hy’s Law criteria, respectively.
6.1.2
Vital Signs 
Each vital sign (temperature, blood pressure (systolic and diastolic), respiration rate, and heart 
rate) and change from baseline for blood pressure will be summarized and presented by 
treatment group and study visit. Subjects with clinically significant abnormalities in vital signs as 
compared to baseline will be listed. 
Data will be summarized and presented according to the following categories: 
Parameter
Criteria for Clinically Significant Abnormality
Systolic 
Blood 
Pressure
Absolute result > 160 mmHg and increase from baseline > 20 mmHg
Absolute result < 90 mmHg and decrease from baseline > 20 mmHg
Diastolic 
Blood 
Pressure
Absolute result > 100 mmHg and increase from baseline > 10 mmHg
Absolute result < 50 mmHg and decrease from baseline > 10 mmHg
Weight
5 - < 10% weight loss from baseline
10 - < 20% weight loss from baseline
>= 20% weight loss from baseline
6.1.3
Electrocardiogram
Electrocardiograms (ECGs) (12-lead) will be recorded at Screening. Abnormalities noted at screening 
will be included in the medical history. 
ARN
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7.
PHARMACOKINETICS
Pharmacokinetic assessment (trough PK samples) will be performed per protocol.
8.
BIOMARKERS
Biomarker analyses will be conducted on archival FFPE blocks or slides, plasma and whole 
blood samples collected from subjects who consented to participate in biomarker analysis to 
assess ARF876L mutation and other resistance markers from all 3 treatment groups. 
Further association may be made with clinical endpoints with: 

Markers identified from RNAseq analysis of archival tumor samples

Plasma DNA at progression or end of treatment will be used to assess the frequency of 
ARF876L mutation

Whole blood samples collected at baseline and end of treatment or progression will be used 
to identify the type and frequency of AR anomalies or other RNA based markers associated 
with apalutamide treatment resistance or response
The association of the rest of the biomarkers with clinical response or relevant survival endpoints 
may be assessed using appropriate statistical methods (eg, analysis of variance [ANOVA], 
categorical or survival models), depending on the endpoints. Analyses may be performed within 
and between each treatment group. Other clinical covariates (such as baseline tumor 
characteristics and subject demographics) may also be included in the model. Correlation of 
baseline biomarker expression levels with clinical response or relevant time-to-event endpoints
may be performed to identify responsive (or resistant) subgroups. 
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
adequate subject material. Therefore, some analyses may be deferred or not done if, for any 
reason, the analysis will have no scientific value. Biomarker data from this study may be 
compared with or combined with data obtained from prior studies.
9.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization will be descriptively summarized by treatment group. This report 
will be prepared separately and will not be a part of the clinical study report.
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Segal RJ, Reid RD, Courneya KS, et al. Resistance exercise in men receiving androgen deprivation therapy for 
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Potosky AL, Knopf K, Clegg LX, et al. Quality-of-life outcomes after primary androgen deprivation therapy: 
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Webster K, Cella D, and Yost K. The Functional Assessment of Chronic Illness Therapy
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tumors. JNCI 2000; 92:205-216.
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Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 
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assessment of cancer therapy-prostate measurement. J Urol 1997; 50(6): 920-928.
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Webster K, Cella D, and Yost K.  The Functional Assessment of Chronic Illness Therapy (FACIT) 
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Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of 
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National Cancer Institute 1993; 85(5): 365-376.
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Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Peña BM.Development and evaluation of an abridged, 5-item 
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