A Phase II Open-label, Parallel Group Study of Abiraterone Acetate Plus Prednisone in African American and Caucasian Men With Metastatic Castrate-resistant Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Duke University

Cover Page for Protocol 
Sponsor Name 
Duke Cancer Institute 
NCT Number 
NCT01940276 
Official title of Study 
Abi Race:  A Phase II open-label, parallel group study of Abiraterone 
Acetate plus Prednisone in African American and Caucasian men 
with metastatic castrate-resistant prostate cancer 
Document date 
24 April 2018 

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A Phase II open-label, parallel group study of Abiraterone Acetate plus Prednisone 
in African American and Caucasian men with metastatic castrate-resistant 
prostate cancer 
An Investigator-initiated study, sponsored by Dr Daniel George, MD 
and Duke University Health System 
Principal Investigator 
Statistician 
Daniel George, MD 
 
Susan Halabi, PhD 
 
Sub-Investigators 
Andrew Armstrong, MD, ScM 
 
Michael Harrison, MD 
 
Responsible Study Coordinator 
Carol Winters, RN, OCN, CCRC 
 
Regulatory Coordinator 
 Steven Gray, PhD, RAC 
 
 
Correlative Science Investigators 
Andrew Nixon, PhD 
Jennifer Freedman, PhD 
Janssen Scientific Affairs, LLC – providing funding 
support and study drug 
Correlative studies will be funded in part by National 
Cancer Institute. 
Protocol Date: September 12, 2013 
Protocol Version 1.0 
Amendment 1: December 2, 2013 
Amendment 2: January 21, 2014 
Amendment 3: July 31, 2014 
Amendment 4: November 17, 2014 
Amendment 5: December 29, 2014 
Amendment 6: January 14, 2015 
Amendment 7: March 20, 2015 
Amendment 8: April 2, 2015 
Amendment 9: June 8, 2015 
Amendment 10: June 25, 2015 
Amendment 11: August 25, 2015 
Amendment 12: October 15, 2015 
Amendment 13: October 23,2015 
Amendment 14: November 11, 2015 
Amendment 15: November 24, 2015 
Amendment 16: March 30, 2016 
Amendment 17: November 30, 2016 
Amendment 18: December 20, 2016 
Amendment 19: January 26, 2017 
Amendment 20: March 29, 2017 
Amendment 21: June 26, 2017 
Amendment 22: October 19, 2017 
Amendment 23: January 26, 2018 
Amendment 24: April 24, 2018
 
 
 
 
 
 

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Responsible Study Personnel 
Medical Director/Monitor 
Daniel George, MD 
 
Deliveries:  
 
 
 
 
 
 
 
  
 
Study Coordinator/Data Manager 
Carol Winters, RN, OCN, CCRC 
 
 
 
 
 
 
 
  
Monika Anand, PhD, CCRP 
 
 
 
 
 
 
 
 
 
Regulatory Coordinator 
Steven Gray, PhD, RAC 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
DUHS Affiliated Sites Participating in This Study 
 
 
Duke Cancer Network 
Site PI : Dr. Daniel George, MD 
DLP Maria Parham- Henderson 
Scotland Memorial- Laurinburg 
Southeastern Regional- Lumberton 
Johnston Memorial- Smithfield 
Spartanburg Regional- Spartanburg SC 
 
 
 
Virginia Oncology Associates 
Site PI : Dr Mark Flemming, MD 
 
 
 
 
 
 
 
 

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External Sites Participating in This Study 
 
 
Birmingham VA Medical Center 
Site PI : Dr. Devika Das, MD 
 
Karmanos Cancer Institute 
Site PI : Elizabeth Heath 
 
Salisbury VA 
Site PI : K.C. Balaji 
 
 
 
Tulane University 
Site PI : Alton O. Sartor, MD 
 
University of North Carolina 
Site PI : Matthew Milowsky 
 
Wake Forest University 
Site PI : K.C. Balaji 
 
 
 
 
 

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TABLE OF CONTENTS 
 
List of abbreviations…………………………………………………………………………………………………………….….06 
 
1.0  Synopsis.................................................................................................................................07 
2.0  Study flow chart....................................................................................................................13 
3.0  Current treatment for metastatic CRPC…………………………………………………………………….…...16 
4.0  Abiraterone acetate..............................................................................................................21 
4.1 Abiraterone acetate and mechanism of action 
4.2 Clinical trials with abiraterone acetate and prednisone 
 
4.3 Rationale for current study 
5.0  Study objectives and endpoints...........................................................................................25 
 
5.1 Study objectives 
 
5.2 Study endpoints  
6.0  Investigational plan..............................................................................................................26 
6.1 Overall study design 
6.2 Study population 
6.3 Inclusion and exclusion criteria  
7.0  Patient registration..............................................................................................................31 
 
7.1 Informed consent 
7.2 Lead Site registration 
7.3 Institutional registration  
8.0  Treatments...........................................................................................................................32 
8.1 Abiraterone acetate formulation 
8.2 Abiraterone acetate administration 
8.3 Concomitant therapy 
8.4 Treatment compliance 
9.0  Study assessments………………..………………………………………………………………………………………....35 
 
9.1 Vital signs, performance status, physical exam 
 
9.2 Laboratory evaluations 
 
9.3 ECG 
 
9.4 Imaging 
 
9.5 Exploratory correlative studies 
 
9.6 Follow up period 
10.0  Monitoring and management of suspected Abiraterone acetate toxicity.……………………39 
 
10.1 Management of Drug-related Adverse Events  
10.2 Interruption or discontinuation of treatment  
11.0  Safety assessments and reporting………………………………………………………………………………….44 
 
11.1 Definitions 
11.2 Management of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
11.3 Recording of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
 
11.4 Maintenance of Safety Information 

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11.5 Reporting Timelines 
 
11.6 Transmission Methods 
11.7 Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), 
Special Reporting Situation, and Product Quality Complaints (PQCs) to JANSSEN 
SCIENTIFIC AFFAIRS 
11.8 Dissemination of Safety Information from JANSSEN SCIENTIFIC AFFAIRS to 
INSTITUTION/PRINCIPAL INVESTIGATORS 
12.0  Efficacy assessments...........................................................................................................51 
 
12.1 Baseline tumor evaluation 
 
12.2 Response criteria 
 
12.3 Confirming time-to-event outcomes 
 
12.4 Duration of overall response 
 
12.5 Progression free survival 
 
12.6 Secondary endpoint assessments 
 
12.7 Exploratory assessments 
13.0  Statistical plan.....................................................................................................................57 
14.0  Data reporting and regulatory requirements………….…………………………………..…………………57 
 
14.1 Data entry 
14.2 Study monitoring and quality assurance 
14.3 Data safety and monitoring 
15.0  Protocol amendments or changes in study conduct………................................................60 
16.0  Procedures and instructions..............................................................................................60 
16.1 Disclosure and confidentiality 
16.2 Discontinuation of study  
16.3 Ethics and Good Clinical Practice  
17.0  References...........................................................................................................................63 
 
APPENDICES……………………………………………………………………………………………….………………………….67 
 
Appendix 1:  Performance status criteria 
Appendix 2:   Known CYP450 isoenzyme inducers, inhibitors, and substrates 
Appendix 3:  NCI Common Toxicity Criteria 
Appendix 4:  Prostate cancer working group 2 (PCWG2) guidelines 

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LIST OF ABBREVIATIONS 
 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
AKT  
See PKB (protein Kinase B) 
ALT  
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
AST  
Aspartate aminotransferase 
BUN  
Blood Urea Nitrogen 
CBC  
Complete Blood Count 
CK  
Creatine Kinase 
CK-MB  Creatine Kinase - Muscle and Brain isoenzyme 
CR  
Complete Response 
CRF 
Case report forms 
CRD  
Clinical Research and Development 
CRPC 
Castration resistant prostate cancer 
CS  
Cowden Syndrome 
CT  
Computed Tomography 
CTC  
Circulating Tumor Cells 
CTCAE  Common Terminology Criteria for Adverse Events 
DLT  
Dose Limiting Toxicity 
ECG  
Electrocardiogram 
ECHO  
Echocardiogram 
EGFR  
Epidermal Growth Factor Receptor 
18F-FDG [18F]-Fluorodeoxyglucose 
FPG  
Fasting Plasma Glucose 
GCP  
Good Clinical Practice 
GI  
Gastrointestinal 
HIV  
Human Immunodeficiency Virus 
ICH  
International Conference on Harmonization 
HDL  
High density lipoprotein 
IEC  
Independent Ethics Committee 
IRB  
Institutional Review Board 
 LDL  
Low density lipoprotein 
LVEF  
Left Ventricular Ejection fraction 
MRI  
Magnetic Resonance Imaging 
MTD  
Maximum Tolerated Dose 
MUGA  Multiple Gated Acquisition Scan 
PC 
Prostate cancer 
PD  
Pharmacodynamic 
PET  
Positron Emission Tomography 
PFS 
Progression free survival 
PI3K  
Phosphatidylinositol 3’-kinase 
PIN 
Prostatic intraepithelial neoplasia 
PK  
Pharmacokinetic 
PKB  
Protein Kinase B (or AKT) 
PR 
Partial response 
PT  
Prothrombin Time 
PTEN  
Phosphatase and Tensin homolog 
PTT  
Partial Thromboplastin Time 
QTc 
QT interval (corrected) 
RBC  
Red Blood Cells 
REB  
Research Ethics Board 
RECIST  Response Evaluation In Solid Tumors 
RP 
Radical prostatectomy 
S6K  
Protein Kinase S6 
SAE  
Serious adverse event 
SD 
Stable disease 
SNP         Single Nucleotide Polymorphism 
SOP  
Standard Operating Procedure 
SUV  
Standardized Uptake Value 
TdP 
Torsades de Pointes 
TTE 
Transthoracic echocardiogram 
TTP  
Time to Progression 
ULN  
Upper Limit of Normal 
WBC  
White Blood Count 
WCBP  Women of Childbearing Potential 
WHO  
World Health Organization 
 
 
 
 
 
 
 
 

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1.0  SYNOPSIS 
Study Title:  A Phase II open-label, parallel group study of abiraterone acetate in African American and Caucasian men 
with metastatic castrate-resistant prostate cancer 
 
Protocol Number 
Pro00046383 
Phase 
II 
Type 
Interventional 
Condition/Disease:  Castration resistant metastatic prostate cancer, chemo-naive 
Number of Subjects 
100 
Duration of Subject Participation 
Up to 24 months on study drug 
Number of Study Centers 
5 
Duration of Study  3 years 
Anticipated 30 months accrual time,  
up to 24 month follow up 
Rationale:  African American men have a 60% greater incidence of being diagnosed with prostate cancer and nearly a 2.5 
fold greater chance of mortality from the disease, yet the underlying cause for this increased mortality remains 
controversial [1].  Hormonal levels vary in men by race, with African American men having higher dihydrotestosterone 
(DHT), androstenedione (ASD) and sex hormone-binding globulin (SHBG) than Caucasian men with localized prostate 
cancer [2, 3]. Historically, African American men with prostate cancer have a worse overall survival than Caucasian men, 
however, this is confounded by the timing of androgen deprivation therapy (ADT) and access to other therapies [4, 5].  To 
what extent race affects response to therapy in prostate cancer is not clear.    
Germline polymorphisms of genes involved in androgen signaling have been shown to vary significantly by race and may 
have important implications with regard to response to therapy targeted towards this pathway. Polymorphisms within the 
promoter region of the androgen receptor (AR) (specifically CAG repeats) have been well documented and vary 
significantly according to race, with African American men having significantly shorter CAG repeats resulting in greater AR 
activity [6].  These CAG repeats have been associated with more aggressive disease characteristics [6].  Recently, germline 
polymorphisms in androgen metabolism genes have been shown to have prognostic value in regards to the time to 
development of CRPC in men with prostate cancer on ADT.  Ross et al tested 129 polymorphisms across 20 genes 
associated with androgen metabolism and identified three polymorphisms in separate genes (CYP19A1, HSD3B1, and 
HSD17B4) that were significantly associated with prolonged time to progression (TTP) on ADT [7].  Specifically, individuals 
carrying more than one of the polymorphisms were associated with improved time to CRPC than individuals carrying zero 
or one (P< .0001).  More recently this group identified polymorphisms in two androgen transporter genes, SLCO2B1 and 
SLCO1B3 that were associated with a significantly shorter time to CRPC alone and in combination [8].  Incidences of these 
polymorphisms ranged from 15 to 81%; unfortunately, the cohort of patients used to identify these polymorphisms had 
limited numbers of African American patients or other racial and ethnic groups.   
Recent studies have focused on discovering molecular mechanisms underlying prostate cancer disparities using DNA 
microarrays and bioinformatics.  These studies have compared the gene expression profiles between African American 
and Caucasian American cancers and between prostate cancer and patient-matched normal prostate from African 
Americans and Caucasian Americans.  By integrating gene expression profiling and pathway analyses, multiple 
components within the androgen receptor signaling pathway were revealed to be up-regulated in African American 
prostate cancer specimens along with the up-regulation of genes within other signaling pathways that converge on 
androgen receptor signaling, portending that androgen receptor pathway activation is a key component of prostate 
cancer health disparities.  Overall the comparison of African American and Caucasian American prostate cancer specimens 
has led to the identification of a number of differentially expressed genes, including CYP19A1, AMFR, CXCR4, MMP9, 
SRD5A2, ADIPOQ, AKT1, ALOX12, ALOX15, ALOX15B, BMP2, CGA, ERG, FASN, IL1B, IL6, IL8, NFKB1, PIK3C3, PIK3CA, 
PI3K3R1, PLA2G2A, TGFB1, TIMP3, TNF, P38MAPK, STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A1, PIK3CB, ARA55, GNA01, 
GNB3, POLR2L, PRKCE, PRKD1, TBP, CALR, GNG2, GNG11, GNG12, CALM1, NFKB2, STAT2, RHOU, FGF13, EIF3B, and GIT1 
[9-12].  Thus, germline polymorphisms of these differentially expressed genes also may have important implications with 
regard to response to therapy targeted towards the androgen signaling pathway. 
To what extent racial differences affect response and time to progression on abiraterone acetate is unknown. Secondarily, 
to what extent differences in systemic hormonal levels as well as androgen transport gene polymorphisms affect response 
to abiraterone acetate is unknown. Understanding any potential differences in response to therapy by race and/or by 

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hormonal/genetic factors could impact on both our clinical use of abiraterone acetate as well as future clinical trial design. 
Finally, as other agents targeting the androgen/androgen receptor pathways become available, it will be important to 
differentiate their activity according to race, genetics and hormonal milieu.   
We propose a pilot study to evaluate in a prospective, parallel group design, radiographic PFS in men with mCRPC treated 
with abiraterone acetate/prednisone by race. Secondary endpoints will describe the response to abiraterone 
acetate/prednisone, PSA kinetics, and safety and tolerability. Exploratory endpoints will describe the incidence and 
associations of key hormonal levels as well as germline polymorphisms in androgen signaling genes and genes that have 
been shown to be differentially expressed in African American versus Caucasian American prostate cancers in both African 
American and Caucasian cohorts.  
Primary Objective:  The primary goal is to prospectively estimate the median radiographic PFS of African American and 
Caucasian men with mCRPC to abiraterone acetate and prednisone. 
Secondary Objectives:  
1) PSA kinetics: to determine  the duration of PSA response, time to nadir, and percent of men who achieve a PSA < 0.1;  
2) Radiographic assessments: to estimate the rate of objective response and incidence of bone flares 
3) Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations 
4) Overall survival 
Exploratory Objectives: 
1) Describe the baseline profile of serum hormone levels (including testosterone, DHT, DHEA, DHEAS, estradiol) and 
lipidomics, the change in levels with subsequent therapy (Cycle 4), and their correlation with response to abiraterone 
acetate.  
2) Describe the germline SNP profiles of target genes involved in androgen signaling and target genes that have been 
shown to be differentially expressed in African American versus Caucasian American prostate cancers as well as a 
genome wide analysis (GWAS) in both African American and Caucasian men with mCRPC and their associations with 
response to abiraterone acetate. 
Design:  This is a non-comparative pilot open-label, parallel arm, multicenter study of abiraterone acetate in African 
American and Caucasian men with mCRPC. The primary goal is to prospectively estimate the median radiographic PFS in 
African American and Caucasian men with mCRPC cancer treated with abiraterone acetate. Patients will self-report on 
race and 50 patients will be enrolled into each group.  Patients will be treated on open-label treatment until evidence of 
disease progression as defined by Prostate Cancer Working Group Two (PCWG2) definition [13] or until two years at which 
point they will roll over to the standard of care at that time.   
  Study schema is shown below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population: This will be a Duke University Health System study conducted through the Duke Cancer Institute, 
composed of a large tertiary referral center and network sites, which treat a high volume of metastatic CRPC patients and 
who prioritize African American patient accrual to clinical trials.  It is anticipated that the Duke Cancer Network and 6 
satellite sites will be needed to accrue 100 subjects (50 African American and 50 Caucasian) over a 30 month accrual 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N
Disease 
Progression 
or 
Adverse 
Event 
 Metastatic, CRPC 
 No history of chemotherapy for CRPC 
 Karnofsky performance status ≥ 70 
 Adenocarcinoma of the prostate 
 No evidence of neuroendocrine ca 
 
Abiraterone 1000 mg po 
daily 
Prednisone 5 mg po BID 

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period.  Typically 20-30 African American subjects per year would be eligible for this protocol at Duke University Medical 
Center alone but this number would be substantially more by including the Duke Cancer Network and outreach sites.  A 
parallel population of Caucasian patients will be accrued. All samples will be analyzed to determine the germline SNP 
profiles of target genes involved in androgen signaling and target genes that have been shown to be differentially 
expressed in African American versus Caucasian American prostate cancers.  In addition, for GWAS, all samples will be 
genotyped using Illumina’s 2.5M beadchip.  
Main Inclusion Criteria:   
 
Male, age ≥ 18 years 
 
Karnofsky performance status ≥ 70 (Appendix 1) 
 
Life expectancy of ≥ 12 months as determined by treating investigator 
 
Written Authorization for Use and Release of Health and Research Study Information (HIPAA authorization per 
institutional requirements) 
 
Willing/able to adhere to the prohibitions and restrictions specified in this protocol  
 
Willing to take abiraterone acetate on an empty stomach; no food should be consumed at least two hours before and 
for at least one hour after the dose of abiraterone acetate is taken  
 
Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate 
barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 1 
week after last dose of abiraterone acetate 
 
Adequate laboratory parameters 
 
Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb>9 g/dL 
 
Serum potassium > 3.5 mEq/L 
 
AST/SGOT and ALT/SGPT ≤ 1.5 x Institutional Upper Limit of Normal (ULN)  
 
Serum bilirubin ≤ 1.5 x Institutional ULN 
 
Serum creatinine ≤ 1.5 x Institutional ULN or 24-hour clearance ≥ 50 mL/min 
 
Serum albumin of > 3.0 g/dl 
 
Histologically confirmed diagnosis of adenocarcinoma of the prostate.  Histologic variants of prostate cancer, 
including neuroendocrine features and small cell carcinoma of the prostate are excluded. 
 
Radiographic evidence of metastatic disease; evaluable non-target lesions and/or bone only metastasis are permitted. 
 
Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. degarelix) must continue on therapy 
unless prior bilateral orchiectomy has been performed.  Screening serum testosterone must be <50 ng/dl.   
 
PSA ≥ 2.0 ng/mL 
 
Evidence of castration resistant disease on ADT as evidenced by one of the following: 
 
Absolute rise in PSA of 2.0 ng/mL or greater, minimum 2 consecutive rising PSA levels with an interval of ≥ 1 
week between each PSA level, OR 
 
2 consecutive PSA levels 50% or greater above the PSA nadir achieved on ADT and separated at least 1 week 
apart, OR 
 
CT or MRI based evidence of disease progression (soft tissue, nodal or visceral disease progression) according 
to modified PCWG2 criteria or modified RECIST 1.1 criteria, or at least 1 new bone scan lesion as compared 
to the most immediate prior radiologic studies. 
 
A minimum of 2 weeks elapsed off of antiandrogen therapy prior to start of study drug (i.e. flutamide, nilutamide, 
bicalutamide)   
 
A minimum of 4 weeks elapsed off of sipuleucel-T prior to start of study drug   
 
A minimum of 4 weeks from any major surgery prior to start of study drug.   
 
Self-reported race of either African American or Caucasian.  
 
Ability to swallow, retain, and absorb oral medication. 
 
Ability to understand and the willingness to sign a written informed consent document. If the subject is unable to 
understand the consent due to comorbidity, such as Alzheimer’s disease, consent by a legally authorized 
representative and assent by the subject will be obtained.  
 
Main Exclusion Criteria:   
Patients who meet any of the following criteria will be excluded from the study: 

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1. Prior treatment with abiraterone acetate or enzalutamide 
2. Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use 
contraindicated 
3. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid 
4. Have known allergies, hypersensitivity, or intolerance to abiraterone acetate or prednisone or their excipients.  
5. Pathological finding consistent with small cell carcinoma of the prostate 
6. Symptomatic Liver or visceral organ metastasis 
7. Have a history of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the 
absorption of the study agents 
8. Known brain metastasis 
9. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC 
10. Previously treated with ketoconazole for prostate cancer for greater than 7 days 
11. Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1. 
12. Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of 
hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment 
13. Poorly controlled diabetes 
14. Active or symptomatic viral hepatitis or chronic liver disease 
15. History of pituitary or adrenal dysfunction 
16. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 
months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection 
fraction measurement of < 50% at baseline 
17. Atrial Fibrillation, or other cardiac arrhythmia requiring therapy 
18. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of recurrence within 24 months 
19. Administration of an investigational therapeutic within 30 days prior to Cycle 1, Day 1 
20. Any condition which, in the opinion of the investigator, would preclude participation in this trial 
Concomitant Treatment:   
Prohibited:  
 
Chemotherapy, radiation therapy, or immunotherapy, or any anti-cancer therapy other than abiraterone acetate and 
prednisone and those described below. 
 
Immunosuppressive doses of systemic corticosteroids greater than prednisone 5mg twice daily or the equivalent. 
 
Agents known to significantly prolong the QTc interval (Appendix 2).   
 
Coumadin or other vitamin K antagonists. 
Permitted: 
 
Standard therapies for preexisting conditions, medical/surgical complications including nausea and diarrhea, and 
palliation. 
 
Non-potent P450 CYPs isoenzyme inhibitors and/or inducers (Appendix 3). 
 
LHRH agonists or antagonists. 
 
Anti-hypertensive medications. 
 
Diabetic medications. 
 
Antidepressants or other medications for mood disorders.   
 
Analgesics including opioids. 
 
Bisphosphonates and/or denosumab. 
 
Erythropoietic agents. 
 
Systemic anticoagulation with low molecular weight heparin. 
 
Focal therapies for localized non-prostate cancers 
Study Intervention and Administration:  The study agent abiraterone acetate will be administered at a dose of 1000mg 
orally once daily with prednisone 5 mg BID in 4-week cycles throughout the treatment period.   Abiraterone acetate must 
be taken on an empty stomach. No food should be consumed for at least two hours before the dose of abiraterone 
acetate is taken and for at least one hour after the dose of abiraterone acetate is taken. Abiraterone acetate should be 

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taken with a glass of water and consumed over as short a time as possible.  Patients should swallow the capsules whole 
and not chew them.  Study drug will be provided by Janssen Scientific Affairs and distributed by DCI Investigational 
Chemotherapy Service. Patients will be instructed to take a 5-mg prednisone tablet, twice daily.  It is not required for the 
prednisone to be taken at the same time as abiraterone acetate. The dose of prednisone will remain unchanged in the 
event that the study drug dose is changed. If a prednisone dose is missed, it should be omitted and will not be made up.  
Should a dose modification of the prednisone be needed due to toxicities, the site will need to discuss this with the 
medical monitor. 
Study Assessments:   
Vital signs, performance status, and physical exam will be assessed at each visit.   The following laboratory studies will be 
obtained at intervals specified in the study flow chart to assess subject safety, specifically the risk of infection, 
hyperglycemia, and/or bone marrow, liver, and kidney abnormalities:  complete blood count, blood urea nitrogen (BUN), 
creatinine, sodium, potassium, calcium, magnesium, phosphorus, glucose, albumin, total protein, total bilirubin, alkaline 
phosphatase, AST (SGOT), ALT (SGPT).   
 
For efficacy assessment, standard-of-care biomarkers including PSA will be drawn prior to initiation and after each cycle 
of therapy.  A CT scan with contrast of chest, abdomen, and pelvis, a bone scan and a circulating tumor cell count will be 
performed within 42 days prior to the intended cycle 1 day 1 visit and every 3 cycles (12 weeks).  
 
Correlative Sciences: 
Whole blood will be collected in purple top EDTA tubes at baseline for DNA isolation and characterization of SNPs for 
androgen metabolism genes as well as genes that have been shown to be differentially expressed in African American 
versus Caucasian American prostate cancers and ancestral genotyping. Additionally, a genome wide analysis (GWAS) is 
planned in both African American and Caucasian men with mCRPC and their associations with response to abiraterone 
acetate, in line with the specified endpoints and biomarkers defined in the trial.  In addition baseline assessments of 
lipidomics and hormonal levels including testosterone, DHT, DHEA, DHEAS, estradiol and their change after  12 weeks on 
therapy will be evaluated.  Finally additional baseline and 4 week plasma samples will be drawn to explore additional 
biomarkers that may have prognostic or predictive value.  
Safety Evaluation:   
Subjects receiving at least one dose of abiraterone acetate will be evaluable for safety.   
 
Safety will be assessed by physical exam, laboratory assessments, review of concomitant medications, adverse event 
(AE) and serious adverse event (SAE) evaluations every cycle throughout the study. 
 
Electrocardiogram prior to initiation and subsequently at the discretion of the treating physician   
 
NCI Common Toxicity Criteria (v 4.0) will be used to record and monitor for adverse events (Appendix 3). 
Treatment will be held and/or dose reduced for certain specified grade 3 or 4 adverse events until resolution to 
grade 1 as specified in the protocol 
Efficacy Evaluation:   
The primary endpoint will be radiographic progression free survival (rPFS) based on PCWG2 criteria or based on the 
onset of a skeletal related event.  Imaging will be obtained every 12 weeks. 
Secondary endpoints will include: 
1. RECIST 1.1 defined radiologic response rates and incidence of bone flares 
2. PSA response, time to nadir, and percent of men who achieve a PSA < 0.1  
3. Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension in the two populations 
 
Statistical Considerations:  Based on Ryan et al. the median time to radiographic progression free survival (rPFS) is 16.5  
months [14]. This trial is non-comparative. Fifty (50) patients will be enrolled in each group (AA and Caucasians). With an 
accrual rate of 50 patients/group over 30-month accrual period,  24-months follow-up, and assuming that rPFS follows an 
exponential distribution, based on 5000 simulations the average width of a two-sided 95% confidence interval for the 
median rPFS is 16. 
 
Ethical Considerations:  
This study will be conducted in accordance with applicable laws and regulations including, but not limited to, the ICH GCP 

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and the ethical principles that have their origins in the Declaration of Helsinki.  The IRB must review and approve the 
protocol and ICF before any subjects are enrolled.  Before any procedures specified in the protocol are performed, the 
subject must sign and date the IRB-approved ICF. 
 

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2.0  STUDY FLOW CHART 
 
 
Procedure 
Screening/ 
Baseline 
Testinga 
 
On-treatment visits 
(+/- 3 for first cycle then +/- 7 days) 
 
 
End of Treatment &  
Follow-up Visits 
 
 Within 30 
days of 
dosing 
     
Intended/ 
Cycle 1  
Day 1p 
 
Cycle 1 
Day 15 
(+/- 5 days) 
Cycle 2, 3  
 Day 1  
Cycle 4 Day 1 & 
every 3rd cycle 
(Cycles 7, 10, 13, 
etc.) 
End of 
Treat- 
mentc 
Follow-
up 
safety 
visitd 
Follow-up visits 
(until disease 
progression or 
new 
treatment)d 
Follow up -
survivald 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior and concomitant non-pharmacologic 
treatments 
X 
X 
X 
X 
X 
X 
X 
 
 
Medical history and AE assessmente 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs, height, and weightf 
X 
X 
X 
X 
X 
X 
X 
 
 
Karnofsky performance statusg 
X 
X  
X 
X 
X 
X 
 
 
 
Physical examinatione 
X  
X 
X 
X 
X 
X 
X 
 
 
Electrocardiogramh 
X 
 
 
 
 
 
 
 
 
Tumor Site Assessments: CT scans (chest, 
abdomen, pelvis) and bone scansi 
Xi 
 
 
 
Xi 
 
Xd 
X 
 
Abiraterone acetate dispensedj 
 
Xp 
 
X 
X 
 
 
 
 
Assess survival 
 
 
 
 
 
 
 
 
Xd 
Standard-of-care laboratory assessmentsk 
 
 
 
 
 
 
 
 
 
CBC with differential  
X 
Xb 
X 
X 
X 
X 
X 
 
 
Serum chemistriesk 
X 
Xb 
X 
X 
X 
X 
X 
 
 
PSA 
X 
Xb 
 
Xk 
Xk 
X 
 
Xk 
 
Testosterone  
X 
 
 
 
Xk 
 
 
 
 
Circulating tumor cell count (optional) k 
X 
 
 
 
Xk 
X 
 
 
 
Lactate dehydrogenase (LDH) 
X 
 
 
 
 
 
 
 
 
Correlative/research studies 
 
 
 
 
 
 
 
 
 
Serum Hormone Levelsl 
X 
 
 
 
Xl 
Xl 
 
 
 
Plasma and serum markersm 
X 
 
 
Xm 
 
 
 
 
 
DNA isolation and characterization of SNPsn 
X 
 
 
 
 
 
 
 
 
Archival tissue collectiono 
X 
 
 
 
 
 
 
 
 

Abiraterone and Race 
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New cancer therapies 
 
 
 
 
 
 
 
X 
 

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Footnotes to Study Flow Chart: 
a. 
Screening/baseline evaluations must be completed within 30 days prior to the intended cycle 1 day 1 visit, with the exception of informed consent (42 days) and scans (42 
days).  
b. 
If the CBC with diff,Serum Chemistries, and PSA are performed within 7 days of intended Cycle 1 Day 1 visit, do not repeat these at the intended Cycle 1 Day 1 visit unless 
requested by the site’s PI. 
c. 
The end of treatment visit is to occur +/- 7 days after the last dose of study agent.     
d. 
The follow-up safety visit is to occur 28 days (+/- 7 days) after the last dose of study agent.  CT and bone scan will be done at the safety follow up visit if scans have not been 
done within the last 8 weeks of the visit.  After the Day 28 safety follow up visit, patients will visit the clinic once every 3 months for up to 24 months (+/- 14 days) from the 
start of therapy. Subjects who  discontinue treatment due to reasons other than radiographic progressive disease will be followed until a new treatment is started or 
disease progression. Abiraterone prescribed off-study is not be considered a new treatment. Disease progression will be obtained through Standard of Care scans. Subjects 
who discontinue due to progression will not be followed. Survival will be assessed by chart review or phone call. 
e. 
Medical history, physical examination and AE assessments will be performed prior to study agent administration, on Day 1 and 15 of cycle 1 and on Day 1 only of each 
subsequent cycles  2, 3, 4 7, 10 and every 3 cycles.  An end-of-study medical history, physical exam, and AE assessment will be performed at the end of treatment or at 
progression.  In addition, one safety follow-up visit with medical history, physical exam, and AE assessment will occur 28 +/- 7 days of the last dose of study drug. 
f. 
Vital signs (BP, pulse, respirations, temperature and weight) will be recorded at each visit.  Height will be measured at screening only.     
g. 
Karnofsky performance status (Appendix 1) will be evaluated and recorded on all clinic visits on study and at the end of treatment.   
h. 
Electrocardiogram prior to initiation and subsequently at the discretion of the treating physician   
i. 
As part of routine tumor assessment, CT and bone scans will be performed within 42 days prior to intended cycle 1 day1 visit and every 3 cycles (approximately every 12 
weeks) thereafter (i.e., baseline, Day 1 of cycles 4, 7, 10 and every 3 cycles).  The timing of the scans will be within 7 days of the next planned cycle initiation.  A CT scan will 
be performed at the above described timepoints with contrast as per radiology protocol of chest, abdomen, and pelvis. If the chest CT at baseline is clear, chest x-rays may 
be used for subsequent assessments at the enrolling physician’s discretion.  These tumor assessments will be performed locally, in strict accordance with the RECIST 1.1 
guidelines.  A total body bone scan will be performed at the above described timepoints and interpreted according to PCWG2 guidelines (Appendix 4).  CT and bone scan 
modalities per standard institutional practices may be used, but the same modality should be used throughout the study for each subject. Scans during follow-up will be 
performed according to standard clinical practice and interpreted as described above.        
j. 
Abiraterone acetate will be dispensed directly from clinic. 
k. 
Standard-of-care laboratory assessments at the times indicated include:   
Complete blood count (CBC) with differential: WBC count with differential, platelet count, hemoglobin, and hematocrit at baseline, Cycle 1 Day 15, Day 1 of  cycles 2, 3, 4 
7, 10 and every 3 cycles, at the end of treatment visit and at safety follow-up visit. 
Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, carbon dioxide or bicarbonate, calcium, magnesium, phosphorus, total 
protein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT),  total bilirubin, and alkaline phosphatase at baseline,  Cycle 1 Day 15, Day 1 of cycles 
2, 3, 4 7, 10 and every 3 cycles, at the end of treatment visit, and at the end of Safety Follow-up Visit. 
PSA:  Drawn at baseline, Day 1 of Cycle 1 and cycles 2, 3, 4, 7, 10 and every 3 cycles, and at the end of treatment visit. During follow-up for subjects who discontinue 
treatment due to reasons other than radiographic progressive disease, PSA will be collected every 3 months (+/- 28 days) and additionally as clinically appropriate. 
Testosterone:  Drawn at baseline and the end of cycle 3 (at Cycle 4 Day 1). 
Circulating tumor cell count (if available):  Standard Cellsearch® CTC test is drawn at baseline, Day 1 of every 3 cycles (i.e. cycles 4, 7, 10, etc.), and at the end of 
treatment visit.   
Note: Intended Cycle 1 Day 1 CBC, Serum Chemistries, &PSA lab tests do not have to be repeated if screening lab tests are obtained within 7 days prior to the intended 
Cycle 1 Day 1 visit.   
l. 
Serum hormone levels include Testosterone (ultrasensitive) DHT, DHEA, DHEAS, and estradiol: One 5ml gold top tube will be collected at baseline, the end of cycle 3 (at 
Cycle 4 Day 1), and at the end of treatment visit, end of treatment research labs may be drawn at safety follow up visit if needed. Lipidomics will also be assessed at 
baseline and cycle 4 day 1 and the samples should be collected after fasting. See lab manual for detailed instructions. 
m. Plasma for blood-based biomarkers: One 6ml lavender top tube and one 4.5ml light blue top tube will be collected at baseline and end of cycle 1 (Cycle 2, Day 1).  

Abiraterone and Race 
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n. 
DNA isolation and characterization of SNPs: One 4ml lavender top tube will be collected at baseline  See lab manual for detailed instructions. 
o. 
If available and consistent with local regulations, banked tumor tissue (unstained slides and/or a paraffin-embedded block) will be obtained and evaluated to assess somatic 
expression of target genes involved in androgen metabolism, target genes that have been shown to be differentially expressed in African American versus Caucasian 
American prostate cancers, and AR splice variants, potentially predictive of abiraterone acetate antitumor activity. See lab manual for detailed instructions. 
p. 
All assessments must be performed on the intended cycle 1 day 1 visit. However, Cycle 1 day 1 is the first day of treatment and must occur within 2 weeks of the intended 
cycle 1 day 1 visit.  
Note: Screening/baseline correlative research studies may be drawn on screening/baseline or Intended Cycle 1 day 1 visit.

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3.0   CURRENT TREATMENT FOR METASTATIC CRPC 
 
3.1 Metastatic Castrate Resistant Prostate Cancer 
 
Prostate cancer has become an increasingly important health issue globally. With 903,500 
men diagnosed in 2008, prostate cancer is the second most diagnosed cancer worldwide [15]. It 
is estimated by the American Cancer Society that in 2012, prostate cancer will be diagnosed in 
241,740 men in the United States alone and that 28,170 will die [1]. 
 
The most significant morbidity of prostate cancer is bone metastasis. It develops initially in the 
axial skeleton and later in the appendicular skeleton in advanced prostate cancer and 
metastasis to bone is present in > 90% of patients [16-18]. These lesions can cause pain, 
skeletal fractures, spinal cord compression, anemia and thrombocytopenia. Clinical sequelae 
can include pain, paralysis, diminished mobility, fatigue and increased risk of infections. Side 
effects such as constipation and delirium from analgesics required to palliate pain are also 
significant. They further compromise patient quality of life.  In addition, soft tissue metastasis 
occurs in about 40% of advanced patients. Pelvic lymphadenopathy may lead to anatomic 
obstruction of the ureters, or fistula formation [16]. When tumor recurs in the prostate gland or 
bed, urethral obstruction may also ensue.  
 
Prostate cancer is hormone sensitive at the time of initial diagnosis. Although most patients 
with advanced metastatic disease initially respond to conventional androgen deprivation with 
medical or surgical castration, the median duration of disease control has been 13-22 months 
and historically overall survival may be as short as 28-36 months from starting androgen 
deprivation therapy [19-21]. The clinical status of patients after failure of castration is 
commonly referred to as hormone-refractory prostate cancer (HRPC), or androgen-
independent prostate cancer (AIPC). However, recent investigations have established that 
tumor progression often remains androgen-dependent albeit at much reduced systemic 
androgen levels after castration. Although used widely in clinical settings, the terms HRPC and 
AIPC do not reflect the biology of advanced prostate cancer where androgen receptor (AR) and 
its ligand remain pivotal in tumor growth. Prostate cancer progression after conventional 
medical or surgical castration should, therefore, be considered castration-resistant prostate 
cancer (CRPC). Patients with metastatic CRPC have a very limited life expectancy and most 
often die of their prostate cancer. 
 
In the castrate state, remaining ligands to the AR have been thought to be derived primarily 
from the adrenal glands. Conventional androgen deprivation therapy removes 90% of 
circulating androgens produced in the gonads. As much as 10% of circulating testosterone 
remains, in part due to the peripheral conversion of adrenal steroids to testosterone. In 
addition, several recent studies suggest that androgen levels in the microenvironment of 
prostate cancer may be maintained in spite of reduced systemic levels [22, 23].  In patients with 
castrate levels of testosterone, the tissue levels of dehydroepiandrosterone, 
dihydrotestosterone, and androstenedione all remain sufficient to activate the AR. 
Furthermore, the ARs are predominately located in the nucleus in biopsy tissue, indicating 

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ligand-binding and the activation of androgen-dependent gene expression. Increased 
expression of the AR is common in advanced prostate cancer, and allows lower ligand levels to 
more strongly activate the AR [24]. A recent investigation made the observation that in high risk 
primary prostate tumors and in metastatic biopsies, CYP17A1 gene expression is highly 
upregulated, suggesting the possibility of in situ production of androgens as autocrine or 
paracrine growth factors despite castration.[25, 26] Similarly, investigators at MD Anderson 
Cancer Center also detected CYP17 expression by immunohistochemistry in bone marrow 
metastasis in CRPC [27]. Although these preliminary findings require further corroborating 
evidence, the need to suppress androgen production in adrenal glands and possibly at tissue 
levels persists in CRPC. 
 
Complete androgen independence in CRPC is thought to be rare. A few patients (9%) have 
mutations in the AR; these changes could allow the AR to be activated by non-androgen ligands, 
or might allow ligand-independent AR association with coactivator molecules.[28] 
 
Although gene fusions are well known to drive the development of blood cancers and 
sarcomas, only rarely have they been detected in the common solid cancers. Recent evidence 
indicates that a gene fusion may be important in the pathogenesis of prostate carcinoma.[29-
33] Chromosomal translocations involving the androgen-responsive gene transmembrane 
protease serine 2 (TMPRSS2) and erythroblast transformation–specific (ETS)-related 
transcription factors ETV1, ETV4, and ETV5, have been identified in 50% to 70% of prostate 
cancer cases.[29, 30] Translocation of TMPRSS2 to the ERG gene, found in a high proportion of 
human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-
TMPRSS2 promoter. ERG and other ETS family members are transcription factors that are 
implicated in the control of cell growth and differentiation and the chimeric protein product of 
the gene translocation appears to retain hormoneresponsiveness.[31] Specific translocations in 
primary tumors have been associated with more aggressive natural clinical history, more 
advanced disease at diagnosis and greater lethality.[32-35] These gene rearrangements may be 
associated with tumor response to androgen deprivation therapy, including abiraterone acetate  
[36]. 
 
3.2 Asymptomatic or Mildly Symptomatic Patients with CRPC 
 
Approximately 50% of patients with metastatic prostate cancer will have no noticeable 
symptoms related to the tumor.[37] The optimal management of these patients with 
asymptomatic or mildly symptomatic metastatic prostate cancer refractory to androgen 
deprivation therapy remains undefined.[38] There are no approved second-line hormonal 
therapies for this population, and cytotoxic chemotherapies (docetaxel, cabazitaxel, or 
mitoxantrone) are ordinarily reserved for patients with symptomatic or rapidly progressive 
cancer.[39] The American Society of Clinical Oncology / Cancer Care of Ontario and EAU 
guidelines for the cytotoxic treatment of CRPC emphasize the need to individualize the timing 
of nonhormonal therapy for prostate cancer and consider routine docetaxel questionable in 
men who have metastatic disease but lack symptoms.[40, 41] Similarly, the current ESMO 
guidelines for metastatic prostate cancer recommend that patients with castrate-resistant 

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disease should receive second and possibly third line hormonal therapies, while chemotherapy 
with docetaxel given every three weeks should be considered for patients with CRPC who are 
symptomatic.[42] Thus the non-cytotoxic treatment of patients with CRPC who are 
asymptomatic or mildly symptomatic remains a significant unmet medical need. 
 
Patients with metastatic CRPC who are not good candidates for immediate chemotherapy may 
still benefit from alternate therapies since they develop symptomatic disease progression in a 
short period of time. This adverse natural history of patients with asymptomatic or mildly 
symptomatic CRPC was documented in two recent Phase III trials of novel agents in this 
population. A multinational, double-blind, placebo-controlled trial of the endothelin antagonist 
atrasentan in patients with meta
static CRPC who had not received chemotherapy and did not require opiates for cancer related 
pain enrolled 809 men.[43] Patients were randomized 1:1 to receive either atrasentan 10 mg 
per day or placebo. The primary endpoint was time to disease progression (TTP), which was 
determined according to radiographic and clinical measures. Analyses of overall survival and 
changes in biomarkers also were performed. Greater than 50% of patients on both the 
experimental and control arms developed protocol defined progression in less than 100 days, 
with 87% of the progressions by radiographic criteria. In addition more than half of patients on 
the control arm had a 50% worsening of the Pain Catastrophizing Scale (PCS) pain score within 
12 months of study entry, primarily due to increasingly painful bone metastases.[44] The 
median survival was 20.5 months for atrasentan treated patients and 20.3 months for the 
control patients.  
 
A second smaller Phase III study compared the investigational immunotherapy product 
Sipuleucel-T with placebo in patients with CRPC who had not received chemotherapy.[45] 
Patients with cancer-related bone pain, those requiring opioid analgesics for cancer pain, and 
those with visceral metastases were not eligible. Disease progression events included 
radiographic progression, cancer pain, and clinical events, with the great majority radiographic. 
The median for time to disease progression (TTP) for Sipuleucel-T was 11.7 weeks compared 
with 10.0 weeks for placebo. Median survival was 25.9 months for Sipuleucel-T and 21.4 
months for placebo. These results demonstrate that patients with asymptomatic or mildly 
symptomatic CRPC have short times to disease progression and to the rapid appearance of 
painful metastases, with an approximate overall survival of two years or less. Therefore the 
development of an alternate non-cytotoxic therapy with an improved safety and toxicity 
profile, capable of delaying tumor progression, blocking onset or worsening of pain, and 
improving survival would be of significant clinical benefit to patients with CRPC. 
 
3.3 Second line hormonal therapies for CRPC 
 
Second line hormonal therapies in prostate cancer have limited efficacy, and none have 
received regulatory approval for this use. Historically, bilateral adrenalectomy was the first 
second line hormonal therapy to be evaluated.[46] Several of the adrenalectomized patients 
with widespread bone metastases had decreases in the bulkiness of their prostate tumor, 
reductions in prostatic acid phosphatase levels, increases in hemoglobin and red blood cell 

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levels, and strikingly, 5 of 7 patients had complete relief of their cancer pain within 48 hours of 
the surgery. However, patient and physician acceptance of adrenalectomy was low, due to the 
morbidity of major surgery in an advanced stage cancer patient population. 
 
3.3.1 Adrenal Androgen Inhibitor 
 
Historical attempts to obtain the benefits of total adrenalectomy medically without the side 
effects of surgery have met with limited success. Aminoglutethimide and ketoconazole both 
inhibit several adrenal enzymes involved with adrenal androgen synthesis. Modest therapeutic 
activities on prostate cancer were observed. However, the side effects were significant. For 
example, in combination with hydrocortisone, aminoglutethimide resulted in a PSA response 
proportion of 37% with the median duration for responders of nine months in a Phase 2 study 
at the expense of lethargy, skin rash, hypothyroidism, nausea and vomiting. Its use has been 
limited.[47, 48] 
 
Ketoconazole inhibits several adrenal enzymes required for steroid biosynthesis. Its efficacy in 
prostate cancer in terms of PSA response is comparable to that of aminoglutethimide. Pilot 
studies in patients after failure of combined androgen blockade where ketoconazole was given 
simultaneously with anti-androgen withdrawal (AAWD) showed that 55% of patients achieved a 
50% PSA decline.[49] When administered after AAWD, 36%-62.5% of patients had a 50% PSA 
decline.[50, 51] In a Phase 3 study conducted by Cancer and Leukemia Group B, PSA response 
rate was 27% with a median duration of response of 9 months in the group of patients 
randomized to the combination arm of AAWD and ketoconazole plus hydrocortisone versus the 
AAWD alone arm.[52] However, ketoconazole inhibits CYP3A4 with substantial risk of drug-drug 
interactions, such as warfarin and statins.[53] It is often poorly tolerated by patients, with 
commonly occurring side effects including diarrhea, nausea, vomiting, and depression.[50-52] 
Ketoconazole is not approved for the treatment of CRPC. 
 
3.3.2 Glucocorticoids 
 
Glucocorticoids appear to possess both hormonal and direct anti-tumor effects in prostate 
cancer. Patients with CRPC may still have hormone-sensitive disease that is stimulated by weak 
androgens of adrenal origin, and these androgens are suppressed by prednisone through its 
negative feedback on secretion of adrenocorticotrophic hormone (ACTH). Tannock et al have 
demonstrated that low-dose prednisone treatment (7.5 to 10 mg daily) led to a decrease in the 
concentration of serum testosterone in seven of nine patients where it was not initially 
suppressed below 2.0 nmol/mL, and caused a decrease in serum levels of androstenedione and 
dehydroepiandrosterone sulfate in more than 50% of patients.[54] These changes were 
associated with symptomatic and clinical improvement. Glucocorticoids may also have direct 
inhibitory effects on prostate cancer cells through enhanced growthinhibitory TGF-ß1 signaling 
and suppression of the transcriptional activities of NF–κB.[55, 56] 
 
Prednisone, dexamethasone, and hydrocortisone have been frequently administered as  
standard of care in advanced prostate cancer because of their modest antitumor activity and  

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alliative effects on disease. Two prospective Phase 3 studies have documented the adverse 
event profile and palliative benefit of prednisone. Prednisone 7.5-10 mg daily was examined 
among 81 patients in one arm of a Phase 3 trial, with 22% of patients achieving a 50% PSA 
decline and a median time to progression of 4.0 months.[57] Likewise, in a randomized study 
control arm where 201 patients were treated with prednisone 5 mg twice daily, PSA decline of 
≥ 50% was observed in 21% of patients.[58] Significant improvements in pain, quality of life and 
fatigue were also reported. 
 
Other glucocorticoids have similar activity in advanced prostate cancer. Hydrocortisone has 
been evaluated as a control arm in prospective Phase 3 studies. In one study, 231 patients 
treated with hydrocortisone alone (control arm) showed that 16% of patients achieved a PSA 
decline of ≥50% with a median duration of response of 2.5 months.[59] Similarly, 14% of 
patients given hydrocortisone 40 mg daily achieved a PSA decline ≥ 50% lasting a median of 2.3 
months in a Cancer and Leukemia Group B (CALGB) study.[60] The antitumor activity of 
hydrocortisone was slightly lower than prednisone in these Phase 3 studies (14%-16% PSA 
response rate for hydrocortisone versus 21%-22% PSA response rate for prednisone; median 
duration of response also favored prednisone). Likewise, dexamethasone has antitumor activity 
in prostate cancer.[61-63] No prostate cancer trials have directly compared 2 glucocorticoids. 
 
3.3.3 Estrogens 
 
Prostate cancer normally expresses estrogen receptors, and estrogenic compounds have been 
used for the treatment of CRPC. The most commonly used estrogen is diethylstilbestrol (DES), 
although DES-diphosphate, and the herbal phytoestrogenic supplement, PC-SPES, have also 
been investigated in clinical trials. 
 
Recently, DES has been evaluated in two studies including 21 and 32 patients.[64, 65] A positive 
PSA response was achieved in 43% and 80%, respectively; the estimated survival at 2 years was 
63%. However, even at low doses, 31% of the patients developed deep venous thrombosis and 
7% experienced myocardial infarction. In another prospective randomized phase II trial, the 
clinical efficacy of the herbal supplement PC-SPES and DES were tested in a cohort of 90 
patients, with PSA progression following initial androgen deprivation.[66] A PSA decline > 50% 
was noted in 40% with PC-SPES and in 24% with DES. Median time to progression was 5.5 
months with PC-SPES and 2.9 months with DES; the differences were statistically not significant. 
 
Although estrogens remain an option for the secondary hormonal treatment of CRPC, their use 
is limited by concerns regarding cardiovascular toxicity.[41] 
 
3.4 Chemotherapy and Bisphosphonates for CRPC 
 
Several agents have been approved as palliative therapy for prostate cancer. Estramustine was 
approved in the 1970s. However, in a randomized study where overall survival was compared, 
diethystilbesterol was found to be superior to estramustine.[67] In 1996, mitoxantrone and 
prednisone were approved in the United States for palliation of pain and improvement in 

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quality of life in a randomized study with prednisone as control.[57] However, there was no 
survival benefit. Recently, zoledronic acid was approved for reduction in skeletal morbidity in 
solid tumors, including prostate cancer.[68] None of these agents improved the overall or 
prostate cancer-specific survival of patients with CRPC. 
 
Docetaxel is the only agent to date that has demonstrated a survival benefit in CRPC. A 3- 
weekly docetaxel regimen had a median overall survival of 18.9 months (95% confidence 
interval 17.0 – 21.2), compared with the mitoxantrone control arm of 16.5 months (95% 
confidence interval 14.4 – 18.6 months). The hazard ratio for death was 0.76 (95% confidence 
interval 0.62 – 0.94, p =0.009) in the docetaxel regimen as compared with control.[69] 
 
Results from the SWOG Study 99-16 trial of 770 men (3-weekly docetaxel + estramustine + 
dexamethasone vs mitoxantrone + prednisone), median overall survival 17.5 months vs 15.6 
months, respectively, p=0.02 were consistent with the TAX-327 data.[70] 
 
Results from TAX-327 were updated at ASCO 2007. Overall survival results were maintained 
after the additional 2 years of follow-up and an additional 276 deaths [71]. The median survival 
in the docetaxel 3-weekly arm and mitoxantrone arms were the same as previously reported in 
2004, 18.9 months (95% confidence interval 17.0-21.2) for docetaxel every 3 weeks plus 
prednisone, and 16.5 months (95% confidence interval 14.4-18.6) for mitoxantrone plus 
prednisone. In an exploratory subset analysis, benefit was seen in patients who were free of 
pain at the time therapy was initiated. However, this analysis confirmed only consistency of 
effect across subpopulations, and the study was not powered to demonstrate survival 
advantage in symptomatic patients. Also, the similar benefit produced by docetaxel treatment 
in patients with or without pain suggests that holding chemotherapy in reserve for 
asymptomatic patients is a reasonable option. 
 
4.0 ABIRATERONE ACETATE (JNJ212082)  
 
4.1  Abiraterone Acetate and Mechanism of Action 
 
Abiraterone (JNJ589485) is [17-(3-pyridyl)androsta-5,16-dien-3β-ol] and is a steroidal inhibitor 
of CYP17 (17α hydroxylase/C17,20-lyase) that blocks two important enzymatic activities in the 
synthesis of testosterone (Figure 1), based on the observation that nonsteroidal 3 pyridyl esters 
improve selectivity for inhibition of 17α-hydroxylase/C17,20 lyase. Abiraterone acetate is a 
potent inhibitor with an apparent inhibition constant of 0.5 nM. Pharmacodynamic studies 
demonstrated that its effects on adrenal steroid synthesis were consistent with its mechanism 
of action. Antitumor effects were evident with PSA response and durable objective responses 
using Response evaluation criteria in solid tumors (RECIST) criteria in Phase 1 and Phase 2 
studies conducted to date.[72] 
 
Abiraterone acetate (JNJ212082) is the 3-acetylated analog of abiraterone and thus a pro-drug 
of abiraterone. The chemical nomenclature of abiraterone acetate is 3β acetoxy-17-(3- pyridyl) 
androsta-5,16-diene; its empirical formula is C26H33NO2 and molecular weight is 391.55. Once 

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absorbed after oral administration, abiraterone acetate is rapidly converted to the active form, 
abiraterone (Figure 2). In initial research studies, abiraterone acetate was the predominant, if 
not the only, metabolite of abiraterone acetate detected in blood, both in preclinical studies 
and in previously conducted clinical studies.[73, 74] 
 
Figure 1. The Enzyme Complexes Inhibited by Abiraterone acetate 
 
Figure 2. Prodrug Abiraterone Acetate is Converted to Abiraterone after Absorption 
 
 
4.2  Clinical Trials with Abiraterone Acetate and Prednisone  
 
COU-AA- 301 was a randomized, double-blind, International Phase III study comparing 
abiraterone acetate, given at 1000 mg once daily with prednisone 5 mg BID to placebo and 
prednisone 5 mg BID in men with mCRPC previously treated with docetaxel-based 
chemotherapy [75].  Overall survival was the primary endpoint and 1195 patients were 
enrolled.  A planned interim analysis after 534 patients met the primary endpoint revealed a 
statistically significant difference in overall survival between the abiraterone acetate and 

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prednisone arm (median OS 14.8 months; 95% CI 14.1- 15.2) and the placebo and prednisone 
arm (median OS 10.9 months; 95% CI 10.2-12.0) with a hazard ratio of 0.646 and a p < 0.0001 
[75]. Secondary endpoints were all statistically significant in favor of abiraterone acetate 
including time to PSA progression, radiographic progression, and PSA response.  Subgroup 
analysis revealed all parameters in favor of abiraterone acetate.   Side effects in this large phase 
III heavily pre-treated population were relatively low and balanced in both arms except for fluid 
retention, hypokalemia, hypertension and cardiac disorders; however, grade 3 or greater 
incidence of these toxicities were less than 5%.  These results have led to the FDA-approval of 
abiraterone acetate with prednisone for patients with mCRPC who have failed doectaxel-based 
chemotherapy.   
 
Early Phase II experience suggested that abiraterone acetate and prednisone was active and 
well tolerated in men with chemo-naïve mCRPC.  A phase II study in 33 men revealed a 67% PSA 
response rate and a median time to PSA progression of 16.3 months [76]. These early results 
led to the COU-AA-302 study, a randomized, double blind, international phase III study 
comparing abiraterone acetate and prednisone to placebo and prednisone in men with mCRPC 
who were chemotherapy-naïve [77]. 1088 patients were randomized in a 1:1 ratio and treated 
until radiographic progression.  Radiographic progression-free survival and overall survival were 
co-primary endpoint.  Three interim analyses were pre-planned.  At the time of the second 
interim analysis, following after 311 events (43% of events) the independent data safety 
monitoring committee recommended halting the study and unblinding the patients due to a 
statistically significant positive effect in favor of abiraterone acetate for radiographic 
progression-free survival (HR 0.43; 95% CI 0.35-0.52; p < 0.0001), a strong trend in favor of 
overall survival  (HR: 0.75; 95% CI 0.61-0.93; p = 0.0097) and positive secondary endpoints as 
well [77].  These results led to the FDA-approval of abiraterone acetate with prednisone for 
patients with mCRPC in December 2012.    
 
For the most comprehensive clinical information regarding the efficacy and safety of 
abiraterone acetate, refer to the latest version of the Package Insert for abiraterone acetate.  
 
4.3 Rationale for the current study 
 
African American men have a 60% greater incidence of being diagnosed with prostate cancer 
and nearly a 2.5 fold greater chance of mortality from the disease, yet the underlying cause for 
this increased mortality remains controversial [1].  Hormonal levels vary in men by race, with 
African American men having higher dihydrotestosterone (DHT), androstenedione (ASD) and 
sex hormone-binding globulin (SHBG) than Caucasian men with localized prostate cancer [2, 
23]. Historically, African American men with prostate cancer have a worse overall survival than 
Caucasian men, however, this is confounded by the timing of androgen deprivation therapy 
(ADT) and access to other therapies [4, 5].  To what extent race affects response to therapy in 
prostate cancer is not clear.    
Germline polymorphisms of genes involved in androgen signaling have been shown to vary 
significantly by race and may have important implications with regard to response to therapy 

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DukeUniversity 
 
 
targeted towards this pathway. Polymorphisms within the promoter region of the androgen 
receptor (AR) (specifically CAG repeats) have been well documented and vary significantly 
according to race, with African American men having significantly shorter CAG repeats resulting 
in greater AR activity [6].  These CAG repeats have been associated with more aggressive 
disease characteristics [6].  Recently, germline polymorphisms in androgen metabolism genes 
have been shown to have prognostic value in regards to the time to development of CRPC in 
men with prostate cancer on ADT.  Ross et al tested 129 polymorphisms across 20 genes 
associated with androgen metabolism and identified three polymorphisms in separate genes 
(CYP19A1, HSD3B1, and HSD17B4) that were significantly associated with prolonged time to 
progression (TTP) on ADT [7].  Specifically, individuals carrying more than one of the 
polymorphisms were associated with improved time to CRPC than individuals carrying zero or 
one (P< .0001).  More recently this group identified polymorphisms in two androgen 
transporter genes, SLCO2B1 and SLCO1B3 that were associated with a significantly shorter time 
to CRPC alone and in combination [8].  Incidences of these polymorphisms ranged from 15 to 
81%; unfortunately, the cohort of patients used to identify these polymorphisms had limited 
numbers of African American patients or other racial and ethnic groups.   
Recent studies have focused on discovering molecular mechanisms underlying prostate cancer 
disparities using DNA microarrays and bioinformatics.  These studies have compared the gene 
expression profiles between African American and Caucasian American cancers and between 
prostate cancer and patient-matched normal prostate from African Americans and Caucasian 
Americans.  By integrating gene expression profiling and pathway analyses, multiple 
components within the androgen receptor signaling pathway were revealed to be up-regulated 
in African American prostate cancer specimens along with the up-regulation of genes within 
other signaling pathways that converge on androgen receptor signaling, portending that 
androgen receptor pathway activation is a key component of prostate cancer health disparities.  
Overall the comparison of African American and Caucasian American prostate cancer 
specimens has led to the identification of a number of differentially expressed genes, including 
CYP19A1, AMFR, CXCR4, MMP9, SRD5A2, ADIPOQ, AKT1, ALOX12, ALOX15, ALOX15B, BMP2, 
CGA, ERG, FASN, IL1B, IL6, IL8, NFKB1, PIK3C3, PIK3CA, PI3K3R1, PLA2G2A, TGFB1, TIMP3, TNF, 
P38MAPK, STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A1, PIK3CB, ARA55, GNA01, GNB3, POLR2L, 
PRKCE, PRKD1, TBP, CALR, GNG2, GNG11, GNG12, CALM1, NFKB2, STAT2, RHOU, FGF13, EIF3B, 
and GIT1 [9-12].  Thus, germline polymorphisms of these differentially expressed genes also 
may have important implications with regard to response to therapy targeted towards the 
androgen signaling pathway. 
To what extent racial differences affect response and time to progression on abiraterone 
acetate is unknown. Secondarily, to what extent differences in systemic hormonal levels as well 
as androgen transport gene polymorphisms affect response to abiraterone acetate is unknown. 
Understanding any potential differences in response to therapy by race and/or by 
hormonal/genetic factors could impact on both our clinical use of abiraterone acetate as well as 
future clinical trial design. Finally, as other agents targeting the androgen/androgen receptor 
pathways become available, it will be important to differentiate their activity according to race, 
genetics and hormonal milieu.   

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We propose a pilot study to evaluate in a prospective, parallel group design, radiographic PFSin 
men with mCRPC treated with abiraterone acetate/prednisone by race. Secondary endpoints 
will describe the response to abiraterone acetate/prednisone, PSA kinetics and safety and 
tolerability. Exploratory endpoints will describe the incidence and associations of key hormonal 
levels as well as germline polymorphisms in androgen signaling genes and genes that have been 
shown to be differentially expressed in African American versus Caucasian American prostate 
cancers in both African American and Caucasian cohorts. 
 
5.0  STUDY OBJECTIVES AND ENDPOINTS 
 
5.1 Study objectives 
 
5.1.1 Primary objective 
 
The primary goal is to prospectively estimate the median radiographic PFS of African American 
and Caucasian men with mCRPC to abiraterone acetate and prednisone. 
 
5.1.2 Secondary objectives 
 
1) PSA kinetics: to determine  the duration of PSA response, time to nadir, and percent of 
men who achieve a PSA < 0.1;  
2) Radiographic assessments: to estimate the rate of objective response and incidence of 
bone flares 
3) Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension 
in the two populations  
4) Overall Survival 
 
5.1.3 Exploratory objectives 
 
1) Describe the baseline profile of serum hormone levels (including testosterone, DHT, 
DHEA, DHEAS, estradiol) and lipidomics, the change in levels with subsequent therapy 
(Cycle 4 ), and their correlation with response to abiraterone acetate.  
2) Describe the germline SNP profiles of target genes involved in androgen signaling 
and target genes that have been shown to be differentially expressed in African 
American versus Caucasian American prostate cancers as well as a genome wide 
analysis (GWAS) in both African American and Caucasian men with mCRPC and their 
associations with response to abiraterone acetate. The status of the aforementioned 
targets as well as AR splice variants will also be assessed in archival tumor tissue, if 
available, by sequencing, IHC and qRT-PCR. 
 
5.2 Study endpoints 
 
 

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5.2.1 Primary endpoint 
 
The primary endpoint will be radiographic progression free survival (rPFS) based on PCWG2 
criteria or based on the onset of a skeletal related event.  Imaging will be obtained every 12 
weeks. 
 
5.2.2 Secondary endpoints 
 
Secondary endpoints will include: 
1) 
RECIST 1.1 defined radiologic response rates and incidence of bone flares 
2) 
PSA response, time to nadir, and percent of men who achieve a PSA < 0.1  
3) 
Safety (NCI CTC v4.0) and tolerability, particularly incidence and grade of hypertension 
in the two populations 
4) 
Overall survival 
 
Exploratory correlative sciences endpoints: 
 
Whole blood will be collected in purple top EDTA tubes at baseline for DNA isolation and 
characterization of SNPs for androgen metabolism genes (including CYP19A1, HSD3B1, 
HSD17B4, SLCO2B1 and SLCO1B3), AR CAG repeats, as well as genes that have been shown to 
be differentially expressed in African American versus Caucasian American prostate cancers 
(including, but not limited to, SLCO2B1, SLCO1B3, CYP19A1, HSD3B1, HSD17B4,AR CAG repeats, 
AMFR, CXCR4, MMP9, SRD5A2, ADIPOQ, AKT1, ALOX12, ALOX15, ALOX15B, BMP2, CGA, ERG, 
FASN, IL1B, IL6, IL8, NFKB1, PIK3C3, PIK3CA, PI3K3R1, PLA2G2A, TGFB1, TIMP3, TNF, P38MAPK, 
STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A1, PIK3CB, ARA55, GNA01, GNB3, POLR2L, PRKCE, 
PRKD1, TBP, CALR, GNG2, GNG11, GNG12, CALM1, NFKB2, STAT2, RHOU, FGF13, EIF3B, and 
GIT1) and ancestral genotyping.  A genome wide analysis (GWAS) is planned in both African 
American and Caucasian men with mCRPC and their associations with response to abiraterone 
acetate, in addition to the aforementioned analyses of germline SNP profiles.  In addition 
baseline assessments of hormonal levels including testosterone, DHT, DHEA, DHEAS, estradiol 
and their change after 12 weeks on therapy will be evaluated along with lipidomics analysis.  
Finally additional baseline and 4 week plasma samples will be drawn to explore additional 
biomarkers that may have prognostic or predictive value. The status of the target genes 
involved in androgen metabolism and the target genes that have been shown to be 
differentially expressed in African American versus Caucasian American prostate cancers as well 
as AR splice variants will also be assessed in archival tumor tissue, if available, by sequencing, 
IHC and qRT-PCR. 
 
6.0  INVESTIGATIONAL PLAN 
 
6.1 Overall study design 
 
This is a non-comparative pilot open-label, parallel arm, multicenter study of abiraterone 
acetate in African American and Caucasian men with mCRPC. The primary goal is to 

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prospectively estimate the median radiographic PFS in African American and Caucasian men 
with mCRPC cancer treated with abiraterone acetate. Patients will self-report on race and 50 
patients will be enrolled into each group.  Patients will be treated on open-label treatment until 
evidence of disease progression as defined by Prostate Cancer Working Group Two (PCWG2) 
definition [13] or until two years at which point they will roll over to the standard of care at that 
time.   
 
Study schema is shown below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2 Study population 
 
This will be a Duke University Health System study conducted through the Duke Cancer 
Institute, composed of a large tertiary referral center and network sites, which treat a high 
volume of metastatic CRPC patients and who prioritize African American patient accrual to 
clinical trials.  It is anticipated that the Duke Cancer Network and 6 satellite sites will be needed 
to accrue 50 African American subjects over a 30 month accrual period.  Typically 20-30 African 
American subjects per year would be eligible for this protocol at Duke University Medical 
Center alone but this number would be substantially more by including outreach sites.  A 
parallel population of Caucasian patients will be accrued to this trial. 
 
6.3 Inclusion and exclusion criteria 
 
Patients must have baseline evaluations performed prior to the first dose of study drug and 
must meet all inclusion and exclusion criteria.  Results of the baseline evaluations, which assure 
that all inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal 
Investigator at Duke University, or his/her designee prior to enrollment of that patient.  In 
addition, the patient must be thoroughly informed about all aspects of the study, including the 
study visit schedule and required evaluations and all regulatory requirements for informed 
consent.  The written informed consent must be obtained from the patient prior to any 
R 
E 
G 
I 
S 
T 
R 
A 
T 
I 
O 
N
Disease 
Progression 
or 
Adverse 
Event 
 Metastatic, CRPC 
 No history of chemotherapy for CRPC 
 Karnofsky performance status ≥ 70 
 Adenocarcinoma of the prostate 
 No evidence of neuroendocrine ca 
Abiraterone 1000 mg po 
daily 
Prednisone 5 mg po BID 

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screening procedures being performed.  The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 
 
 
Inclusion criteria: 
 
 
1. Male, age ≥ 18 years 
2. Karnofsky performance status ≥ 70 (Appendix 1) 
3. Life expectancy of ≥ 12 months as determined by treating investigator 
4. Written Authorization for Use and Release of Health and Research Study Information 
(HIPAA Authorization per institutional requirements)  
 
5. Willing/able to adhere to the prohibitions and restrictions specified in this protocol  
  
6. Willing to take abiraterone acetate on an empty stomach; no food should be 
consumed at least two hours before and for at least one hour after the dose of 
abiraterone acetate is taken, and should be able to swallow tablets whole, without 
crushing/chewing tablets.  
 
7. Patients who have partners of childbearing potential must be willing to use a 
method of birth control with adequate barrier protection as determined to be 
acceptable by the principal investigator and sponsor during the study and for 1 week 
after last dose of abiraterone acetate 
 
8. Adequate laboratory parameters 
 Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 
109/L, Hb>9 g/dL 
 Serum potassium > 3.5 mEq/L 
 AST/SGOT and ALT/SGPT ≤ 1.5 x Institutional Upper Limit of Normal (ULN)  
 Serum bilirubin ≤ 1.5 x Institutional ULN 
 Serum creatinine ≤ 1.5 x Institutional ULN or 24-hour clearance ≥ 50 mL/min 
 Serum albumin of > 3.0 g/dl 
9. Histologically confirmed diagnosis of adenocarcinoma of the prostate.  Histologic 
variants of prostate cancer, including neuroendocrine features and small cell 
carcinoma of the prostate are excluded. 

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10. Radiographic evidence of metastatic disease; evaluable non-target lesions and/or 
bone only metastasis are permitted. 
11. Ongoing ADT using an LHRH agonist (e.g. leuprolide, goserelin) or antagonist (e.g. 
degarelix) must continue on therapy unless prior bilateral orchiectomy has been 
performed.  Screening serum testosterone must be <50 ng/dl.   
12. PSA ≥ 2.0 ng/mL 
13. Evidence of disease progression on ADT as evidenced by one of the following: 
 Absolute rise in PSA of 2.0 ng/mL or greater, minimum 2 consecutive rising PSA 
levels with an interval of ≥ 1 week between each PSA level, OR 
 2 consecutive PSA levels 50% or greater above the PSA nadir achieved on ADT and 
separated at least 1 week apart, OR 
 CT or MRI based evidence of disease progression (soft tissue, nodal or visceral 
disease progression) according to modified PCWG2 criteria or modified RECIST 1.1 
criteria, or at least 1 new bone scan lesion as compared to the most immediate prior 
radiologic studies. 
14. A minimum of 2 weeks elapsed off of antiandrogen therapy prior to start of study 
drug (i.e. flutamide, nilutamide, bicalutamide) .  
15. A minimum of 4 weeks elapsed off of sipuleucel-T prior to start of study drug. 
16. A minimum of 4 weeks from any major surgery prior to start of study drug.   
17. Self-reported race of either African American or Caucasian.  
18. Ability to swallow, retain, and absorb oral medication. 
19. Ability to understand and the willingness to sign a written informed consent 
document. If the subject is unable to understand the consent due to comorbidity, 
such as Alzheimer’s disease, consent by a legally authorized representative and 
assent by the subject will be obtained.  
 
Exclusion criteria: 
 
Patients who meet any of the following criteria will be excluded from the study: 
1. Prior treatment with abiraterone acetate or enzalutamide 

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2. Active infection or other medical condition that would make 
prednisone/prednisolone (corticosteroid) use contraindicated. 
3. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg 
prednisone/prednisolone bid. 
4. Have known allergies, hypersensitivity, or intolerance to abiraterone acetate or 
prednisone or their excipients. 
5. Pathological finding consistent with small cell carcinoma of the prostate. 
6. Symptomatic Liver or visceral organ metastasis. 
7. Have a history of gastrointestinal disorders (medical disorders or extensive surgery) 
that may interfere with the absorption of the study agents. 
8. Known brain metastasis. 
9. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC. 
10. Previously treated with ketoconazole for prostate cancer for greater than 7 days. 
11. Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 
weeks of Cycle 1, Day 1. 
12. Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). 
Patients with a history of hypertension are allowed provided blood pressure is 
controlled by anti-hypertensive treatment. 
13. Poorly controlled diabetes 
14. Active or symptomatic viral hepatitis or chronic liver disease. 
15. History of pituitary or adrenal dysfunction. 
16. Clinically significant heart disease as evidenced by myocardial infarction, or arterial 
thrombotic events in the past 6 months, severe or unstable angina, or New York 
Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction 
measurement of < 50% at baseline. 
17. Atrial Fibrillation or other cardiac arrhythmia requiring therapy. 
18. Other malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of 
recurrence within 24 months. 
19. Administration of an investigational therapeutic within 30 days of Cycle 1, Day 1. 

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20. Any condition which, in the opinion of the investigator, would preclude participation 
in this trial. 
 
7.0  PATIENT REGISTRATION 
After signing informed consent and completing eligibility screening, patients who are selected 
to participate will be registered with the lead site (Duke) and with their study site/institution.  A 
record of patients who fail to meet entry criteria (i.e., screen failures) will be maintained.  
Patients who are registered and do not start study drug within 2 weeks of intended Cycle 1 Day 
1 will be replaced. Patient registration must be complete before beginning any treatment.  
 
7.1  Informed Consent 
Authorized study personnel should fully explain the scope of the study to each patient before 
obtaining informed consent.  If the patient is not able to fully understand the informed consent 
due to a known comorbidity, such as Alzheimer’s disease, a legally authorized representative 
will be included in the consent process. Patients, and a legally authorized representative if 
appropriate, should be advised of any known risks inherent in the planned procedures, of any 
alternative treatment options, of their right to withdraw from the study at any time for any 
reason, and of their right to privacy. If a legally authorized representative signs the consent, the 
patients’ assent will also be documented. 
 
When obtaining informed consent, study personnel should: 
First: Confirm that the patient is a potential candidate for study participation. 
Next: Obtain dated and signed informed consent. 
Finally: Confirm that the patient is eligible as defined in Section 6.3 (Inclusion/Exclusion 
Criteria).  A record of patients who fail to meet entry criteria (i.e., screening failures) will 
be maintained. 
For patients consented at the lead site ONLY, registration in the Duke clinical trial subject 
registry must be completed within 1 business day of the patient providing informed consent. 
 
7.2  Lead Site Registration 
 
Patient registration for all patients signing informed consent will be completed by Duke 
University Medical Center Genitourinary Oncology Group. Following consent and completion of 
the Eligibility Checklist, documents will be submitted for review and registration of subject. All 
subjects will be assigned a unique study ID.  
 
Refer to Subject Registration Instructions for details.   
 
Patients will be enrolled only after all pre-treatment screening evaluations are completed and 
all eligibility criteria are met. Once the patient has signed consent and been found to meet all 
eligibility criteria, the subject will be registered. The patient will be considered enrolled on the 

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day of first treatment. A unique patient study identification number will be assigned upon 
consenting.  Treatment must not commence until the patient has received his approved 
documentation from the lead site. Treatment will commence according to the guidelines in the 
protocol. 
7.3  Institutional Registration 
Patient registration at each study site/institution will be conducted according to the 
institution’s established policies.  Prior to registration, patients will be asked to sign and date an 
Institutional Review Board (IRB)-approved consent form.  Patients must be registered with their 
local site/institution and with the lead site before beginning any treatment or study activities.  
 
 
8.0  TREATMENTS 
 
8.1  Abiraterone acetate formulation 
 
Abiraterone acetate 250-mg tablets are oval, white to off-white and contain abiraterone 
acetate and compendial (USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, colloidal 
silicon dioxide, and purified water, in descending order of concentration (the water is 
removed during tabletting). 
Handling abiraterone acetate tablets 
This medicine may cause harm to the unborn child if taken by women who are pregnant. It 
should not be taken by women who are breast-feeding. Women who are pregnant or who may 
be pregnant should wear gloves if they need to touch abiraterone acetate tablets. You should 
notify any caregivers and staff personnel of this information, to ensure the appropriate 
precautions are taken. 
 
8.2  Abiraterone acetate administration 
 
The study agent abiraterone acetate will be administered by the patient at a dose of 1000mg 
orally once daily with prednisone 5 mg BID in 4-week cycles throughout the treatment period.  
Abiraterone acetate must be taken on an empty stomach. No food should be consumed for at 
least two hours before the dose of abiraterone acetate is taken and for at least one hour after 
the dose of abiraterone acetate is taken. Abiraterone acetate should be taken with a glass of 
water and consumed over as short a time as possible.  Patients should swallow the capsules 
whole and not chew them.  Study drug will be provided by Janssen Scientific Affairs and 
distributed by DCI Investigational Chemotherapy Service, which will be distributing drug to the 
satellite sites. 
 
Abiraterone acetate must be taken on an empty stomach. No food should be consumed for at 
least two hours before the dose of abiraterone acetate is taken and for at least one hour after 

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the dose of abiraterone acetate is taken. Abiraterone Cmax and AUC0-∞ (exposure) were 
increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate 
was administered with a meal compared to a fasted state. The safety of these increased 
exposures when multiple doses of abiraterone acetate are taken with food has not been 
assessed. 
 
Patients will be instructed to take a 5-mg prednisone tablet, twice daily with food.  It is not 
required for the prednisone to be taken at the same time as abiraterone acetate. The dose of 
prednisone will remain unchanged in the event that the study drug dose is changed. If a 
prednisone dose is missed, it should be omitted and will not be made up. Should a dose 
modification of the prednisone be needed due to toxicities, the site will need to discuss this 
with the medical monitor. 
 
Each treatment cycle consists of 28 consecutive days. No cycle will be delayed.  If doses of study 
drug are held or missed, they will not be made up. The subject could complete a maximum of 
26 cycles during the 24 month duration of the study.  During the study period, starting with 
cycle 4, the patient will return to clinic every 3 cycles.  The patient will be given enough study 
drug to last for 12 weeks.  Patients may take abiraterone acetate plus prednisone until 
radiographic disease progression and/or unequivocal clinical progression (as defined in Section 
12.5), at which time study treatment will be discontinued. The dose of prednisone may be 
gradually reduced if clinically indicated. 
 
If vomiting occurs during the course of treatment, no redosing of the patient is allowed before 
the next scheduled dose.  If the patient forgets to take her/his dose before 12:00 noon, then 
the dose should be withheld that day and abiraterone acetate should be restarted the following 
day. 
 
Effects of Abiraterone Acetate on Drug Metabolizing Enzymes 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 
substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given 
with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-
administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic 
index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and 
consider a dose reduction of the concomitant CYP2D6 substrate drug. 
  
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 
substrate) was increased by 46% when pioglitazone was given together with a single dose of 
1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of 
toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly 
with ZYTIGA. 
 
Drugs that Inhibit or Induce CYP3A4 Enzymes 

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Based on in vitro data, abiraterone acetate is a substrate of CYP3A4.  In a clinical 
pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer 
(rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1000 mg, 
the mean plasma AUC∞ of abiraterone was decreased by 55%. 
 
Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, 
phenobarbital) during treatment with abiraterone acetate are to be avoided, or used with 
careful evaluation of clinical efficacy. 
 
In a separate clinical pharmacokinetic interaction study of healthy subjects, coadministration of 
ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the 
pharmacokinetics of abiraterone. 
 
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded.  If a patient requires a abiraterone acetate dose delay of >21 days from the 
previous dose, the patient must be discontinued from treatment (unless unrelated to study 
drug and approved by the medical monitor), return for an end of treatment visit  +/- 7 days of 
the last dose or the day of the decision to remove from the study, and return for a follow-up 
safety visit 28 days (+/- 7 days) from date of last dose. 
 
Medication labels will comply with US legal requirements and be printed in English.  They will 
supply no information about the patient.  The storage conditions for study drug will be 
described on the medication label. 
 
8.3  Concomitant therapy 
 
All medications (excluding prior chemotherapy and biologic, immunologic or radiation therapy) 
taken within 4 weeks prior to the administration of abiraterone acetate and all concomitant 
therapy administration during the study with reasons for therapy should be recorded.   
Patients on chronic medications that can be given concomitantly with abiraterone acetate 
should be maintained on the same dose and dose schedule throughout the study period, as 
medically feasible.  The investigator should instruct the patient to notify the study site about 
any new medications he takes after the start of the study drug.  All new medications, changes in 
medication dosing, and significant non-drug therapies (including herbal medicines, physical 
therapy and blood transfusions) administered after the patient starts treatment with study drug 
will be recorded. 
 
The following concomitant medication/therapies are permitted if deemed necessary for the 
care of the patient:  
 Standard therapies for preexisting conditions, medical/surgical complications including 
nausea and diarrhea, and palliation. 
 Non-potent CYP3A4 isoenzyme inhibitors and/or inducers. 
 LHRH agonists or antagonists. 

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 Anti-hypertensive medications. 
 Diabetic medications. 
 Antidepressants or other medications for mood disorders.   
 Analgesics including opioids. 
 Bisphosphonates and/or denosumab. 
 Erythropoietic agents. 
 Systemic anticoagulation with low molecular weight heparin. 
 Provenge, after the first 3 cycles on treatment are completed. 
 Focal therapies for localized non-prostate cancers 
 
The following medications/therapies are prohibited while the patient is on study: 
 Other investigational therapies must not be used while the patient is on the study. 
 Chemotherapy, radiation therapy, or immunotherapy, or any anti-cancer therapy other 
than abiraterone acetate and prednisone and those described above and below. 
 Coumadin or other vitamin K antagonists. 
 Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng.  Patients 
should stop using these herbal medications 7 days prior to first dose of study drug. 
 In lieu of surgical castration, the use of an LHRH agonist or antagonist must continue while 
on this study.  However, antiandrogens, ketoconazole, estrogens, and all other forms of 
hormonal manipulation are not permitted for the treatment of cancer. 
 Investigators should keep in mind the possibility that abiraterone acetate may interact with 
concomitant medications, particularly those that are metabolized or activated by P450 CYPs 
2D6 and 1A2 (see Appendix 2 for prohibited medications).    Please see comments above 
regarding interactions.  If at any time an investigator suspects a drug-drug interaction due 
to abiraterone acetate therapy, an adverse event report should be completed and Duke 
University notified. 
 
 8.4  Treatment compliance 
Participating sites will be provided with a medication diary for each patient to document his 
self-administration of Abiraterone Acetate per cycle.  A current and accurate account of the 
number of study treatment tablets the investigator received from Duke University, dispensed to 
the patients, the number of units returned to the investigator by the patient, and the number 
of units returned to Duke University during and at the completion of the study must be 
maintained.  A detailed inventory must be completed for the study treatment. Records of study 
medication used, dosages administered, and intervals between visits will be recorded during 
the study.  Drug accountability will be noted and patients will be asked to return all unused 
study medication. 
 
9.0  STUDY ASSESMENTS 
 
9.1  Vital signs, performance status, and physical exam 

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Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight per the visit schedule.   
 
Performance status will be assessed at screening and per the visit schedule using the Karnofsky 
performance status scale (Appendix 1).  
 
Physical examination will comprise a total body examination (general appearance, skin, 
including eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and 
basic nervous system).  Significant findings made after the start of study drug which meet the 
definition of an Adverse Event must be recorded. 
 
 
9.2  Laboratory evaluations 
 
The following laboratory studies will be obtained at specified intervals to assess subject safety, 
specifically the risk of infection, hyperglycemia, and/or bone marrow, liver, and kidney 
abnormalities. Abnormalities will be captured as AEs only if deemed clinically significant by the 
treating physician/provider/investigator.  This does not include the labs designated as an 
adverse event of special interest in 11.1.  
 Hematology:   Complete blood count (CBC) consisting total white blood cell count (WBC) 
with differential (total neutrophil count, lymphocyte, monocyte, eosinophil, and 
basophil counts), hemoglobin, hematocrit, and platelet count. 
 Blood chemistry:   Blood urea nitrogen (BUN), creatinine, sodium, potassium, calcium, 
chloride, bicarbonate (CO2), magnesium, phosphorus, glucose, albumin, total protein, 
total bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT). 
 
PSA to be obtained at baseline, Day 1 of intended Cycle 1 and cycles  2, 3, 4, 7, 10 and every 3 
cycles, and at the end of treatment visit. During follow-up for subjects who discontinue 
treatment due to reasons other than radiographic progressive disease, PSA will be collected 
every 3 months (+/- 28 days) and additionally as clinically appropriate. Testosterone to be 
obtained at baseline and the end of cycle 3 (at Cycle 4 Day 1). 
 
9.3 ECG 
 
A standard 12-lead ECG is to be performed at screening and significant findings must be 
recorded.  Additional EKGs may be performed at the discretion of the treating physician.   
 
 
9.4  Imaging 
 
A CT scan with contrast of chest, abdomen, and pelvis will be performed within 42 days prior to 
the intended C1D1 visit, and every 3 cycles (approximately every 12 weeks) as part of routine 
tumor assessment.  These scans are to be performed on day 1 of every 3 cycles (i.e. baseline, 
Day 1 of cycles 4, 7, 10, etc.) within 7 days prior to starting the next cycle.  If the chest CT at 
baseline is clear, chest x-rays may be used for subsequent assessments at the enrolling 

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physician’s discretion. The tumor assessments will be performed locally, in strict accordance 
with the RECIST 1.1 guidelines.  A total body bone scan will be performed within 42 days of the 
intended C1D1 visit and every 3 cycles (approximately every 12 weeks) and interpreted 
according to PCWG2 guidelines. CT and bone scan modalities per standard institutional 
practices may be used, but the same modality should be used throughout the study for each 
subject. 
 
 
Because the primary endpoint is progression free survival based upon radiographic disease 
progression, patients will continue to have CT scans and Bone Scans performed according to 
standard clinical practice even if study treatment is discontinued for reasons other than 
radiographic disease progression.  
 
9.5  Exploratory correlative studies 
 
 
 
9.5.1  SNP Analysis 
 
Human whole blood will be collected in a 4mL lavender top K2EDTA tube at baseline for DNA 
isolation and characterization of SNPs.  Mix by gentle inversion 8-10 times. Do not centrifuge. 
Freeze tubes at -20oC.  Genomic DNA will be purified using the Qiagen QiaAmp DNA Blood Mini 
Kit or equivalent.  Starting material used will be 200µl whole blood per column.  Genomic DNA 
will be considered of appropriate quantity and quality if at least 300ng (preferably 1200ng) of 
A260nm/A280nm > 1.5 is obtained.  Characterization of SNPs for androgen metabolism genes 
(including CYP19A1, HSD3B1, HSD17B4, SLCO2B1 and SLCO1B3), AR CAG repeats, as well as 
genes that have been shown to be differentially expressed in African American and Caucasian 
American prostate cancers (including, but not limited to, SLCO2B1, SLCO1B3, CYP19A1, 
HSD3B1, HSD17B4,AR CAG repeats, AMFR, CXCR4, MMP9, SRD5A2, ADIPOQ, AKT1, ALOX12, 
ALOX15, ALOX15B, BMP2, CGA, ERG, FASN, IL1B, IL6, IL8, NFKB1, PIK3C3, PIK3CA, PI3K3R1, 
PLA2G2A, TGFB1, TIMP3, TNF, P38MAPK, STAT1, RHOA, ITGB5, MAPKAPK2, CSNK2A1, PIK3CB, 
ARA55, GNA01, GNB3, POLR2L, PRKCE, PRKD1, TBP, CALR, GNG2, GNG11, GNG12, CALM1, 
NFKB2, STAT2, RHOU, FGF13, EIF3B, and GIT1) and ancestral genotypingwill be performed.  A 
genome wide analysis (GWAS) is planned in both African American and Caucasian men with 
mCRPC and their associations with response to abiraterone acetate. The GWAS will be done 
using Illumina’s 2.5M beadchip.  The local site will process these samples and prepare them for 
shipment to the lead site per shipping instructions below.  The lead site will perform the 
laboratory analysis.  Neither the local sites nor the patients will receive information regarding 
individual subjects’ results. 
 
An additional 4mL lavender top K2EDTA tube may be collected from subjects whose tube 
collected at baseline yielded no usable sample after DNA isolation. This additional tube would 
be used for DNA isolation and characterization of SNPs as described above.  
 
 
9.5.2  Hormonal Levels 

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Serum testosterone, DHT, DHEA, DHEAS, and estradiol will be collected at baseline, the end of 
cycle 3 (at Cycle 4 Day 1), and the end of treatment visit.  
 
For hormone levels, collect blood into one 5mL gold top SST vacutainer tube. Invert 5 times. 
Allow blood to clot for 30 minutes. Centrifuge for 10 minutes at 1100-1300 x g. Aliquot the 
serum into 1.8mL cryovials. Label according to instructions below and freeze cryovials at     -
80°C. Samples should be frozen within 2 hours of collection. If a -80°C freezer is not available 
and samples are being stored at -20°C, then all samples will remain frozen and shipped within 
48 business hours on dry ice following the directions below. 
 
 
9.5.3 Plasma samples for blood-based biomarkers 
 
Plasma samples will be collected at baseline and at the end of cycle 1 (at Cycle 2 Day 1) to 
explore additional biomarkers that may have prognostic or predictive value. These additional 
biomarker analyses will be in support of the specified endpoints in the protocol. 
 
For plasma samples, collect blood into one 6mL lavender top (K2EDTA coagulant vacutainer) 
AND one 4.5 mL light blue top (3.2% sodium citrate) vacutainer.  Invert the tubes several times 
and centrifuge for 15 minutes at 2500 x g.  Remove the plasma and transfer to a clean 5 mL 
glass test tube.  Repeat centrifuge at 2500 x g for 15 minutes.  Aliquot the plasma – 0.5 mL into 
the provided 1.8mL cryovials.  Label according to instructions below and freeze cryovials at -
80°C. If a -80°C freezer is not available and samples are being stored at -20°C, then all samples 
will remain frozen and shipped within 48 business hours on dry ice following the directions 
below. 
 
Storage and Shipping Instructions 
 
See Laboratory Manual for further details regarding sample collection and shipping. 
 
Once complete, these samples will be analyzed for their appropriate endpoints as indicated in 
the study (i.e. SNP analysis, lipidomics, hormone or plasma biomarker levels). SNP analysis will 
be done in collaboration with the Duke University DNA Analysis Facility, 
 
 ancestral genotyping by Rick Kittles, PhD, City of Hope, Duarte, CA and 
lipidomics, hormone, and plasma biomarker levels will be done in collaboration with Andrew 
Nixon, PhD, Phase I Biomarker Laboratory, Duke University Medical Center, 
 
  Access to these samples will be limited to Drs George, 
Freedman, Nixon, Kittles and their proxy staff.  These samples will be maintained indefinitely or 
until they are exhausted. Any future analyses not specified in this protocol will be agreed upon 
by prior approval from Janssen Scientific Affairs, LLC.   
 
 
 
9.5.4 
Collection of Archival Tumor Tissue for somatic SNP assessments 

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Formalin-fixed, paraffin-embedded archival tumor tissue will be collected from all patients 
whenever available.  This tissue will come from diagnostic core biopsies and/or surgical 
specimens (prostatectomy or metastatic sampling).  Tissue should be labeled and sent to the 
address in the lab manual.  Up to five 10 micron thick sections from tumor blocks and/or 20 
unstained slides should be de-identified except for protocol and subject number and sent at 
room temperature (see Laboratory Manual for further details regarding sample collection).  
Samples will be batched and evaluated collectively by sequencing, IHC, and qRT-PCR for the 
status of target genes involved in androgen metabolism and signaling, target genes that have 
been shown to be differentially expressed in African American versus Caucasian American 
prostate cancers, and AR splice variants.  Sections of the FFPE tumor tissue will be utilized to 
assess the status of the aforementioned targets by IHC and DNA as well as RNA isolated from 
the FFPE tumor tissue will be utilized to assess the status of the aforementioned targets and AR 
splice variants by sequencing and qRT-PCR. 
 
In patients without target SNP alterations, it will be important to confirm that there are not 
somatic tumor alterations within these genes.  In order to evaluate for somatic tumor 
alterations within our target genes we will perform SNP analyses in available specimens.  
Discrepancies between germline and somatic mutations will be further evaluated by 
sequencing.  Samples will be stored by Dr. Jennifer Freedman, PhD with access limited to key 
personnel.  DUHS will maintain these samples indefinitely or until they are exhausted. Any 
future analyses not specified in this protocol will be agreed upon by prior approval from 
Janssen Scientific Affairs, LLC.    
 
9.6  Follow-Up Period 
 
During the Follow-up Period, subsequent therapy for prostate cancer should be assessed every 
3 months for up to 24 months after the first dose of study drug.  Since the primary endpoint is 
progression free survival based upon radiographic disease progression, patients will continue to 
have CT scans and Bone Scans performed according to standard clinical practice and their PSA 
measured every 3 months and additionally as clinically appropriate until they have radiographic 
progression or untill they have started another therapy. All subjects will be followed up for 
survival every 6 months +/- 1 month by phone or chart review. 
 
10.0 MONITORING AND MANAGEMENT OF SUSPECTED ABIRATERONE TOXICITY 
 
10.1  Management of Drug-Related Adverse Events 
 
The most common adverse drug reactions (≥10%) reported in clinical studies were fatigue, joint 
swelling or discomfort,  edema,  hot flush, diarrhea, vomiting, urinary tract infection, cough, 
hypertension, dyspnea, and contusion.  The administration of prednisone is expected to 
mitigate these side effects by supplementing cortisol and abrogating ACTH drive. 
 

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Following prolonged therapy with corticosteroids, subjects may develop Cushing’s syndrome 
characterized by central adiposity, thin skin, easy bruising, and proximal myopathy. Withdrawal 
of the corticosteroid may result in symptoms that include fever, myalgia, fatigue, arthralgia, and 
malaise. This may occur even without other evidence of adrenal insufficiency. 
 
For guidance on management of side effects of glucocorticoid usage, symptoms related to 
castration (androgen deprivation), severe and refractory headaches, fatigue, or other toxicities 
the Principal Investigator at Duke University should be contacted.   
 
 
10.1.1  Management of hypokalemia 
 
Subjects who experience hypokalemia are to be managed as presented in Table 1. 
Table 10.1: Hypokalemia Management 
Serum K+ 
Grade of 
Hypokalemia 
Action 
Further Action or 
Maintenance 
Low K+ or history 
of hypokalemia 
 
Weekly (or more frequent) 
laboratory electrolyte 
evaluations 
Titrate dose to maintain a serum 
K+ >3.5 mM <5.0 mM 
 
(maintenance of subjects at 
>4.0 mM is recommended) 
<3.5 mM – 3.0 mM 
Grade 1 
Initiate oral or i.v. K+ 
supplementation. 
 
Consider monitoring magnesium 
and replace if needed 
Titrate dose to maintain a serum 
K+ >3.5 mM <5.0 mM 
 
(maintenance of subjects at 
>4.0 mM is recommended) 
<3.5 mM – 3.0 mM 
Symptomatic 
 
Grade 2 
Initiate oral or i.v. K+ 
Supplementation 
 
Consider monitoring magnesium 
and replace if needed 
Titrate dose to maintain a serum 
K+ >3.5 mM <5.0 mM 
 
(maintenance of subjects at 
>4.0 mM is recommended) 
<3.0 mM – 2.5 mM 
Grade 3 
Withhold abiraterone acetate 
and initiate oral or i.v. K+ and 
cardiac monitoring. 
 
Consider monitoring magnesium 
and replace if needed 
Call the Duke Principal Investigator or 
Project manager prior to re-initiating 
study treatment 
 
<2.5 mM 
Grade 4 
Withhold abiraterone acetate 
and initiate oral or i.v. K+ and 
cardiac monitoring 
 
Consider monitoring magnesium 
and replacement if needed 
Call the Duke Principal Investigator 
prior to 
re-initiating study treatment 
 
i.v.=intravenous; K+=potassium; mM=millimole 
 
Correct hypokalemia before and during treatment with abiraterone acetate.  Monitor serum 
potassium at least monthly until stable. 
 
10.1.2  Management of hypertension 

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 
If Grade 1 or 2 adverse events occur, management per investigator.  No study medication 
dose reduction. 
 
If Grade 3 or 4 adverse events occur, hold study medication. Adjust or add medications to 
mitigate the toxicity or consider the specific mineralocorticoid receptor blocker, 
eplerenone. When hypertension improves to <140/90 (< Grade 1), resume study 
medication at full dose. 
 
If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When blood pressure improves to <140/90 (< Grade 1),, resume study medication 
with the first dose level reduction (3 tablets, 750 mg of study medication).  
 
If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When hypertension improves to <140/90 (< Grade 1), resume study medication 
with the second dose level reduction (2 tablets, 500 mg of study medication).  If blood 
pressure remains <140/90 (< Grade 1), for at least one month, the site investigator has the 
option of increasing the patient’s dose by (1 tablet) 250mg to 750mg (3 tablets).  
 
If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue study medication. 
 
Control hypertension before and during treatment with abiraterone acetate.  Monitor blood 
pressure at least monthly. 
 
10.1.3 Management of edema, fluid retention 
 
 
If pedal edema occurs, supportive management per investigator. No study medication dose 
reduction. 
 
If anasarca or pulmonary edema requiring supplemental oxygen occurs, hold study 
medication. Adjust or add medications to mitigate the toxicity and consider the specific 
mineralocorticoid receptor blocker, eplerenone. When toxicity resolves to ≤Grade 1, 
resume study medication at full dose. 
 
If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the first dose level 
reduction (3 tablets, 750 mg of study medication). 
 
If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the second dose level 
reduction (2 tablets, 500 mg of study medication). 
 
If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue study medication 
 
Monitor for symptoms of fluid retention at least monthly. 
 
 
 
 
10.1.4 Monitoring and management of adrenocortical insufficiency 
 

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 Monitor for symptoms and signs of adrenocortical insufficiency.   
 
 Use caution and monitor for symptoms and signs of adrenocortical insufficiency, 
particularly if patients are withdrawn from prednisone, have prednisone dose 
reductions, or experience unusual stress.  Symptoms and signs of adrenocortical 
insufficiency may be masked by adverse reactions associated with mineralocorticoid 
excess seen in patients treated with abiraterone acetate.  If clinically indicated, perform 
appropriate tests to confirm the diagnosis of adrenocortical insufficiency.  Increased 
dosage of corticosteroids may be indicated before, during and after stressful situations. 
 
10.1.4  Management of abnormal liver function tests 
 
Hepatic Impairment 
 
 Baseline Moderate Hepatic Impairment (Child-Pugh Class B) 
o Reduce recommended abiraterone acetate dose to 250 mg once daily. A once 
daily dose of 250 mg in patients with moderate hepatic impairment is predicted 
to result in an area under the concentration curve (AUC) similar to the AUC seen 
in patients with normal hepatic function receiving 1,000 mg once daily. However, 
there are no clinical data at the dose of 250 mg once daily in patients with 
moderate hepatic impairment and caution is advised. 
o Monitor ALT, AST, and bilirubin 
 Prior to starting treatment with Abiraterone Acetate 
 Every week for the first month 
 Every two weeks for the following two months 
 Monthly after completing three months of treatment 
 If ALT and/or AST > 5 x ULN (upper limit of normal), discontinue 
abiraterone acetate and do not retreat 
 If total bilirubin > 3 x ULN, discontinue abiraterone acetate and do not 
retreat 
 
 Baseline severe hepatic impairment (Child-Pugh Class C) – Avoid treating with 
Abiraterone Acetate. 
 
        Hepatotoxicity - For patients who develop hepatotoxicity during treatment with 
abiraterone acetate 
 
 If Grade 3 hepatotoxicity occurs (ALT and/or AST greater than 5X ULN or total bilirubin 
greater than 3X ULN), interrupt treatment with abiraterone acetate.  Treatment may be 
restarted at a reduced dose of 750 mg once daily following return of liver function tests 
to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total 
bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, monitor 
serum transaminases and bilirubin at a minimum of every two weeks for three months 
and monthly thereafter.  

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 If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted 
at a reduced dose of 500 mg once daily following return of liver function tests to the 
patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin 
less than or equal to 1.5X ULN. 
 
 If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment 
with abiraterone acetate. The safety of abiraterone acetate re-treatment of patients 
who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than 
or equal to 10X ULN is unknown. 
 
10.1.5  Management of other non-mineralocorticoid based side effects 
 
 
If Grade 1-2 toxicities occur, give supportive care per institutional guidelines. No study 
medication dose reduction. 
 
If Grade 3 or higher toxicities occur, including headache (interferes with activities of daily 
living), nausea (total parenteral nutrition/intravenous fluids), vomiting (6 or more episodes 
in 24 hours, total parenteral nutrition/intravenous fluids), diarrhea (intravenous fluids, 
hospitalization, hemodynamic collapse), or any other toxicity judged related to study 
treatment is observed where the subjects safety is jeopardized, hold study medication. For 
unrelated Grade 3 adverse events, study medication can be held per PI discretion. 
 
When toxicity resolves to ≤Grade 1, the patient may resume study medication at full dose 
or with a dose level reduction. 
 
If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the first dose level 
reduction (3 tablets, 750 mg of study medication).  
 
If toxicity recurs, hold study medication, and adjust or add medications to mitigate the 
toxicity. When resolved to ≤Grade 1, resume study medication with the second dose level 
reduction (2 tablets, 500 mg of study medication). 
 
If toxicity recurs despite aggressive medical management and 2 dose-level reductions, 
discontinue study medication. 
 
10.2 Interruption or discontinuation of treatment 
 
All interruptions or changes to study drug administration must be recorded. 
 
It will be documented whether or not each patient completed the clinical study.  If for any 
patient either study treatment or observations were discontinued the reason will be recorded.   
 
Reasons that a patient may discontinue participation in a clinical study are considered to 
constitute one of the following: 
i. Disease progression by PCWG2 criteria 
ii. Clinical progression by the discretion of the treating physician 

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iii. Need for radiation or new systemic therapy for prostate cancer 
iv. Unacceptable toxicity requiring cessation of therapy, including adverse 
event(s), abnormal laboratory value(s), or abnormal test/procedure result(s):  
Patients who have sustained toxicities that do not return to NCI CTCAE (version 
4.0) Grade 1 or less with appropriate medical management, should be 
discontinued from the study treatment. 
v. Protocol violation 
vi. Patient withdrawal of consent - the reason(s) for withdrawal must be 
documented and clarification requested whether withdrawal of consent 
applies only to the Treatment Phase (i.e. patient has not withdrawn consent 
for data collection during the post-treatment Follow-Up Phase) or to both the 
Treatment and Follow-Up Phases. A patient’s decision to take part in the study 
is voluntary, and he may choose not to take part in the study or to stop taking 
part at any time. If he chooses not to take part or to stop at any time, it will not 
affect his future medical care. 
vii. Death 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
must be followed in clinic at 4-week intervals or closer until resolution to Grade I or less.  For 
clinically significant laboratory changes resulting in treatment interruption or discontinuation, 
patients must have their values monitored at least once a week for 4 weeks, and subsequently 
at 4-week intervals, until resolution to < Grade II or stabilization of the event, whichever comes 
first.  If a patient requires a dose delay of >21 days from the intended day of the next scheduled 
dose, then the patient should be discontinued from the study (unless unrelated to study drug 
and approved by the medical monitor).  If the patient requires more than 2 dose reductions, 
the patient should be discontinued from the study.  All patients must be followed for adverse 
events and serious adverse events for 30 days following the last dose of Abiraterone acetate.  
All SAEs must be reported to Duke University as detailed in section 11.2-3. 
 
An investigator may withdraw a patient from the study Treatment Phase at any time based on 
clinical judgment or for any of the following reasons listed above.  
 
11.0  SAFETY ASSESSMENTS AND REPORTING 
 
Safety assessments will consist of monitoring and recording all adverse and serious adverse 
events, the regular monitoring of hematology and blood chemistry values, regular 
measurement of vital signs and the performance of physical examinations. 
 
These assessments should be performed within ±3 days of the scheduled day of assessment for 
the first cycle and +/- 7 days thereafter except for adverse events that will be evaluated 
continuously through the study.  Safety and tolerability will be assessed according to the 
NIH/NCI CTCAE v. 4.0. 
 
11.1  Definitions 

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Definition of Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product. Lab abnormalities will be captured as 
AEs only if deemed clinically significant by the treating physician/provider/investigator.  This 
does not include the labs designated as an adverse event of special interest. 
 
Adverse Events of Special Interest  
 
For Abiraterone acetate, the adverse events of special interest are: 
 Mineralocorticoid excess (Hypertension, Hypokalemia, Fluid retention) 
 Hepatotoxicity 
 Cardiac disorders 
 Osteoporosis including osteoporosis-related fractures 
 Increased exposure with food 
 Rhabdomyolysis/myopathy 
 Acute liver failure/hepatitis which might be fatal 
 Drug-drug interaction (CYP2D6) 
 Allergic alveolitis 
 
Note: Hypertension will be reported as an adverse event of special interest if there is a one 
grade increase from a baseline grade of ≥ grade 1.  See 11.5 Reporting Timelines  
Definition of Adverse Drug Reaction (ADR) 
 
A noxious and unintended response to any dose of the drug (or biological) product for which 
there is a reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event. Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
J&J Medicinal Product 
 
The specific J&J drug under study and any other J&J medicinal product. 
 
Product Quality Complaint (PQC) 
 
Any discrete concern that questions the identity, quality, durability, reliability, safety, efficacy 
or intended performance of a drug product. 

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A complaint may allege an injury or malfunction associated with the use of the drug product. It 
may also involve the design, literature, packaging, advertising, availability, physical appearance 
or promotion of the drug product. 
 
Serious Adverse Event (SAE) 
 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either 
the treating physician or PI, it results in any of the following outcomes:  
 
Death,  
 
a life-threatening adverse event,  
o 
Life-threatening adverse event or life-threatening suspected adverse reaction.  
 
An adverse event or suspected adverse reaction is considered ‘‘life-threatening’’ 
if, in the view of either the treating physician or PI, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused death. 
 
inpatient hospitalization or prolongation of existing hospitalization,  
 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or  
 
a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 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. 
 
Special Reporting Situations  
 
When a report contains a J&J product, an identifiable patient, and identifiable reporter, the 
following events represent Special Reporting Situations: 
 
overdose of  a Johnson & Johnson medicinal product 
 
pregnancy exposure (maternal and paternal) 
 
suspected abuse/misuse of  a medicinal Johnson and Johnson product 
 
inadvertent or accidental exposure to  a medicinal Johnson and Johnson   
product 
 
any failure of expected pharmacological action (i.e., lack of effect) of  a 
Johnson & Johnson medicinal product 
 
unexpected therapeutic or clinical benefit from use of  a Johnson & 
Johnson medicinal product 
 
medication error involving a Johnson & Johnson product  
 
suspected transmission of any infectious agent via  a medicinal product. 
 

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11.2 
Management of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
 
In general, the PI or designate must immediately report to JANSSEN SCIENTIFIC AFFAIRS any 
serious adverse event and Special Reporting Situations, whether or not considered drug 
related. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the drug and the event (e.g., death as a result of anaphylactic reaction or 
fatal hepatic necrosis). In that case, the investigator must immediately report the event to 
JANSSEN SCIENTIFIC AFFAIRS. The PI must record non-serious adverse events and report them 
to JANSSEN SCIENTIFIC AFFAIRS following completion of the accrual and follow up period or to 
fulfill regulatory reporting requirements. 
 
For each subject, AEs SAEs, and Special Reporting Situations should be recorded after informed 
consent is obtained until the subject has completed participation in the study as follows: 
 
A Serious Adverse event or Special Reporting Situations must be reported if it occurs during a 
subject’s participation in the Study (whether receiving Study Product or not) and within 30 days 
of receiving the last dose of Study Product. 
 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject 
completes his/her participation in the Study must be followed until any of the following occurs: 
 
-the event resolves or stabilizes; 
 
-the event returns to baseline condition or value (if a baseline value is available); 
 
-the event can be attributed to agents(s) other than the study product, or to factors 
unrelated to Study conduct. 
 
11.3 
Recording of Adverse Events, Serious Adverse Events and Special Reporting 
Situations 
 
Recording should be done in a concise manner using standard, acceptable medical terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a 
laboratory value or vital sign) but should reflect the reason for the procedure or the diagnosis 
based on the abnormal measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study should also be 
recorded (a preexisting condition that does not worsen is not an adverse event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to the 
procedure or surgery is considered an adverse event. Any event requiring in-patient 
hospitalization that occurs during the course of a subject’s participation in a trial must be 
reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are: 
A: 
Reasons described in the Protocol, e.g. drug administration, Protocol-required testing 

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B. 
Surgery or procedure planned prior to entry into the Study. 
 
If, in the PRINCIPAL INVESTIGATOR’s judgment, a clinical significant worsening from baseline is 
observed in any laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), 
physical exam finding, or vital sign, a corresponding clinical adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded 
as the adverse event, whenever possible.  However, a complete description of the signs, 
symptoms and investigations which led to the diagnosis should be provided. For example, if 
clinically significant elevations of liver function tests are known to be secondary to hepatitis, 
“hepatitis” and not “elevated liver function tests” should be recorded. If the cause is not 
known, the abnormal test or finding should be recorded as an adverse event, using appropriate 
medical terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation). 
 
 
11.4 
Maintenance of Safety Information 
 
Safety information will be maintained in a clinical database/repository in a retrievable format. 
At a minimum, at the end of the treatment phase (=”last patient off treatment”) as well as the 
end of the follow-up phase (=”last patient out”) of the Study, the PI shall provide all adverse 
events, both serious and non-serious, in report format. However, in certain circumstances more 
frequent review of the safety data may be necessary, e/g/ to fulfill a regulatory request, and as 
such the data shall be made available within a reasonable timeframe at JANSSEN SCIENTIFIC 
AFFAIRS’s request. 
 
11.5. Reporting Timelines 
 
Serious safety information (SAEs, Adverse Events of Special Interest, Special Reporting 
Situations, and PQCs), whether or not considered drug related, should be reported to the lead 
site/sponsor within 24 hours of becoming aware of the event(s), using the provided Janssen 
SAE Report Form and the DCI SAE Review Form (Site Assessment). These documents should be 
sent to: 
 
The DCI Safety Desk fax: 
 
 
 
If the safety desk cannot be reached within 24 hours, the Medical Director/Monitor should be 
contacted: Dr. Daniel George 
 
 
 
The initial report for each SAE or death should include at minimum the following information: 
• 
protocol # and title 
• 
patient initials, study identification number, sex, age 
• 
date the event occurred 

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• 
description of the SAE 
• 
dose level and cycle number at the time the SAE occurred 
• 
description of the patient’s condition 
• 
indication whether the patient remains on study 
• 
causality 
 
Signature by physician 
 
Follow-up information including severity, action taken, concomitant medications, and outcome 
should be communicated to Duke as soon as possible. 
 
Upon receipt of the Serious Adverse Event Reporting form by DCI Safety Desk, the PI will be 
notified and be required to complete the PI assessment of the DCI Safety SAE Report Review 
Form.  The DCI safety desk will, in turn, send the Janssen SAE Report Form to Janssen Scientific 
Affairs. Safety information will be sent to Janssen Scientific Affairs by encrypted email using 
Cisco Registered Envelope Service to 
 Delivery and read 
receipt of the secure email will serve as evidence of successful communication.  
 
 
11.5.1   Reporting SAEs at Participating Institutions 
 
Staff at participating sites are responsible for reporting all SAEs to the lead site/sponsor within 
24 hours of becoming aware of the event. The DCI Safety Desk at Duke University 
 
should be contacted 
when reporting an SAE or death.  If this person cannot be reached within 24 hours, the Principal 
Investigator should be contacted: Dr. Daniel George 
 
 
 
All non-serious AEs should be reported according to the timeframe outlined in the Research 
Funding Agreement section entitled Reporting of Data. 
 
 
11.5.2   FDA Reporting Requirements 
 
The Sponsor/Investigator (Duke) is responsible for reporting serious adverse events to the FDA 
in accordance with applicable IND Safety Requirements (21 CFR 312.32).  
 
11.6. Transmission Methods 
 
The following methods are acceptable for transmission of safety information to JANSSEN 
SCIENTIFIC AFFAIRS: 
 
Facsimile (fax), receipt of which is evidences in a successful fax transmission report, 
 
Electronically subject to strict compliance with the following condition: Reporting may 
be done electronically only upon written approval by JANSSEN SCIENTIFIC AFFAIRS, which 
approval must acknowledge that the electronic transmission is in an acceptable encrypted 
email format. Without such acknowledgement, the approval to use an electronic transmission 
shall not be valid. The Parties hereby acknowledge the importance of strict precautions with 

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the use of electronic transmission for the security, protection and maintenance of 
confidentiality of patient health information contained in the reports, or 
 
Telephone (for business continuity purposes, if fax or authorized electronic system is 
non-functional). 
 
Please use the contact information and process information provided by JANSSEN SCIENTIFIC 
AFFAIRS  
 
11.7  Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), 
Special Reporting Situation, and Product Quality Complaints (PQCs) to JANSSEN 
SCIENTIFIC AFFAIRS 
 
A: 
Serious Adverse Events (SAE), Adverse Events of Special Interest, and Special 
Reporting Situations 
In clinical trials (including reports unblinded as to treatment for blinded studies) involving the 
Study Product regardless of whether causality with the administration of the Study Product is 
suspected by the PRINCIPAL INVESTIGATOR.  
 
The INSTITUTION/PRINCIPAL INVESTIGATOR will transmit these reports in a form to be provided 
(or a form substantially similar to the form provided and approved for use by JANSSEN 
SCIENTIFIC AFFAIRS in writing) in accordance with Section VII Transmission methods, in English 
within 24 hours of becoming aware of the event(s) along with their determination of whether 
the event was caused by a J&J product. 
 
All available clinical information relevant to the evaluation of an SAE, Adverse Events of Special 
Interest, and Special Reporting Situations including pregnancy reports (with or without an AE) 
including paternal exposure are required. 
 
 The INSTITUTION and/ or PRINCIPAL INVESTIGATOR is responsible for ensuring that 
these cases from clinical studies are complete and if not are promptly followed-up. 
This includes ensuring the reports are fully investigated and thoroughly documented 
by the PRINCIPAL INVESTIGATOR and that follow-up information is summarized e.g. 
hospital records, coroner’s reports, autopsy results and recorded on the appropriate 
forms. 
 A study case is not considered complete until all clinical details needed to interpret 
the case are received and the event has resolved, or otherwise explained, or the 
patient is lost to follow-up. Reporting of follow-up information should follow the 
same timeline as initial reports. 
 Copies of any and all relevant correspondences with regulatory authorities and 
ethics committees regarding any and all serious adverse events, irrespective of 
association with the Study Drug in the course of the Study, by facsimile within 24 
hours of such report or correspondence being sent to applicable health authorities. 
 
B. 
Product Quality Complaints 

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Any PQC, with or without an AE, (including reports of suspicion of counterfeiting, diversion, or 
tampering, and suspected transmission of pathogens) will be transmitted by the INSTITUTION 
and the PRINCIPAL INVESTIGATOR in the form provided by JANSSEN SCIENTIFIC AFFAIRS in 
accordance with Section VII Transmission methods, in English, within 24 hours of becoming 
aware of the event(s). 
 
C. 
Reconciliation of SAEs 
 
At a minimum, on a quarterly basis and at the end of the Study, JANSSEN SCIENTIFIC AFFAIRS 
will provide to the INSTITUTION and/or PRINCIPAL INVESTIGATOR, a listing of all SAEs reported 
to JANSSEN SCIENTIFIC AFFAIRS.  SPONSOR and/or PRINCIPAL INVESTIGATOR will review this 
listing and provide any discrepancies to the JANSSEN SCIENTIFIC AFFAIRS. 
 
Upon request, INSTITUTION and PRINCIPAL INVESTIGATOR shall provide JANSSEN SCIENTIFIC 
AFFAIRS with a summary list of all SAEs, and AEs of Special Interest and Special Reporting 
Situation reports to date, for reconciliation purposes. 
 
 
11.8 
Dissemination of Safety Information from JANSSEN SCIENTIFIC AFFAIRS to 
INSTITUTION/PRINCIPAL INVESTIGATORS 
 
JANSSEN SCIENTIFIC AFFAIRS will provide to the  INSTITUTION/PRINCIPAL INVESTIGATOR IND 
safety reports/SUSAR (Serious Unexpected Suspect Adverse Reaction) reports generated by the 
JANSSEN SCIENTIFIC AFFAIRS for the Study Product as they become available until all subjects in 
the Protocol have completed their last Study visit according to the Protocol  (i.e. Last Subject 
Last Visit has occurred). 
 
12.0  EFFICACY ASSESSMENTS 
 
12.1  Baseline tumor evaluation 
 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [78]and the guidelines for prostate cancer endpoints developed by the Prostate 
Cancer Clinical Trials Working Group (PCWG2) [13]. 
 
Traditional measures of response reflect when a treatment is working and measures of 
progression indicate when a drug should be stopped.  Because assessing response in bone (the 
most common site of prostate cancer spread) is uncertain and the clinical significance of PSA 
changes in response to therapy is not a reliable predictor of response, measures of response 
have been expanded in consortium trials to include measures of progression. 
Patients will be reevaluated for response every cycle according to the guidelines below: 
 

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Measurable disease:   According to RECIST 1.1, measurable disease is defined as at least 1 
lesion ≥ 10 mm in its longest diameter as measured by CT scan with slice thickness ≤ 5 mm, ≥ 10 
mm by clinical exam with caliper measurement, or ≥20 mm by CXR.  A lymph node is 
measurable if it is ≥ 15 mm in the short axis when assessed by CT scan.   All tumor 
measurements will be taken using a ruler or calipers and recorded in millimeters. 
 
Nonmeasurable disease:  Following RECIST 1.1, all other lesions (or sites of disease) will be 
considered nonmeasurable disease.  This includes small lesions (longest diameter < 10 mm) and 
any of the following: 
1. Leptomeningeal disease 
2. Ascites 
3. Pleural or pericardial effusion 
4. Lymphagitic involvement of the skin or lung 
5. Abdominal mass or organomegaly identified by physical exam but not by imaging 
techniques 
6. Bone lesions 
7. Lesions occurring within a previously irradiated area unless they are documented as 
new lesions since the completion of radiation therapy 
 
Target (nodal and visceral) lesions:  Following RECIST 1.1, progression in a nodal or visceral site 
(i.e., liver and lung) is sufficient to document disease progression.  The presence or absence of 
nodal and visceral disease before and after treatment should be recorded separately.  All 
measurable lesions (up to a maximum of 2 lesions per organ and 5 lesions in total) will be 
identified as target lesions to be measured and recorded at baseline.  The target lesions should 
be representative of all involved organs.  Target lesions will be selected on the basis of size (i.e., 
the largest area) and suitability for accurate, repeated measurements.  Lymph nodes can be 
considered a target lesion if the short axis is ≥ 15 mm by CT.  The sum of diameters (long-axis 
for non-nodal lesions and short-axis for nodal lesions) of all target lesions will be calculated and 
reported as the baseline sum diameter.  The baseline sum diameter will be used as a reference 
by which to characterize the objective tumor response.   
 
Non-target lesions:  All other lesions (or sites of disease) will be identified as nontarget lesions 
and recorded at baseline.  Nontarget lesions will include measurable lesions that exceed the 
maximum number per organ (2) or total of all involved organs (5), as well as nonmeasurable 
lesions.  The presence or absence of these lesions will be recorded on the CRF and should be 
evaluated at the same assessment time points as all target lesions. 
 
PSA:   Because the rate of rise has known prognostic significance, estimate a pretreatment PSA 
doubling time (PSA-DT) if at least 3 values are available, but do not delay either treatment or 
enrollment onto a trial simply to estimate PSA-DT.   
 
12.2  Response Criteria  
 
 
 
12.2.1  Evaluation of target lesions: 

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Table 5 RECIST 1.1 response criteria for target lesions 
Response 
Evaluation of Target Lesions 
Complete response (CR) 
The disappearance of all target lesions.  Any pathologic 
lymph nodes (target or non-target) must have reduction 
in short axis to <10 mm.   
Partial response (PR) 
A ≥30% decrease in the sum diameter of target lesions as 
compared to the baseline sum diameter. 
Progressive disease (PD)  
A ≥20% increase in the sum diameter of target lesions as 
compared to the smallest sum diameter on study.  This 
must show an absolute increase of at least 5 mm.  
The appearance of one or more new lesions.   
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD based on the smallest 
sum diameter on study.  
 
 
 
Target lesions that are too small to measure will be given a measurement of either 0 mm, if the 
radiologist believes the lesion has disappeared, or 5 mm, if the lesion is felt to be present.  In 
some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of complete response depends on this determination, the residual lesion 
will be investigated with a fine needle aspirate or biopsy before confirming the complete 
response status.   
If lymph nodes have been identified as target lesions, the short axis measurement will be 
recorded even if the nodes regress to < 10 mm.  Therefore, the sum diameter may not be zero 
even if complete response criteria are met.       
 
 
 
 
 
12.2.2 Evaluation of non-target lesions: 
 
Table 6   RECIST 1.1 response criteria for non-target lesions 
Response 
Evaluation of Non-target Lesions 
Complete response (CR) 
The disappearance of all non-target lesions.  All lymph 
nodes must be <10 mm by short axis.  
Non-CR, Non-PD 
The persistence of one or more non-target lesions. 
Progressive disease (PD) 
Unequivocal progression of existing non-target lesions 
and/or the appearance of one or more new lesions. 
 

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A clear progression of nontarget lesions only is exceptional.  In such circumstances, the 
progression status, as assigned by the investigator, may be reviewed by a PCCTC panel. 
 
New lesions:  If unequivocal, the appearance of new lesions denotes disease progression.  If a 
new lesion is equivocal, therapy will be continued and this lesion will be reevaluated on follow-
up imaging as planned in the study flow chart.  If repeat scans confirm the new lesion, 
progression will be documented using the date of the initial equivocal scan.  New brain 
metastases identified while on study are considered new even if there was no baseline brain 
imaging. 
 
 
 
12.2.3 Bone lesions 
 
Record post-treatment changes as either “no new lesions” or “new lesions.”  When the bone 
scan is the sole indicator of progression, disease progression in bone is defined as 2 or more 
new lesions seen on bone scan compared with the baseline scan used for trial entry.  In 
situations where scan findings suggest a flare reaction or where new lesion(s) may represent 
trauma, confirm these results with other imaging modalities.  In the absence of clearly 
worsening soft-tissue (nodal and visceral) disease or disease-related symptoms, progression at 
the first scheduled assessment should be confirmed on a second scan performed 6 or more 
weeks later.   
 
 
 
12.2.4 PSA 
 
To report PSA-based outcomes, PCWG2 recommends that the percent of change in PSA from 
baseline to 12 weeks (or earlier for those who discontinue therapy) and the maximum decline 
in PSA that occurs at any point after treatment be reported for each patient using a waterfall 
plot.  Because declines in serum PSA, if they occur, may not do so for several weeks, PSA 
measurements obtained during the first 12 weeks should not be used as the sole criterion for 
clinical decision making.  As long as patient safety is the primary concern, in the absence of 
other indicators of disease progression, therapy should not be discontinued solely on the basis 
of a rise in PSA.   
 
 
 
12.2.5 Symptoms 
 
Transient increases in pain may occur before improvement, and those occurring in the first 12 
weeks should not affect the course of treatment in the absence of other compelling evidence of 
disease progression.  Changes in symptoms should be documented and confirmed as per other 
outcome measures.   
 
12.2.6 Evaluating best overall response 
 
The best overall response is the best response recorded from the start of treatment until the 
end of treatment. The investigator’s determination of best overall response will be based both 
on response criteria and on confirmation criteria.  To be assigned a status of partial response or 

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complete response, changes in tumor measurements must be confirmed by repeat assessment 
performed 6-8 weeks after the criteria for response are first met.  To confirm stable disease, 
follow-up measurements must meet SD criteria at a minimum interval of 6 weeks after SD was 
first documented.  Table 7 will be used as an assessment tool. 
 
Table7. Assessing Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial 
response; SD, stable disease. 
 
Patients with global deterioration of health status who require treatment to be discontinued 
without objective evidence of disease progression should be classified as having symptomatic 
deterioration.  Every effort should be made to document their objective progression, even after 
discontinuing treatment. 
Patients who do not have tumor response assessment due to rapid progression or toxicity will 
be considered nonresponders, will be included in the denominator for the response rate, and 
will be classified into one of the categories listed below: 
 Death attributed to disease progression 
 Early discontinuation attributed to disease progression 
 Death attributed to drug toxicity 
 Early discontinuation attributed to drug toxicity 
 
Note:  If a patient receives subsequent therapy before tumor progression is documented, the 
reason for changing therapy must be reported.  Reasons include clinical progression, drug 
toxicity, or secondary therapy for maintaining tumor response. 
 
12.3 Confirming time-to-event outcomes 
 
Any post treatment change in disease status, be it favorable or unfavorable, should be 
confirmed using a second assessment at a later time point, either 6 weeks later or at the next 
scheduled scan. 

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12.4 Duration of overall response 
 
Duration of overall response is measured from the time when partial response or complete 
response is first noted until the date when recurrent or progressive disease is objectively 
documented.  Duration of overall complete response is measured from the time the criteria for 
complete response are first met until the first date that recurrent disease is objectively 
documented.  Duration of stable disease is measured from the start of treatment until the 
criteria for progression are met. 
 
12.5 Progression-free survival 
 
The primary endpoint is radiographic progression-free survival (rPFS), a composite endpoint 
using the time from study entry to disease progression.   
 
Progression is defined as:  
1) Radiologic progression by RECIST 1.1 [78] and/or bone scan progression by PCWG2 
criteria [13](Appendix 4), or  
2) Symptomatic progression, including clinical deterioration requiring new systemic 
therapy or a new a skeletal-related event (pathologic fracture, need for radiation to 
tumor site, malignant spinal cord compression).   
 
A rise in PSA alone or CTC number alone, in the absence of radiologic or symptomatic indicators 
of disease progression, will not be considered disease progression.   Increased pain alone, in the 
absence of changes in imaging or need for radiation therapy, will not be considered disease 
progression. 
 
All assessments of disease should be collected at the same time interval.  Post-treatment 
changes will be confirmed based on measurable target lesions, radionuclide bone scans, and 
symptoms as indicated below.  Patients who withdraw from study treatment for reasons 
other than radiographic disease progression should continue to have results of their CT and 
Bone scans collected and recorded during the Follow-Up phase until demonstration of 
radiographic progression. 
 
12.6  Secondary endpoint assessments 
 
 
12.6.1  RECIST 1.1 defined radiologic response rates   
 
Tumor assessments by CT chest/abdomen/pelvis and bone scan will be made at baseline and 
every 12 weeks while on therapy.   If the chest CT at baseline is clear, chest x-rays may be used 
for subsequent assessments at the enrolling physician’s discretion. Response rates will be 
calculated based on RECIST 1.1 criteria, as detailed in section 12.2 above centrally.   Response 
rates will be analyzed using objective (defined as CR or PR) parameters. Response rates and 

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exact 95% confidence intervals based on the binomial distribution for the response rates will be 
computed. 
 
 
12.6.2  Post-therapy changes in PSA 
 
The proportion of patients achieving 30%, 50%, and 90% declines in PSA from baseline within 3 
months on study and overall will be assessed.  Response rates and exact 95% confidence 
intervals based on the binomial distribution for the response rates will be computed. Time to 
PSA progression as defined by the PCWG2 definition will also be captured. 
 
12.6.3  Safety and toxicity monitoring  
 
National Cancer Institute Common Toxicity Criteria (v 4.0) will be used to record and monitor 
for adverse events (Appendix 4). Data for safety and severe adverse events will be monitored 
on an ongoing basis through monthly investigator and staff meetings, including data from all 
centers involved.  
 
12.7 Exploratory endpoints 
 
i. 
Hormonal levels 
We will describe the baseline profile of serum hormone levels (including testosterone, DHT, 
DHEA, DHEAS, estradiol), the change in levels with subsequent therapy (Cycle 4 ), and their 
association with response to abiraterone acetate as well as with race (self-reported and 
ancestral genotyping).  
 
ii. 
SNP Analyses 
We will describe the germline SNP profiles of target genes involved in androgen signaling as 
well as genes that have been shown to be differentially expressed in African American and 
Caucasian American prostate cancersas well as a genome wide analysis (GWAS) in both African 
American and Caucasian men with mCRPC and their associations with response to abiraterone 
acetate. 
  
 
 
13.0  STATISTICAL METHODS 
 
 
Sample Size Computation 
This trial is non-comparative. Based on Ryan et al. the median time to radiographic progression 
free survival (rPFS) is 16.5  months [14]. Fifty (50) patients will be enrolled in each group (AA 
and Caucasians). With an accrual rate of  50 patients/group over 30-month accrual period,  24-
months follow-up, and assuming that rPFS follows an exponential distribution, based on 5000 
simulations the average width of a two-sided 95% confidence interval for the median rPFS is 16. 

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Because of the small sample size and short follow-up period, 26 radiographic PFS events/group 
are expected. Consequently, the radiographic PFS distribution by racial group will not be 
estimated with high precision.  
Data Analysis 
The proportion of patients who experience PSA decline of at least 30%, 50% and 90%  at 
3months from baseline and over the entire treatment period will be estimated with exact 95% 
confidence intervals based on the binomial distribution will be computed. In addition, post 
therapy changes in PSA will be explored as a continuous outcome. The Kaplan-Meier product 
limit method will be used to estimate the rPFS. Interim results at 3 months will not be reported, 
but will be used in the planning of larger trials. 
 
The GWAS analysis will be mostly exploratory as the trial limited sample size will not permit 
definitive analyses.  The SNP will be summarized using descriptive statistics. 
 
14.0  DATA REPORTING AND REGULATORY REQUIREMENTS  
 
14.1 Data Entry 
 
Data collected during this study will be entered into a secure Oracle database.  Staff at Duke 
University will be responsible for the initial study configuration and setup in the electronic 
database as well as for any future changes.   
 
 
14.1.1 Case report forms 
Electronic case report forms (CRFs) will be generated by Duke University for the collection of all 
study data.  Site Investigators or designee will be responsible for ensuring that the CRFs are 
kept up-to-date. Each site will enter their own data into CRFs from source documents on site.   
 
 
 
14.1.2 Source documents 
 
Study documentation includes all paper case report forms, data correction forms, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence 
and regulatory documents (e.g., signed protocol and amendments, Ethics or Institutional 
Review Committee correspondence and approval, approved and signed subject consent forms, 
Statement of Investigator form, and clinical supplies receipts and distribution records). 
 
The investigator will prepare and maintain complete and accurate study documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local laws, 
rules and regulations; and, for each subject participating in the study, promptly complete all 
original case report forms and such other reports as required by this protocol following 
completion or termination of the clinical study or as otherwise required pursuant to any 
agreement with the Sponsor-Investigator. 

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By signing the protocol, the investigator acknowledges that, within legal and regulatory 
restrictions and institutional and ethical considerations, study documentation will be promptly 
and fully disclosed to the Sponsor-Investigator/Regulatory Specialist by the investigator upon 
request and also shall be made available at the investigator’s site upon request for inspection, 
copying, review and audit at reasonable times by representatives of Sponsor-Investigator or 
responsible government agencies as required by law.  The investigator agrees to promptly take 
any reasonable steps that are requested by Sponsor-Investigator as a result of an audit to cure 
deficiencies in the study documentation and case report forms. 
 
14.1.3 Record retention 
 
The investigator will maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.  After study 
closure, each participating site’s PI will maintain all source documents, study-related 
documents, and CRFs.  Because the length of time required for retaining records depends upon 
a number of regulatory and legal factors, documents should be stored until the investigator is 
notified that the documents may be destroyed.  In this study, records are to be retained and 
securely stored for a minimum of 6 years after the completion of all study activities. 
 
 
14.2  Study monitoring and quality assurance 
 
The Sponsor-Investigator is responsible for monitoring the protocol to ensure that the 
investigation is conducted in accordance with the general investigational plan and all applicable 
regulatory requirements.  In addition, the protocol will be monitored independently via the 
Duke Cancer Center (DCI) Monitoring Team 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure 
that the protocol is conducted, recorded, and reported in accordance with the protocol, 
standard operating procedures, good clinical practice, and applicable regulatory requirements.  
As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct 
routine monitoring after the third subject is enrolled, followed by annual monitoring of 1 – 3 
subjects until the study is closed to enrollment and subjects are no longer receiving study 
interventions that are more than minimal risk.   
 
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI 
Monitoring Team visit and additional safety and toxicity data submitted by the Principal 
Investigator. 
 
Additional monitoring may be prompted by findings from monitoring visits, unexpected 
frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon 
request of DUHS and DCI leadership, the CPC, the Safety Oversight Committee (SOC), the Duke 
CTQA, the sponsor, the Principal Investigator, or the IRB.  All study documents must be made 
available upon request to the DCI Monitoring Team and other authorized regulatory 
authorities, which may include but is not limited to the National Institute of Health, National 

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Cancer Institute, and the FDA.  Every reasonable effort will be made to maintain confidentiality 
during study monitoring. 
 
14.3  Data Safety and Monitoring  
 
Data for safety and severe adverse events will be monitored on an ongoing basis through 
monthly investigator and staff meetings, including data from all centers involved.   
 
In addition a recruitment and withdrawal summary will be discussed at these meetings.  
Withdraws will be broken down into those due to AEs and what they were.  
  
In terms of internal review, the Investigator will continuously monitor and tabulate adverse 
events.  Appropriate reporting to the DUHS IRB will be made.  If an unexpected frequency of 
Grade III or IV events occurs, depending on their nature, action appropriate to the nature and 
frequency of these adverse events will be taken.  This may require a protocol amendment, dose 
de-escalation, or closure of the study.  The Investigator of this protocol will also continuously 
monitor the conduct, data, and safety of this protocol to ensure that: 
 Risk/benefit ratio is not altered to the detriment of the subjects 
 Appropriate internal monitoring of adverse events and outcomes is done 
 Over-accrual does not occur 
 Under-accrual is addressed with appropriate amendments or actions 
 Data is being appropriately collected in a reasonably timely manner 
 
This protocol is being conducted at additional sites external to Duke University Health Systems.  
The Sponsor-Investigator is responsible for monitoring these sites to assure the safety and 
protection of all subjects, and to assure that the study is conducted, recorded, and reported in 
accordance with the protocol and applicable regulations.  To assure that the investigator 
obligations are fulfilled and all applicable regulations and guidelines are being followed, the 
Sponsor-Investigator will designate the DCI Monitoring Team to assure that the external site 
facilities are acceptable, the protocol and investigational plan are being followed, the IRB/IEC has 
been notified of approved protocol changes as required, complete records are being maintained, 
appropriate and timely reports have been made to the Sponsor-Investigator and the IRB/IEC, study 
drug and study drug inventory are controlled and the Investigator is carrying out all agreed 
activities.  Monitoring also includes review of regulatory and eligibility, conduct, data quality and 
adverse event reporting for select cases.  
 
As pre-arranged by the Sponsor-Investigator, DCI Monitoring Team will monitor 1-3 subjects 
annually at external sites until closed to enrollment or subjects are no longer receiving study 
drug or other interventions that are more than minimal risk.  Study teams will provide 
requested data for remote monitoring when possible.  If feasible, the first visit will be 
conducted on site.  Additional on-site visits will be completed as deemed necessary and as 
requested.  Additional review will be performed on a site-by-site basis, as warranted by the 
findings of previous monitoring visits.  Key variables (demographics, inclusion/exclusion criteria, 

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and safety) on the CRFs will be compared with select subject’s source documents.  Any 
discrepancies will be noted and resolved. 
 
15.0  PROTOCOL AMENDMENTS OR CHANGES IN STUDY CONDUCT 
 
Any change or addition to this protocol requires a written protocol amendment that must be 
reviewed by Duke University and Janssen Scientific Affairs before implementation.   
 
16.0  PROCEDURES AND INSTRUCTIONS 
 
16.1 Disclosure and confidentiality 
 
The investigator agrees to keep all information provided by participating sites and by Janssen 
Scientific Affairs in strict confidence and to request similar confidentiality from his/her staff and 
the IRB/IEC/REB.  Study documents provided by participating sites and Janssen Scientific Affairs 
(investigators' brochures and other material) will be stored appropriately to ensure their 
confidentiality. The information provided by participating sites and Janssen Scientific Affairs to 
the investigator may not be disclosed to others without direct written authorization from 
Janssen Scientific Affairs, except to the extent necessary to obtain informed consent from 
patients who wish to participate in the trial. 
 
16.2  Discontinuation of study 
 
Duke University or Janssen Scientific Affairs reserves the right to discontinue any study under 
the conditions specified in the clinical trial agreement. 
 
16.3 Ethics and Good Clinical Practice 
 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in ICH Harmonized Tripartite Guidelines for Good Clinical Practice 
1996. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community.  US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations).  The investigator agrees to adhere to 
the instructions and procedures described in it and thereby to adhere to the principles of Good 
Clinical Practice that it conforms to. 
 
16.3.1 Institutional Review Board/Independent Ethics Committee 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB).  A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Janssen before study initiation.  Any amendments to the 

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protocol, other than administrative ones, must be reviewed by Janssen Scientific Affairs, and 
approved by this committee. 
 
16.3.2 Informed consent 
 
The investigator or designee must explain to each subject (or legally authorized representative) 
the nature of the study, its purpose, the procedures involved, the expected duration, the 
potential risks and benefits involved and any discomfort it may entail.  Each subject must be 
informed that participation in the study is voluntary and that he may withdraw from the study 
at any time and that withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician. 
 
This informed consent should be given by means of a standard written statement, written in 
non-technical language.  The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document.  If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents.  No patient can enter the study before 
his/her informed consent has been obtained.  The informed consent form is considered to be 
part of the protocol, and must be submitted by the investigator with it for IRB/IEC/REB 
approval. 
 
16.3.3 Declaration of Helsinki 
 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki and amendments, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects). Copies of the Declaration of 
Helsinki and amendments will be provided upon request or can be accessed via the website of 
the World Medical Association at http://www.wma.net/e/policy/17-c_e.html. 

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Demichelis, F., et al., TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a 
watchful waiting cohort. Oncogene, 2007. 26(31): p. 4596-9. 
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Mehra, R., et al., Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate 
adenocarcinoma: molecular evidence for an independent group of diseases. Cancer Res, 2007. 
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prostate cancer. Oncogene, 2008. 27(3): p. 253-63. 
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Attard, G., et al., Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, 
confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin 
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37. 
Logothetis, Provenge, F. Presentation, Editor. 
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cancer? J Clin Oncol, 2008. 26(14): p. 2413-4; author reply 2414-5. 
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Calabro, F. and C.N. Sternberg, Current indications for chemotherapy in prostate cancer patients. 
Eur Urol, 2007. 51(1): p. 17-26. 
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Basch, E.M., et al., American Society of Clinical Oncology endorsement of the Cancer Care 
Ontario Practice Guideline on nonhormonal therapy for men with metastatic hormone-refractory 
(castration-resistant) prostate cancer. J Clin Oncol, 2007. 25(33): p. 5313-8. 
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Heidenreich, A., et al., EAU guidelines on prostate cancer. Eur Urol, 2008. 53(1): p. 68-80. 
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Horwich, A., C. Parker, and V. Kataja, Prostate cancer: ESMO clinical recommendations for 
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43. 
Carducci, M.A., et al., A phase 3 randomized controlled trial of the efficacy and safety of 
atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer, 2007. 110(9): p. 
1959-66. 
44. 
Sleep D. Atrasentan, O.P., Sept 13, 2005 and 
http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4174S1_Slide-Index.htm. 
45. 
Small, E.J., et al., Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T 
(APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin 
Oncol, 2006. 24(19): p. 3089-94. 
46. 
Huggins, C. and D.M. Bergenstal, Inhibition of human mammary and prostatic cancers by 
adrenalectomy. Cancer Res, 1952. 12(2): p. 134-41. 
47. 
Kruit, W.H., G. Stoter, and J.G. Klijn, Effect of combination therapy with aminoglutethimide and 
hydrocortisone on prostate-specific antigen response in metastatic prostate cancer refractory to 
standard endocrine therapy. Anticancer Drugs, 2004. 15(9): p. 843-7. 
48. 
Dawson, N., et al., Phase II study of suramin plus aminoglutethimide in two cohorts of patients 
with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior 
antiandrogen withdrawal. Clin Cancer Res, 1998. 4(1): p. 37-44. 
49. 
Small, E.J., A. Baron, and R. Bok, Simultaneous antiandrogen withdrawal and treatment with 
ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer, 1997. 
80(9): p. 1755-9. 
50. 
Millikan, R., et al., Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in 
androgen independent prostate cancer. Urologic oncology, 2001. 6(3): p. 111-115. 
51. 
Small, E.J., et al., Ketoconazole retains activity in advanced prostate cancer patients with 
progression despite flutamide withdrawal. J Urol, 1997. 157(4): p. 1204-7. 
52. 
Small, E.J., et al., Antiandrogen withdrawal alone or in combination with ketoconazole in 
androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol, 
2004. 22(6): p. 1025-33. 
53. 
Itakura, H., et al., Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and 
simvastatin in prostate cancer. J Urol, 2003. 169(2): p. 613. 
54. 
Tannock, I., et al., Treatment of metastatic prostatic cancer with low-dose prednisone: 
evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol, 1989. 7(5): p. 
590-7. 
55. 
Nishimura, K., et al., Potential mechanism for the effects of dexamethasone on growth of 
androgen-independent prostate cancer. J Natl Cancer Inst, 2001. 93(22): p. 1739-46. 
56. 
Li, Z., et al., Glucocorticoid up-regulates transforming growth factor-beta (TGF-beta) type II 
receptor and enhances TGF-beta signaling in human prostate cancer PC-3 cells. Endocrinology, 
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57. 
Tannock, I.F., et al., Chemotherapy with mitoxantrone plus prednisone or prednisone alone for 
symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end 
points. J Clin Oncol, 1996. 14(6): p. 1756-64. 
58. 
Fossa, S.D., et al., Flutamide versus prednisone in patients with prostate cancer symptomatically 
progressing after androgen-ablative therapy: a phase III study of the European organization for 
research and treatment of cancer genitourinary group. J Clin Oncol, 2001. 19(1): p. 62-71. 
59. 
Small, E.J., et al., Suramin therapy for patients with symptomatic hormone-refractory prostate 
cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo 
plus hydrocortisone. J Clin Oncol, 2000. 18(7): p. 1440-50. 
60. 
Kantoff, P.W., et al., Hydrocortisone with or without mitoxantrone in men with hormone-
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61. 
Morioka, M., et al., Prostate-specific antigen levels and prognosis in patients with hormone-
refractory prostate cancer treated with low-dose dexamethasone. Urol Int, 2002. 68(1): p. 10-5. 
62. 
Saika, T., et al., Treatment of androgen-independent prostate cancer with dexamethasone: a 
prospective study in stage D2 patients. Int J Urol, 2001. 8(6): p. 290-4. 
63. 
Storlie, J.A., et al., Prostate specific antigen levels and clinical response to low dose 
dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer, 1995. 76(1): p. 
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Petrylak, D.P., et al., Docetaxel and estramustine compared with mitoxantrone and prednisone 
for advanced refractory prostate cancer. N Engl J Med, 2004. 351(15): p. 1513-20. 
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Berthold, D.R., et al., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced 
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O'Donnell, A., et al., Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor 
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de Bono, J.S., et al., Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-
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Ryan, C.J., et al., Phase II study of abiraterone acetate in chemotherapy-naive metastatic 
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Ryan, C.J., et al., Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of 
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APPENDIX 1:  PERFORMANCE STATUS CRITERIA 
Karnofsky Performance Scale 
% 
Description 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease 
80 
Normal activity with effort, 
some signs or symptoms of 
disease 
70 
Cares for self, unable to carry 
on normal activity or to do 
active work 
60 
Requires occasional assistance 
but is able to care for most 
needs 
50 
Requires considerable 
assistance and frequent 
medical care 
40 
Disabled, requires special care 
and assistance 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
20 
Very sick, hospitalization 
indicated. Death not 
imminent. 
10 
Moribund, fatal processes 
progressing rapidly 
0 
Dead 
 
 

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APPENDIX 2:  CYP450 ISOENZYME INHIBITORS AND INDUCERS 
 
PROHIBITED CYP450 ISOENZYME INHIBITORS AND INDUCERS 
Strong CYP3A4,5,7 inhibitors 
Moderate CYP3A 4,5,7 inhibitors 
CYP3A4 inducers 
Clarithromycin 
 Amprenavir 
 Avasimibe 
Conivaptan 
Aprepitant 
 Bosentan 
grapefruit juice 
Atazanavir 
Carbamazepine 
Indinavir 
Cimetidine 
Efavirenz  
Itraconazole 
 
 Modafinil  
Ketoconazole 
Darunavir 
Nafcillin  
Lopinavir 
Diltiazem 
Oxcarbazepine 
Mibefradil 
Elvitegravir  
Phenobarbital 
Nefazodone 
Erythromycin 
Phenytoin 
Nelfinavir 
Fluconazole 
pioglitazone  
Posaconazole 
Fosamprenavir  
Rifabutin 
Ritonavir 
Tofisopam 
Rifampin 
Saquinavir 
Tipranavir 
St. John's wort 
Telithromycin 
Verapamil 
Topiramate 
Troleandomycin 
 
 
Voriconazole 
 
 
This database of CYP inhibitors was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table and from the 
University of Washington’s Drug Interaction Database based on in vitro studies. Strong inhibitors are predicted to increase Abiraterone acetate 
AUC > 5-fold, and moderate inhibitors are predicted to increase Abiraterone AUC ≥ 2-fold but < 5-fold.  
This database of CYP inducers was compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies;” from the Indiana University 
School of Medicine’s “Clinically Relevant” Table; and from (Pursche et al. 2008). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CYP450 SUBSTRATES TO BE USED WITH CAUTION 
 
CYP2C8 
CYP2C9 
CYP2C19 
CYP3A4,5,7** 
amodiaquine 
celecoxib 
amitriptyline 
Adinazolam 
fentanyl2 
cerivastatin 
diclofenac 
citalopram 
alfentanil1,2 
flunitrazepam 
pioglitazone 
flurbiprofen 
clobazam 
alpha-
dihydroergocryptine1 
fluticasone1 
repaglinide 
fluvastatin 
clomipramine 
alprazolam 
lovastatin1 
rosiglitazone  
glibenclamide 
(glyburide) 
clopidogrel 
amlodipine 
maraviroc1 
torsemide 
gliclazide 
diazepam 
aripiprazole 
midazolam1 
troglitazone 
glimepiride 
fluoxetine 
atorvastatin 
nifedipine 
 
glipizide 
imipramine 
brotizolam1 
nisoldipine 
 
indomethacin 
lansoprazole 
budesonide1 
nitrendipine 
 
irbesartan 
moclobemide 
buspirone1 
perospirone1 
 
ketobemidone 
omeprazole 
cerivastatin 
quinine 
 
lornoxicam 
pantoprazole 
chlorpheniramine 
sildenafil1 
 
losartan 
progesterone 
cyclosporine2 
simvastatin1 
 
meloxicam 
propranolol 
darifenacin1 
sirolimus1,2 
 
naproxen 
quazepam 
Diazepam 
tipranavir1 
 
nateglinide 
rabeprazole 
diergotamine2 
trazodone 
 
piroxicam 
sertraline 
ebastine1 
triazolam1 
 
S-ibuprofen 
S-mephenytoin 
eletriptan1 
 
 
sulfamethoxazole 
 
eplerenone1 
 
 
tenoxicam 
 
ergotamine2 
 
 
tolbutamide 
 
Estazolam 
 
 
torsemide 
 
everolimus1 
 
 
valdecoxib 
 
 
 
* This database of CYP substrates was compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table, and from 
(Zhou et al. 2009) 
** CYP3A4,5,7 substrates were compiled from the Indiana University School of Medicine’s “Clinically Relevant” Table; and supplemented by 
the FDA’s “Guidance for Industry, Drug Interaction Studies” and the University of Washington’s Drug Interaction Database. 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co-administered with a potent 
inhibitor of the respective enzyme. 
2 Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their exposure levels by the 
concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
 
 

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APPENDIX 3:  NCI COMMON TOXICITY CRITERIA  
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 can be found here: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 

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APPENDIX 4:  CRITERIA FOR DISEASE PROGRESSION 
PROSTATE CANCER WORKING GROUP 2 (PCWG2) GUIDELINES [13] 
 
Variable 
Assessments 
Progression 
Soft-tissue lesions 
Use RECIST 1.1 criteria, except: 
 
Only report changes in lymph 
nodes that were ~2 cm in 
diameter at baseline 
 
Record changes in nodal and 
visceral soft tissue sites separately 
 
Record complete elimination of 
disease at any site separately 
 
Confirm favorable change with 
next planned scan 8 weeks later 
Use RECIST 1.1 criteria for progression, except:  
 
Progression at first assessment must 
be confirmed by a second scan 6-8 
weeks later 
(For some treatments, a lesion may increase in size 
before it decreases)  
Bone 
Record as either new lesions or  
no new lesions 
 
If no new lesions, continue therapy 
 
If new lesions:  continue therapy but 
perform a confirmatory scan 6-8 weeks 
later. 
 
If confirmatory scan has no new lesions, 
continue therapy.  If there are additional 
new lesions, this is progression. 
The appearance of ≥ 2 new lesionsAND 
 
A confirmatory scan 6-8 weeks later showing at 
least 2 additional new lesions 
 
The date of progression is the date of the first 
scan that shows the change 
Symptoms 
 
Consider independently of other outcome measures 
One or more of the following criteria indicates disease progression: 
 
Need for new systemic therapy 
 
Need for palliative radiation therapy 
 
Development of a new skeletal-related event