Conditions: Metastatic ER+ Her2- Breast Cancer Postmenopausal
Keywords: Breast cancer Abiraterone Postmenopausal Metastatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 297
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and efficacy of oral abiraterone acetate plus oral prednisone and oral abiraterone acetate plus oral prednisone plus oral exemestane, each compared with oral exemestane alone, in postmenopausal women with estrogen receptor-positive (ER+) metastatic (spreading) breast cancer that has relapsed after treatment with letrozole or anastrozole.

Detailed description:
This is a randomized (study drug assigned by chance), open-label (all participants will know the identity of the assigned study drug) study divided into three phases, screening, treatment, and follow-up. During screening, potential patients will be assessed for study eligibility after providing signed informed consent. The treatment phase will comprise a series of 28-day cycles with continuous study treatment until breast cancer progression, when an end-of-treatment visit will be completed before the follow-up phase begins. The duration of participation in the study for an individual patient may be up to approximately 7 years, including follow-up evaluations. Patients will be evaluated for the safety and effectiveness of study treatments. During the treatment phase, patients will take the following study drugs by mouth once daily: abiraterone acetate, 1 g/day, as four 250-mg tablets, on an empty stomach, and patients must not eat for at least 1 hour after abiraterone acetate; prednisone (prednisolone when prednisone is not available), 5 mg/day; and exemestane, 25 mg/day, as a single tablet. The treatment phase will consist of a series of 28-day cycles with continuous study treatment until breast cancer progression. At the planned interim analysis, the Data Review Committee has recommended that further randomization to the abiraterone acetate alone group be stopped and that the study is to be continued otherwise.

Arms:
arm 1: Abiraterone acetate + Prednisone or Prednisolone Abiraterone acetate type=equal unit=mg number=250 form=tablet route=oral use 4 tablets Prednisone or Prednisolone type=equal unit=mg number=5 form=tablet route=oral use. All drugs are taken once daily. arm 2: Abiraterone acetate + Prednisone/Prednisolone + Exemestane Abiraterone acetate type=equal unit=mg number=250 form=tablet route=oral use 4 tablets Prednisone or Prednisolone type=equal unit=mg number=5 form=tablet route=oral use Exemestane type=equal unit=mg number=25 form=tablet route=oral use. All drugs are taken once daily. arm 3: Exemestane Exemestane type=equal unit=mg number=25 form=tablet route=oral use. All drugs are taken once daily.

Interventions: intervention 1: Exemestane intervention 2: Abiraterone acetate + Prednisone/ Prednisolone + Exemestane intervention 3: Abiraterone acetate + Prednisone or Prednisolone
Intervention descriptions: intervention 1: Abiraterone acetate, type=equal, unit=mg, number=250, form=tablet, route=oral use, 4 tablets intervention 2: Prednisone or Prednisolone, type=equal, unit=mg, number=5, form=tablet, route=oral use. All drugs are taken once daily. intervention 3: Abiraterone acetate, type=equal, unit=mg, number=250, form=tablet, route=oral use, 4 tablets

Protocol document:
Prot_000.pdf: 
1
Status: Approved Date: 27 April 2015
Janssen Research & Development*
Clinical Protocol
Randomized, Open-Label Study of Abiraterone Acetate (JNJ-212082) Plus Prednisone 
With or Without Exemestane in Postmenopausal Women With ER+ Metastatic Breast 
Cancer Progressing After Letrozole or Anastrozole Therapy
Protocol 212082BCA2001; Phase 2
Amendment INT-7
JNJ-212082 (abiraterone acetate)
*Janssen Research & Development is a global organization that operates through different legal entities in various 
countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, 
such as, but not limited to Janssen Biotech, Inc.; Janssen Products, L.P.; Janssen Biologics, B.V.; Janssen-Cilag 
International N.V.; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen Sciences Ireland UC; or Janssen
Research & Development, L.L.C. The term “sponsor” is used throughout the protocol to represent these various 
legal entities; the sponsor is identified on the Contact Information page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations
(21 CFR Part 312) for US sites.
EudraCT NUMBER:  2011-000621-80
Status:
Approved
Date:
27 April 2015
Prepared by:
Janssen Research & Development, LLC
EDMS no & version:
EDMS-ERI-22298356; 9.0
Compliance: This study will be conducted in compliance with this protocol, Good Clinical Practice, and applicable regulatory 
requirements.
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged
or confidential.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
2
Status: Approved Date: 27 April 2015
TABLE OF CONTENTS
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES.......................................................................................................................... 4
PROTOCOL AMENDMENTS....................................................................................................................... 5
SYNOPSIS.................................................................................................................................................. 18
TIME AND EVENTS SCHEDULE .............................................................................................................. 22
ABBREVIATIONS ...................................................................................................................................... 25
1.
INTRODUCTION............................................................................................................................ 26
2.
OBJECTIVES AND HYPOTHESIS ............................................................................................... 28
2.1.
Objectives ...................................................................................................................................... 28
2.2.
Hypothesis ..................................................................................................................................... 29
3.
STUDY DESIGN AND RATIONALE ............................................................................................. 29
3.1.
Overview of Study Design.............................................................................................................. 29
3.2.
Study Design Rationale.................................................................................................................. 31
4.
SUBJECT POPULATION.............................................................................................................. 33
4.1.
Inclusion Criteria ............................................................................................................................ 34
4.2
Exclusion Criteria ........................................................................................................................... 35
4.3
Prohibitions and Restrictions ......................................................................................................... 36
5.
TREATMENT ALLOCATION AND RANDOMIZATION................................................................ 37
6.
DOSAGE AND ADMINISTRATION .............................................................................................. 37
6.1.
Dose Reduction and Toxicity Management ................................................................................... 38
6.1.1.
Management of Hypokalemia........................................................................................ 39
6.1.2.
Management of Hypertension........................................................................................ 39
6.1.3.
Management of Edema and Fluid Retention................................................................. 40
6.1.4.
Management of Non-Mineralocorticoid Side Effects ..................................................... 40
6.1.5.
Management of Abnormal Liver Function Tests............................................................ 41
7.
TREATMENT COMPLIANCE........................................................................................................ 41
8.
PRESTUDY AND CONCOMITANT THERAPY ............................................................................ 41
8.1.
Required Study Medication NOT Reported as Concomitant ......................................................... 42
8.2.
Permitted Supportive Care and Interventions................................................................................ 42
8.3
Special Concomitant Therapy........................................................................................................ 43
9.
STUDY EVALUATIONS ................................................................................................................ 43
9.1.
Study Procedures........................................................................................................................... 43
9.1.1.
Overview........................................................................................................................ 43
9.1.2.
Screening Phase ........................................................................................................... 44
9.1.3.
Treatment Phase ........................................................................................................... 45
9.1.4.
End-of-Treatment Procedures ....................................................................................... 45
9.1.5.
Follow-Up Phase ........................................................................................................... 45
9.2.
Efficacy Evaluation......................................................................................................................... 45
9.2.1.
Progression-Free Survival ............................................................................................. 45
9.2.2.
Long-Term Benefit ......................................................................................................... 46
9.3.
Safety Evaluation ........................................................................................................................... 47
9.4.
Biomarker Evaluation..................................................................................................................... 48
9.4.1.
Formalin-Fixed Paraffin-Embedded Tumor Tissue........................................................ 48
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Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
9.4.2.
Endocrine Markers......................................................................................................... 48
9.4.3.
Circulating Tumor Cells ................................................................................................. 48
9.4.4.
Fresh Tumor Biopsies (Selected Study Sites)............................................................... 49
9.5.
Pharmacogenomics Evaluation ..................................................................................................... 49
9.6.
Pharmacokinetics Evaluation (Selected Study Sites) .................................................................... 49
9.7.
Sample Collection and Handling.................................................................................................... 50
10.
SUBJECT COMPLETION/WITHDRAWAL................................................................................... 50
10.1.
Completion ..................................................................................................................................... 50
10.2.
Discontinuation of Study Drug ....................................................................................................... 50
10.3.
Withdrawal From the Study............................................................................................................ 51
11.
STATISTICAL METHODS............................................................................................................. 52
11.1.
Sample Size Determination ........................................................................................................... 52
11.2.
Analysis Populations...................................................................................................................... 53
11.3.
Demographics and Baseline Characteristics ................................................................................. 53
11.4.
Efficacy Analyses ........................................................................................................................... 53
11.4.1.
Primary Efficacy Endpoint.............................................................................................. 53
11.4.2.
Secondary Efficacy Endpoints....................................................................................... 53
11.4.3.
Analyses Methods ......................................................................................................... 54
11.5.
Biomarker Analyses ....................................................................................................................... 54
11.6.
Pharmacokinetics Analyses ........................................................................................................... 55
11.7.
Safety Analyses ............................................................................................................................. 55
11.8.
Interim Analysis.............................................................................................................................. 55
11.9.
Data Review Committee ................................................................................................................ 55
12.
ADVERSE EVENT REPORTING .................................................................................................. 56
12.1.
Definitions ...................................................................................................................................... 56
12.1.1.
Adverse Event Definitions and Classifications .............................................................. 56
12.1.2.
Attribution Definitions..................................................................................................... 57
12.1.3.
Severity Criteria ............................................................................................................. 58
12.2.
Special Reporting Situations.......................................................................................................... 58
12.3.
Procedures..................................................................................................................................... 58
12.3.1.
All Adverse Events......................................................................................................... 58
12.3.2.
Serious Adverse Events ................................................................................................ 59
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 60
13.
PRODUCT QUALITY COMPLAINT HANDLING.......................................................................... 61
13.1.
Procedures..................................................................................................................................... 61
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 61
14.
STUDY DRUG INFORMATION..................................................................................................... 61
14.1.
Physical Description of Study Drugs.............................................................................................. 61
14.2.
Packaging ...................................................................................................................................... 61
14.3.
Labeling.......................................................................................................................................... 62
14.4.
Preparation, Handling, and Storage............................................................................................... 62
14.5.
Drug Accountability ........................................................................................................................ 62
15.
STUDY-SPECIFIC MATERIALS ................................................................................................... 63
16.
ETHICAL ASPECTS...................................................................................................................... 63
16.1.
Study-Specific Design Considerations........................................................................................... 63
16.2.
Regulatory Ethics Compliance....................................................................................................... 63
16.2.1.
Investigator Responsibilities .......................................................................................... 63
16.2.2.
Independent Ethics Committee or Institutional Review Board ...................................... 64
16.2.3.
Informed Consent .......................................................................................................... 65
16.2.4.
Privacy of Personal Data ............................................................................................... 66
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Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
17.
ADMINISTRATIVE REQUIREMENTS .......................................................................................... 67
17.1.
Protocol Amendments.................................................................................................................... 67
17.2.
Regulatory Documentation ............................................................................................................ 68
17.2.1.
Regulatory Approval/Notification.................................................................................... 68
17.2.2.
Required Prestudy Documentation................................................................................ 68
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 69
17.4.
Source Documentation................................................................................................................... 69
17.5.
Case Report Form Completion ...................................................................................................... 69
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 70
17.7.
Record Retention ........................................................................................................................... 70
17.8.
Monitoring ...................................................................................................................................... 71
17.9.
Study Completion/Termination....................................................................................................... 71
17.9.1.
Study Completion .......................................................................................................... 71
17.9.2.
Study Termination.......................................................................................................... 72
17.10.
On-Site Audits ................................................................................................................................ 72
17.11.
Use of Information and Publication................................................................................................ 72
REFERENCES............................................................................................................................................ 74
INVESTIGATOR AGREEMENT ................................................................................................................. 93
LAST PAGE................................................................................................................................................ 93
LIST OF ATTACHMENTS
Attachment 1:  
Response Evaluation Criteria in Solid Tumors (RECIST) .......................................... 76
Attachment 2:  
European Organization for Research and Treatment of Cancer Core 30.................. 79
Attachment 3:  
Euro-QoL (EQ-5D-5L) ................................................................................................ 80
Attachment 4:  
Pain Intensity Scale (of Brief Pain Index–Short Form)............................................... 82
Attachment 5: 
Progressive Disease Notification Fax......................................................................... 83
Attachment 6:  
National Cancer Institute Common Terminology Criteria for Adverse Events ........... 85
Attachment 7:  
Laboratory Tests......................................................................................................... 86
Attachment 8:  
Eastern Cooperative Oncology Group ....................................................................... 87
Attachment 9:  
Amendment INT-5 Changes to Randomization and Crossover................................. 88
Attachment 10:  
Modified Schedule of Events for Subjects Continuing to Receive Study 
Medication Under Amendment INT-6 (after the Clinical Cut Off Date for Final 
Analysis) ..................................................................................................................... 89
LIST OF IN-TEXT TABLES 
Table 1:
CYP3A4 Inducers .................................................................................................................... 37
Table 2: 
Hypokalemia Management...................................................................................................... 39
Table 3:
Approximate Blood Volume Through Four Treatment Cycles................................................. 44
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
11 March 2011
Amendment INT-1
25 March 2011
Amendment INT-2
20 June 2011
Amendment INT-3
4 November 2011
Amendment INT-4
19 September 2012
Amendment INT-5
18 March 2013
Amendment INT-6
20 January 2014
Amendment INT-7
27 April 2015
Amendments are listed beginning with the most recent amendment.
Amendment INT-7 (27 April 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to extend the period for long-
term safety follow up to a maximum of 5 years from the final analysis clinical cut off.
Applicable Section(s)
Description of Change(s)
Rationale: Specified that follow-up for safety will continue for an additional duration of up to 3 years from the 
existing date of 20th Sep 2015 in the current protocol (i.e., up to 20 September 2018)
Synopsis (Overview 
of Study Design); 
3.1 Overview of 
Study Design; 
5 Treatment 
Allocation and 
Randomization; 
16.2.3 Informed 
Consent; 
Individual subjects who continue to derive benefit from the treatment they are currently 
receiving, will be offered the opportunity to continue on their existing study medication 
and followed-up for safety for an additional duration of up to 3 years (ie, up to 
20 September 2018) from the date previously stated (20 September 2015) in the 
Amendment INT-6 protocol. The situation may be reassessed periodically for subjects still
receiving study medication
Rationale: To comply with current internal standards for protocol development
Throughout the 
protocol
Mandatory protocol text was updated
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
6
Status: Approved Date: 27 April 2015
Amendment INT-6 (20 January 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for the amendment: The final analysis of the primary endpoint, progression-free survival 
(PFS) was performed after the predefined total of 150 PFS events were reported in the abiraterone plus exemestane 
group and in the exemestane alone group; the clinical cutoff date for the final analysis (CCO-FA) was 20 September 
2013. The results did not show a clinically meaningful or statistically significant advantage of abiraterone acetate 
plus exemestane or abiraterone acetate alone over exemestane alone. There was also a slight increase in the 
incidence of adverse events in subjects treated with abiraterone acetate or with the combination of abiraterone 
acetate plus exemestane versus single-agent exemestane.  However, individual subjects may derive benefit from the 
treatment they are currently receiving with continued control of disease in the absence of significant toxicity. 
Therefore, it was decided to offer all subjects still on study treatment the opportunity to continue on their existing
study medication for up to 2 years from the CCO-FA (ie, up to 20 September 2015), at which point the situation will 
be reassessed for subjects still receiving study medication. Subjects who do not continue on study medication and
those in long-term follow up will be discontinued from the study. The decision to continue on study medication or 
withdraw from the study will be made by the subject and the investigator.
Applicable Section(s)
Description of Change(s)
Rationale: Based on the results of the final analysis, the primary endpoint of the study was not met. 
Synopsis (Overview 
of Study Design; 
Time and Events 
Schedule); 3.1 
Overview of Study 
Design; 5 Treatment 
Allocation and 
Randomization; 9.1.1 
Overview (of Study 
Evaluations); 9.1.5 
Follow-Up Phase; 
10.1 Completion; 
16.2.3 Informed 
Consent; Attachment 
10
The study is being amended to allow remaining subjects to continue to receive study 
medication for up to 2 years after the CCO-FA and to reduce the number of study-related 
procedures and amount of data to be collected.
Subjects will be required to sign an updated informed consent form to continue 
participation under Amendment INT-6.
Attachment 10 has been added which includes a description of all procedures to be 
performed under Amendment INT-6. The Schedule of Events in this Attachment 
supersedes the Time and Events Schedule in the previous version of the protocol 
(Amendment INT-5).
Rationale: To advise investigators where potential new information regarding drug-drug interactions for
abiraterone acetate may be found. 
8.3 Special 
Concomitant Therapy
A reference to the Investigator Brochure has been added.
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Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
Amendment INT-5 (18 March 2013)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: The overall reason for the amendment is to incorporate the 
recommendations of the Data Review Committee (DRC) following their review of the efficacy and safety results 
from the protocol-specified interim analysis of progression-free survival (PFS) (110 [50%] of progression or death 
events).
Applicable Section(s)
Description of Change(s)
Rationale: The criterion for futility was met for the abiraterone acetate group and the DRC recommended that 
subjects no longer be randomized to this group. The sponsor is stopping randomization of subjects to the 
abiraterone acetate group. The criteria for futility or efficacy were not met for the abiraterone acetate plus 
exemestane group; the DRC recommended that this group continue per protocol. The sponsor will continue per 
protocol. Based on the findings in the 2 groups noted above, the DRC stated the study team may consider that 
subjects who progress in the exemestane alone group be allowed to crossover to the abiraterone acetate plus 
exemestane group. The sponsor considered this option but decided not to allow crossover and for subjects who 
progress on exemestane to discontinue study treatment. The sponsor also decided that subjects in the abiraterone 
acetate group be informed of the sponsor decision to discontinue randomized assignment to the abiraterone acetate 
group and to allow ongoing subjects to make their own decision about whether or not to continue further study 
treatment.
Synopsis Overview of Study 
Design; Sample Size 
Determination; Section 3.1 
Overview of Study Design; 
Section 11.1 Sample Size 
Determination
Added a description of the DRC recommendations in the overview of study 
design. Added Attachment 9 to explain the revisions to the protocol based on the 
DRC recommendations. 
Added a revised sample size and number of events for the final analysis of PFS 
based on 2 treatment groups.
Rationale: Added cautionary wording for women who are pregnant or may be pregnant to avoid handling of 
abiraterone acetate tablets without protection. This wording is being incorporated into all new or amended 
abiraterone acetate protocols. 
Section 14.4 
Preparation, Handling 
and Storage
To avoid inadvertent exposure, women who are pregnant or women who may be pregnant 
should not handle abiraterone acetate without protection, eg, gloves. It is not known if 
either abiraterone acetate or its metabolites are excreted in human breast milk.
Rationale: Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. A drug-drug interaction study of 
abiraterone acetate and ketoconazole showed no clinically meaningful influence on abiraterone pharmacokinetics 
(PK). A drug-drug interaction study of abiraterone acetate and rifampicin showed reduced mean abiraterone 
plasma AUC∞. This information is being incorporated into all new or amended abiraterone acetate protocols.
Section 8.3 Special 
Concomitant Therapy
Added this wording to Section 8.3: In a clinical pharmacokinetic interaction study of 
healthy subjects pretreated with a strong CYP3A4 inducer (rifampicin, 600 mg daily for 6 
days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC∞
of abiraterone was decreased by 55%. Strong inducers of CYP3A4 (eg, phenytoin, 
carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) during treatment with 
abiraterone acetate are to be avoided, or used with careful evaluation of clinical efficacy.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
8
Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Removed cautionary wording regarding CYP3A4 inhibitors because drug interaction studies did not 
show any clinically meaningful effects of the strong CYP3A4 inhibitor, ketoconazole, on the pharmacokinetics of 
either exemestane or abiraterone.
Section 4.3 
Prohibitions and 
Restrictions
Removed reference to CYP3A4 inhibitors in text and in Table 1. 
Rationale: The storage conditions for prednisone and prednisolone were not correct and have been updated. 
Section 14.4 
Preparation, Handling 
and Storage
The correct temperature for storage of prednisone is 20 to 25ºC  (68 to 77 ºF) and for 
prednisolone is below 25ºC
Rationale: Updated Attachment 5: Progressive Disease Notification Fax Sheet; Tom Griffin has replaced Margaret 
Yu as the project physician.
Attachment 5
Updated contact information.
Rationale: Made minor editorial revisions for consistency with other protocols and incorporated minor changes 
from revised protocol template. 
Throughout the 
protocol
Minor editorial changes and incorporation of new template language.
Amendment INT-4 (19 September 2012)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: A prothrombin time (PT) is not done by many sites in Belgium, France, 
the Netherlands, and Spain, but an international normalized ratio (INR) is done instead. In addition, some subjects 
have abnormal but not clinically significant PT, which strictly per the current wording, would violate the protocol. 
This amendment allows an INR to be done whenever PT is not available. It also allows subjects with out of range 
PTs that are of no clinical significance to be eligible for the study.
Applicable Section(s)
Description of Change(s)
Rationale: To allow INR to be done in place of PT, and to allow for subjects with PTs/ INRs, or PTT out of 
normal range but not clinically significant to be eligible for enrollment.
Time and Events 
Schedule
Specified coagulation as PT or INR, and PTT; defined INR in footnote.
4.1 Inclusion Criteria 
bullet 7
Changed criterion to: Clinically normal prothrombin time (PT) or international 
normalized ratio (INR) and partial thromboplastin time (PTT) per investigator 
assessment.
Rationale: To fix the discrepancy between the Time and Events Schedule and Section 9.4.4 on the timing of the 
tumor biopsy.
Time and Events 
Schedule, Tumor 
Biopsy row and 
footnote w
Changed timing of tumor biopsy from Day 1 of Cycle 1 to screening
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
9
Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
9.4.4 Fresh Tumor 
Biopsies
Changed timing of tumor biopsy from 14 days within randomization to screening
Rationale: To avoid the risk of the fax number changing again before the study is done.
Attachment 5
Replaced fax numbers with “Janssen LTM include number”.
Rationale: To comply with current internal standards for the company name (new legal entity).
Title page;
Investigator Signature 
Page; Attachment 5
Replaced Johnson & Johnson Pharmaceutical Research & Development, LLC with 
Janssen Research & Development, LLC.
Amendment INT-3 (4 November 2011)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: To collect circulating tumor cells (CTCs) from all subjects on study in 
order to improve the power of the CTC sub-study.
Applicable Section(s)
Description of Change(s)
Rationale: Blood samples will be collected for CTC analysis from all subjects at baseline. Additional blood
samples will be collected only if the CTCs meet the required minimum threshold at baseline. 
Synopsis Overview;
Synopsis Biomarker 
Evaluations ;Time  
and Events Schedule 
footnote r; 9.1.1 
Overview Table 3;
9.4.3 Circulating 
Tumor Cells
Modified language to indicate that CTCs will be assessed from all subjects. The sites will 
be notified if a subject’s Day 1 Cycle 1 sample does not meet a minimum threshold and 
no further CTC sampling should be done for the subject.
9.1.1 Table 3
Blood volumes increased.
Rationale: In certain countries, drawing of 40 mL of blood per timepoint may not be acceptable by their Ethics 
Committee.
Time and Events 
Schedule footnote r;
9.1.1 Overview; 
Table 3; 9.4.3 
Circulating Tumor 
Cells
Added "where local regulations permit".
Rationale: Clarified Type I error.
Synopsis Sample 
Size; 11.1 Sample 
Size
Indicated that for each of the pair-wise comparisons, the statistical tests of treatment 
effects on primary endpoint of PFS will be conducted independently at the 2-sided 0.10 
level of significance.
NCT01381874


JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
10
Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Stratified log-rank test provides a method to adjust for the possible effect of prognostic factors on 
treatment responsiveness.
Synopsis Statistical 
Methods;
11.4.3 Analysis 
Methods
Nonstratified log-rank test was modified to stratified log-rank test.
Rationale: No further assessment of endocrine markers, pharmacogenomics, PK, or CTCs will be done for 
subjects who have progressed on exemestane because there is no expectation that these tests will provide valuable 
information for the study.
Time and Events 
Schedule and 
footnotes r, s, t, ,and v;
10.2 Discontinuation
Samples for evaluating the endocrine markers, pharmacogenomics, PK, or CTCs will not 
be collected from subjects receiving abiraterone acetate after crossing over from the 
exemestane treatment.
Rationale: Specified the assays to be done on the CTCs.
3.2 Rationale
Added language to indicated that CTC samples will be taken to characterize AR, ER, PR, 
CYP17, CYP19, and other candidate markers related to abiraterone or to breast cancer.
Rationale: Timing of cardiac evaluations using MUGA or ECHO and the timing of imaging to confirm disease 
progression were specified.
Time and Events 
Schedule and footnote 
g; 9.3 Safety 
Evaluation
MUGA (or ECHO) will be captured at baseline and at every 3rd cycle thereafter.
3.2 Rationale
Imaging will be done on Day 1 of Cycles 3, 5 and 7, then on Day 1 of every 3rd cycles 
thereafter.
Rationale: Clarified eligibility criteria for consistency with other sections in the study protocol.
4.1 Inclusion Criteria
Criterion 2 indicated that in a subject with multiple biopsies of metastatic sites, the most 
recent biopsy prior to study entry should be submitted for evaluation of hormone receptor 
status.
Criterion 3 specified that subjects with purely sclerotic lesions may not participate in the 
study as indicated in Section 9.2.1 of the protocol.
Criterion 7 was modified for subjects to meet the hemoglobin, neutrophils, and platelets 
criteria, independent of growth factors and transfusions.
Criterion 10 specified that bisphosphonate or denosumab may be initiated on the same 
day as the assigned study treatment.
4.2 Exclusion Criteria
Criterion 1 indicated prior treatment with ketoconazole for ≤7 days is permitted and 
topical formulations of ketoconazole are permitted.
Criterion 2 specified that potential subjects must not have taken anastrozole, letrozole, 
fulvestrant, or any chemotherapy for at least 2 weeks (bevacizumab for at least 3 weeks) 
before randomization to be consistent with the other therapies.
Criterion 10 specified that subjects with any active or uncontrolled disease that may 
require oral corticosteroid therapy should be excluded.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
11
Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Clarified that CYP3A4 inhibitors and inducers should be avoided and not prohibited.
4.3 Prohibitions
Modified language in the first bullet and in the title of Table 1 to indicate that CYP3A4 
inhibitors and inducers should not be prohibited, but rather used with caution or avoided.
Rationale: Clarified which food and beverages were allowed during the PK substudy.
4.3 Prohibitions
Specified which food and beverages are prohibited during the PK sampling.
Rationale: Specified that 2 dose reductions are allowed for drug-related adverse events, and not those attributable 
to disease progression.
6.1 Dose Reduction
Up to 2 dose reductions of abiraterone acetate are allowed for adverse events that the 
investigator attributes to abiraterone acetate.
Rationale: Deleted to avoid redundancy with Section 12.1.3 of the protocol.
6.1 Dose Reduction
Adverse events including laboratory adverse events will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE), Version 4.0.
Rationale: Made consistent with the U.S. package insert (USPI) for ZYTIGA.
6.1.1 Management of 
Hypokalemia
Changed "the subject hospitalized" to "hospitalization considered".
Rationale: Further revised permitted supportive care and interventions for subjects enrolled in the study.
8.2 Permitted 
Supportive Care 
Conventional multivitamins, selenium, and soy supplements.
8.2 Permitted 
Supportive Care 
Bisphosphonates or denosumab is permitted for bone disease, provided a stable dose is 
documented for at least 2 doses before randomization.
8.2 Permitted 
Supportive Care
Deleted the wording referring to the use of anti-infectives, hematopoietic cytokines, blood 
transfusions, and any medications to treat serious adverse events, because all details 
pertaining to these concomitant medications are to be documented in the eCRF.
8.2 Permitted 
Supportive Care
Language has been modified to indicate that if a subject is suspected of having progressed 
but has a not fully met all criteria for progression then certain treatment options are 
available.
8.2 Permitted 
Supportive Care
Changed "documented" to "suspected".
Rationale: The occurrence of neutropenia is unlikely in this study.
8.3 Special 
Concomitant Therapy
Deleted language concerning the use of colony stimulating factors.
Rationale: Provided the details around the collection of tumor samples for molecular analyses.
9.1.1 Overview
Tumor samples are collected for ER subtyping and other molecular analyses.
Rationale: Specified when the End-of-Treatment visit should occur.
9.1.4 End-of-
Treatment 
….occurs when the subject has met the criteria for discontinuation of study drug(s).
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Clarified language regarding the assessment of response in subjects with only bone metastasis.
9.2.1 Progression-
Free Survival
Disease progression should not be based on assessments of new sclerotic bone 
lesions. When bone disease is the only basis for determination of progression or 
response, only lytic bone lesions should be used.
All disease progressions should be confirmed by the sponsor company via a faxed 
confirmation form (Attachment 5).
Rationale: Revised to reflect current biomarker storage policy.
9.5 Pharmacogenomic 
Evaluation;
Stored DNA samples and relevant clinical data are made nonidentifiable will be double-
coded and stored for a period of 5 years.
10.3 Withdrawal
Deleted language that indicated that all samples would be made unidentifiable.
Rationale: Laboratory requisition forms and not the eCRFs will be used to record sample collection.
9.7 Sample Collection
…sample collection must be recorded on the eCRF laboratory requisition forms.
Rationale: Clarified that the fax should document discontinuation due to disease progression only.
10.2 Discontinuation
Specified that the study drug discontinuation due to disease progression only should be 
communicated to the Sponsor via a fax; and only after the reasons are accepted by the 
sponsor, the study drugs can be discontinued.
Rationale: Specified the subject’s options regarding pharmacogenomic research at the time of withdrawal from the 
study.
10.3 Withdrawal 
DNA extracted will be retained and used in accordance with the subject's original 
pharmacogenomic informed consent or if a subject withdraws the consent then the DNA 
sample will be destroyed.
Rationale: Revised for consistency with the storage conditions specified in the ZYTIGA label.
14.4 Preparation, 
Handling, and Storage
Modified to state that abiraterone acetate, exemestane, and prednisone/prednisolone are 
all stored at room temperature (15 to 30°C; 59 to 86°F).
Rationale: Subjects and not their legally accepted representative need to be able to complete the PRO scales in this 
study.
14.5 Accountability
Deleted language regarding the subjects' legally accepted representative.
Rationale: Results from tests and procedures that are considered part of standard of care that were performed 
before signing of the ICF may be used for the study.
16.2.3 Informed 
Consent
Results from laboratory tests, medical procedures and imaging or scans done as part 
of standard of care that have been performed before the consent form signature date 
may be used for the study.
Rationale: For compliance reasons, subjects should not be able to be identified by their initials.
17.3 Subject 
Identification, 
Enrollment, and 
Screening Logs
…will identify subjects by initials and assigned number. only.
Rationale: To clarify response assessment.
Attachment 1 
Confirmations of PR and CR will be documented by a second CT or MRI at least 4 
weeks after the initial response.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Provided the Progressive Disease Notification FAX form.
Attachment 5
Attachment 5 was added.
Rationale: Specified the clinical laboratory tests to be performed. Luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) were missing in the previous amendment.
Attachment 7
Added Clinical Laboratory: luteinizing hormone (LH), follicle stimulating hormone 
(FSH).
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Abbreviations
Made abbreviations consistent throughout.
Amendment INT-2 (20 June 2011)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: To clarify the language regarding concomitant therapies with CYP2D6 
substrates and dosing of abiraterone acetate to be consistent with the existing label.
Applicable Section(s)
Description of Change(s)
Rationale: Added language to provide consistency with the USPI regarding concomitant therapies with CYP2D6 
substrates
Section 8.3 Special 
Concomitant Therapy
Added the following: “Abiraterone acetate is an inhibitor of the hepatic drug-
metabolizing enzyme CYP2D6. Avoid co-administration of abiraterone acetate with 
CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment 
cannot be used, exercise caution and consider a dose reduction of the concomitant 
CYP2D6 substrate.”
Rationale: Added language to provide consistency with USPI regarding the dosing of abiraterone acetate with 
respect to food consumption
Synopsis, Dosage and
administration; Time 
and Events Schedule
footnote f; Section 6.1
Dosage and 
administration
Clarified the dosing of abiraterone acetate with respect to consumption of food. 
“Abiraterone acetate must be taken on an empty stomach. No food should be consumed 
for at least 2 hours before the dose of abiraterone acetate is taken and for at least 1 hour 
after the dose of abiraterone acetate is taken.”
Rationale: Consistency within the protocol. This was an oversight during the last amendment.
Section 6.1 Dose 
Reduction and 
Toxicity Management
Removed incorrect text stating that the first level dose reductions of abiraterone acetate 
due to toxicity is from 1 g/day to 500 mg/day. Clarified the language with respect to dose 
reductions of abiraterone acetate, and provided consistency with the USPI.
Rationale: Consistency within the protocol. This was an oversight during the last amendment.
Section 6.1 Dose 
Reduction and 
Toxicity Management
Adverse events including laboratory adverse events will be graded according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-
CTCAE), Version 4.0.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Additional clarity provided regarding prednisone discontinuations.
Section 6.1 Dose 
Reduction and 
Toxicity Management
Discontinuation of prednisone will be individualized depending on investigator judgment. 
Abrupt discontinuation of prednisone after chronic therapy may trigger symptoms and 
signs consistent with adrenal insufficiency.
Rationale: Not previously defined in the protocol. This is now defined to be consistent within the abiraterone 
acetate program.
Section 7 Treatment 
compliance
Added the language “Drug non-compliance is defined as missing 75% of doses in 2 
consecutive cycles or more than 14 days of therapy in 1 cycle”
Rationale: Inclusion criteria clarification based on questions from investigators.
Section 4.1 Inclusion 
criteria
Divided the inclusion criteria #2 to 2 separate criteria; Subjects with disease confined 
only to bone may be included and Subjects with ER+, Her2- metastatic breast cancer, 
confirmed within 7 days before randomization with FFPE tissue from either primary or 
metastatic breast cancer site, that recurred during or within 6 months of discontinuing 
anastrozole or letrozole therapy in adjuvant or metastatic setting.
Rationale: The End-of-Treatment blood sample for PK evaluation is not needed.
Pharmacokinetic 
Evaluation Section of 
the synopsis; Time 
and Events Schedule 
and footnote “u”; 
Section 9.1.1. 
Overview of Study 
procedures; 
Section 9.6 
Pharmacokinetics 
Evaluation
Removed the language referring to PK sampling at End-of-Treatment 
Rationale: Some sites indentified for PK sampling cannot support overnight stays for patients.
Time and Events 
Schedule footnote 
“u”; Section 9.1.1 
Overview of Study 
procedures; Section 
9.6 Pharmacokinetics 
Evaluation 
Added language to specify that sites that are not capable of overnight stays for subjects
will not collect the 12, 16, and 22 hour PK sampling timepoints on Days 1 and 15 of 
Cycle 1.
Added “approximate” to the total volumes of blood collected per subject
Rationale: Increased blood volume is needed to be taken for CTC analyses
Time and Events 
Schedule footnote 
“v”; Section 9.1.1 
Overview of Study 
procedures and 
Table 3; Section 9.4.3 
Circulating Tumor 
Cells
The blood sample volume was changed from 20 mL to 40 mL to be taken on Day 1 of 
Cycles 1 and 2 and at End-of-Treatment for CTC analyses.
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale: Analyses for CTC only to be performed on samples from subjects on the monotherapy arms of the 
study
Time and Events 
Schedule footnote 
“v”; Section 9.4.3 
Circulating Tumor 
Cells
Clarification that blood for circulating tumor cell (CTC) analyses will only be taken from 
subjects randomized from the abiraterone/prednisone and exemestane treatment groups.
Rationale: Biopsy of tumor more convenient with procedures done on Day 1 Cycle 1
Time and Events 
Schedule footnote 
“w”;
Eliminated the biopsy of tumor at baseline time point
Rationale: Minor errors were noted.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
Amendment INT-1 (25 March 2011)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for the amendment is to clarify the description of the
Follow-up phase versus the anticipated total study duration and to revise the timing of the CTC collection.
Applicable Section(s)
Description of Change(s)
Rationale: The description of the study’s Follow-up phase versus the anticipated total study duration has been 
clarified.
Synopsis, Overview 
of Study Design; 
3.1 Overview of 
Study Design;
9.1.5 Follow-Up 
Phase; 
10.1 Completion
Whenever study drug is discontinued, subjects should be evaluated within 30 days during 
the End-of-Treatment visit and entered into the Follow-Up phase regardless of reason for 
study drug discontinuation, and monitored every 3 months (7 days) until death, loss to 
follow-up, consent withdrawal, or abiraterone acetate development in this indication is 
discontinued. The total duration of the study is anticipated to be up to 3 years.
Rationale: The CTC collection at Cycle 3 Day 1 has been removed. 
Time and Events 
Schedule, Circulating 
Tumor Cells line 
entry and Footnote u;
9.4.3 Circulating 
Tumor Cells 
(Selected Study Sites)
Blood samples (20 mL) will be taken Day 1 of Cycles 1 and 2 and during the
End-of-Treatment visit for CTC enumeration and molecular characterization.
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Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
9.1.1 Overview, 
Table 3: Approximate 
Blood Volume 
Through Four 
Treatment Cycles
Circulating tumor cells (CTCs): Samples per subject=2; volume per subject (mL)=40. 
The total blood volume to be drawn with PK, CTC, DNA=220-320 mL.
Rationale: Minor modifications were made to reduce the exploratory biomarker analyses and provide flexibility in 
identifying which exploratory analyses may be performed.
3.2 Study Design 
Rationale, DNA and 
Biomarker Collection;
9.4.1 Formalin-Fixed 
Paraffin-Embedded 
Tumor Tissue;
11.5 Biomarker 
Analyses
The text was revised from “will be performed” to “may be performed” and “will be 
analyzed” to “may be analyzed.” Also “and” has been replaced with “or” in some 
instances to provide flexibility.
3.2 Study Design 
Rationale, DNA and 
Biomarker Collection; 
9.4.3 Circulating 
Tumor Cells 
(Selected Study Sites)
Ki-67 and 3β-hydroxysteroid dehydrogenase were removed from the CTC analysis and 
replaced with “other candidate markers.”
Rationale: To simplify the study, blood pressure home monitoring for subjects with suspected anxiety-induced 
hypertension has been removed, and study inclusion blood pressure was clarified as <160/95 mm Hg.
Time and Events 
Schedule, Footnote j;
9.3 Safety Evaluation, 
Vital Signs
Upright sitting blood pressure, heart rate, respiratory rate, and oral or aural body 
temperature, should be recorded. If anxiety-induced hypertension is suspected, subject 
must document systolic blood pressure <140 mm Hg and diastolic blood pressure <90 
mm Hg with at least two home morning measurements within 7 days before a scheduled 
visit.
4.1 Inclusion Criteria 
Criterion #7
Subjects must have systolic blood pressure <160 mm Hg and diastolic blood pressure <95 
mm Hg [Note: Hypertension controlled by antihypertensive therapy is permitted]. For 
patients with suspected anxiety-induced hypertension, systolic blood pressure<140 mm 
Hg and diastolic blood pressure<90 mm Hg may be confirmed via home monitoring 
within 14 days of randomization.
6.1.2 Management of 
Hypertension
Grade 1-2: Management per investigator; investigators should maintain blood pressure 
<160/95 mm Hg with antihypertensive agents; do not reduce abiraterone acetate dose.
Rationale: To correct an inconsistency, specific details regarding the timing of blood sampling have been 
removed.
Time and Events 
Schedule, Footnote f; 
6 Dosage and 
Administration
All study drugs are oral and should be taken once daily. Abiraterone acetate 1 g/day must 
be taken as four 250-mg tablets on an empty stomach and subjects must not eat for at 
least 1 hour after abiraterone acetate; prednisone (prednisolone when prednisone is not 
available) 5 mg/day should be taken daily with abiraterone acetate; if gastric intestinal 
upset occurs, prednisone may be taken with food and separately from abiraterone acetate. 
Exemestane 25 mg/day should be taken as a single tablet, preferably after a meal. Predose 
review of clinical laboratory results will be done Day 1 of every cycle.
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Clinical Protocol 212082BCA2001 Amendment INT-7
17
Status: Approved Date: 27 April 2015
Applicable Section(s)
Description of Change(s)
Rationale (Cont.): To correct an inconsistency, specific details regarding the timing of blood sampling have been 
removed.
3.1 Overview of 
Study Design
During the Treatment phase, study visits and study procedures are scheduled Day 1 of 
every 28-day cycle (±2 days) as well as Day 15 (±2 days) of Cycles 1 through 3. Because 
review of clinical laboratory results should precede dosing every visit, subjects are 
instructed not to take study drugs at home on visit days. Study drug treatment will 
continue until the earliest of the following events: disease progression, unacceptable 
toxicity, or death. Subjects with no disease progression for 12 treatment cycles may 
continue study treatment at the discretion of the investigator, in which case study visits 
will continue every 3 cycles. 
9.1.1 Overview
The Time and Events Schedule summarizes the frequency and timing of all study 
evaluations. When study procedures occur on the same visit day, PROs should be 
completed before any other procedures or consultations for that visit and blood sampling 
should follow all visit procedures.
9.3 Safety Evaluation, 
Clinical Laboratory 
Tests
Blood samples for hematology and chemistry will be taken for evaluation of laboratory 
safety parameters (Attachment 6). The investigator must review the laboratory report
before visit day dosing, document this review, and record any clinically relevant changes 
during the study in the adverse event section of the eCRF. Baseline values, including 
Screening coagulation and dipstick urinalysis, should be measured within 7 days before 
randomization.
Rationale: The term “Data Monitoring Committee (DMC)” has been revised to “Data Review Committee (DRC)” 
in alignment with a new SOP coming into effect.
Synopsis, Interim 
Analysis and Data 
Review Committee;
Abbreviations;
11.8 Interim Analysis;
11.9 Data Review 
Committee;
16.1 Study-Specific 
Design 
Considerations
After review of interim data, the Data Review Committee (DRC) will make 
recommendations regarding study continuation.
Rationale: To correct an inconsistency, the term “Study Pharmacy Manual” has been revised to “Study Laboratory 
Manual.”
9.7 Sample Collection 
and Handling
PK sample collection, processing, storage, and shipping instructions are detailed in the 
Study Laboratory Manual.
Rationale: To clarify the intended protocol conduct, check marks for survival status assessment during the 
Treatment phase have been removed from the Time and Events Schedule.
Time and Events 
Schedule, Survival 
Status line entry
Survival Status to be assessed during Follow-up (every 3 months)
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
SYNOPSIS
Randomized, Open-Label Study of Abiraterone Acetate (JNJ-212082) Plus Prednisone With or Without 
Exemestane in Postmenopausal Women With ER+ Metastatic Breast Cancer Progressing After Letrozole or 
Anastrozole Therapy
Abiraterone [17-(3-pyridyl)androsta-5,16-dien-3β-ol] is an irreversible inhibitor of cytochrome P450 (CYP)17 
(17-hydroxylase/ C17,20-lyase), a dual-function enzyme that catalyzes 2 critical reactions in the synthesis of 
testosterone. Abiraterone acetate (JNJ-212082) is the prodrug of the active drug abiraterone (JNJ-589485). Once 
absorbed after oral administration, abiraterone acetate is rapidly converted to the active form, abiraterone.
OBJECTIVES AND HYPOTHESIS
This Phase 2 study evaluates whether estrogen receptor (ER) signaling remains important to breast cancer growth in 
the setting of aromatase inhibition failure in postmenopausal women with estrogen-receptor-positive (ER+) 
metastatic breast cancer. This study also evaluates if continued aromatase inhibition, through the use of exemestane, 
is required to maximally suppress estrogen biosynthesis when abiraterone acetate is used.
Primary Objective
The primary objective is to assess the safety and efficacy of abiraterone acetate plus prednisone and abiraterone 
acetate plus prednisone combined with exemestane, each compared with exemestane alone, in postmenopausal 
women with ER+ metastatic breast cancer progressing after letrozole or anastrozole therapy.
Secondary Objectives
Secondary objectives are to assess abiraterone acetate plus prednisone and abiraterone acetate plus prednisone 
combined with exemestane, each compared with exemestane alone, in postmenopausal women with ER+ metastatic 
breast cancer progressing after letrozole or anastrozole therapy, with respect to the following:

Overall survival 

Overall response rate 

Patient-reported outcomes (PROs), EORTC-C30, EQ-5D-5L, and BPI-SF pain intensity scale

Endocrine markers estradiol, testosterone, estrone, and other biomarkers 

Pharmacokinetics (PK) characterization of abiraterone and exemestane
Hypothesis
Abiraterone acetate plus prednisone and abiraterone acetate plus prednisone combined with exemestane, each
compared with exemestane alone, are safe and prolong progression-free survival (PFS) in postmenopausal women 
with ER+ metastatic breast cancer still sensitive to treatment with endocrine therapy.
OVERVIEW OF STUDY DESIGN
This is a randomized, open-label, parallel-group, multicenter Phase 2 study of abiraterone acetate plus prednisone 
(or prednisolone when prednisone is not available) and abiraterone acetate plus prednisone combined with 
exemestane, each compared with exemestane alone, in postmenopausal women with ER+ metastatic breast cancer 
progressing after letrozole or anastrozole therapy. This study is divided into 3 phases: Screening, Treatment, and 
Follow-Up. The Treatment phase comprises a series of 28-day cycles with continuous study treatment until disease 
progression, when an End-of-Treatment visit is completed before the Follow-Up phase begins. At selected study 
sites, PK and fresh tumor biopsies are assessed. Circulating tumor cells (CTC) will be assessed in samples from all 
subjects at baseline. Sites will be notified if a subject’s Day 1 Cycle 1 sample does not meet a minimum threshold. If 
low CTCs are found in the baseline sample, no further CTC sampling should be done for the subject.
During Screening, potential study subjects are assessed for study eligibility after providing signed informed consent. 
Eligible subjects, stratified by number of prior therapies in the metastatic setting (0 or 1 versus 2) and by setting of 
prior letrozole or anastrozole treatment (adjuvant versus metastatic), are randomly assigned in a 1:1:1 ratio to 
3 treatment groups: abiraterone acetate plus prednisone, abiraterone acetate plus prednisone combined with 
exemestane, or exemestane alone.
During Treatment, study visits are scheduled Day 1 of every 28-day cycle (2 days) as well as Day 15 (2 days) of 
Cycles 1 through 3. Treatment will continue until the earliest of the following events: disease progression, 
unacceptable toxicity, or death. At disease progression, subjects randomized to exemestane alone may be switched 
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JNJ-212082 (abiraterone acetate)
Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
to abiraterone acetate plus prednisone at the discretion of the investigator; if not switched, these subjects must be 
discontinued from study drug. At disease progression, subjects randomized to either abiraterone acetate plus 
prednisone or abiraterone acetate plus prednisone combined with exemestane must be discontinued from study drug. 
Whenever study drug is discontinued, subjects should be evaluated within 30 days during the End-of-Treatment visit 
and entered into the Follow-Up phase regardless of reason for study drug discontinuation, and monitored every 
3 months (7 days) until death, loss to follow-up, consent withdrawal, or abiraterone acetate development in this 
indication is discontinued. The total duration of the study will be extended up to September 2018. Subjects with no 
disease progression for 12 treatment cycles may continue study treatment at the discretion of the investigator, in 
which case, study visits will continue every 3 cycles to measure safety and efficacy parameters.
The clinical cutoff for the planned interim analysis (110 [50%] of progression or death events) occurred on 
14 December 2012. At the time of the clinical cutoff, safety data were available for 231 subjects. The DRC reviewed 
the efficacy and safety outcomes of the interim analysis. They also reviewed biomarker data in relation to the PFS 
data. On 08 March 2013, the DRC recommended the study continue as follows:

abiraterone acetate + exemestane group: The interim analysis criteria were not met for either for futility nor 
efficacy. The DRC therefore recommends that this group continue as stipulated in the protocol. 

abiraterone acetate group: The interim analysis criterion for futility was met. The DRC therefore recommends 
that randomized assignment to this group be discontinued. 

exemestane group: Patients with progressive disease in this group are offered crossover to abiraterone acetate 
alone. Given the findings regarding the other 2 groups noted above, the study team may consider crossover to the 
combination of exemestane + abiraterone acetate. 

The biomarker studies should continue as planned.
Protocol Amendment INT-5 incorporates the recommendations of the DRC. The sponsor considered the crossover 
option but decided not to allow crossover and for subjects who progress on exemestane to discontinue study 
treatment. The sponsor also decided that subjects in the abiraterone acetate group be informed of the decision to 
discontinue randomized assignment to the abiraterone acetate group and to allow ongoing subjects to make their 
own decision about whether or not to continue further study treatment. The changes in randomization and crossover 
are outlined in Attachment 9 of the protocol.
The clinical cutoff for the final analysis for the study (after the predefined total of 150 PFS events were reported in 
the abiraterone plus exemestane group and in the exemestane alone group) occurred on 20 September 2013. The 
results of the analysis did not show a significant benefit in PFS (the primary endpoint of the study) of adding 
abiraterone acetate to exemestane, while a slight increase in the incidence of reported adverse events was observed 
in the combination treatment group and in the abiraterone acetate group versus the exemestane alone group. 
However, individual subjects in the study may derive benefit from the treatment they are currently receiving with 
continued control of disease in the absence of significant toxicity. Therefore, the study has been amended to allow 
subjects to continue receiving their existing study medication and to reduce the number of required study-related 
procedures and amount of data collected (Attachment 10). The decision to continue to receive study medication or 
withdraw from the study will be based on updated study information and made together with the subject and the 
investigator. Subjects who elect not to continue on study medication and those currently in long-term follow-up will 
be discontinued from the study. Under Amendment 7, individual subjects who may continue to derive benefit from 
the treatment they are currently receiving, will be offered the opportunity to continue on their existing study 
medication and followed-up for safety for an additional duration of up to 3 years (ie, up to 20 September 2018) from 
the date previously stated (20 September 2015) in the Amendment INT-6. The situation may be reassessed 
periodically for subjects still receiving study medication.
SUBJECT POPULATION
Postmenopausal women at least 18 years of age with ER+, Her2- metastatic breast cancer (confirmed with 
prerandomization formalin-fixed paraffin-embedded [FFPE] tissue) will be enrolled in this study. Subjects with 
disease confined only to bone may be included. Their disease must have been sensitive to anastrozole or letrozole 
therapy prior to disease progression, defined as either stable disease or better for 6 months in the metastatic setting 
or relapse free for 2 years in the adjuvant setting. Subjects must have had no more than 2 prior lines of therapy in 
the metastatic setting, of which no more than 1 was chemotherapy; simultaneous combination treatment is 
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Status: Approved Date: 27 April 2015
considered 1 line of therapy. They must have an Eastern Cooperative Oncology Group (ECOG) performance status 
score of 1.
DOSAGE AND ADMINISTRATION
All study drugs are oral and should be taken once daily. Abiraterone acetate 1,000 mg/day should be taken as four 
250-mg tablets and must be taken on an empty stomach. No food should be consumed for at least 2 hours before the 
dose of abiraterone acetate is taken and for at least 1 hour after the dose of abiraterone acetate is taken. Prednisone 
5 mg/day should be taken daily with abiraterone acetate; if gastric intestinal upset occurs, prednisone may be taken 
with food and separately from abiraterone acetate. Exemestane 25 mg/day should be taken as a single tablet, 
preferably after a meal.
EFFICACY EVALUATION
Determination of PFS will use radiographic progression defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) on measurable lesions captured by computed tomography (CT) or magnetic resonance imaging (MRI) at 
baseline and, using the same modality, repeated every 2 cycles initially (Day 1 Cycle 3, Day 1 Cycle 5, and Day 1 
Cycle 7) and every 3 cycles thereafter (eg, Day 1 Cycle 10, Day 1 Cycle 13) until, and including, the 
End-of-Treatment visit. Since disease progression should be documented by CT or MRI, imaging with whichever 
modality was used at baseline should be completed as soon as possible if a new breast-cancer-related symptom 
appears that requires medical intervention. Determination of long-term benefit will use survival status and PRO 
scores throughout the study and during Follow-Up.
BIOMARKER EVALUATION
Tumor samples (FFPE) will be assessed for ER, progesterone receptor (PR), and Her2 at randomization. These 
tumors may also be analyzed for microRNA (miRNA) expression patterns, mutations or amplification of the ER, or 
for other biomarkers. Serum samples are analyzed for estrogens or androgens. At selected study sites, fresh tumor 
biopsies will be taken. Blood samples for CTC analysis will be collected from all subjects. Biomarker studies are 
designed to identify markers predictive of response (or resistance) to abiraterone.
PHARMACOGENOMICS EVALUATION
Where local regulations permit, if separate consent is granted, blood samples will be taken for pharmacogenomics 
research.
SAFETY EVALUATION
Evaluations include periodic physical examination, vital sign measurement, and clinical laboratory tests. Cardiac 
function is assessed by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) and 12-lead 
electrocardiogram (ECG). Adverse events, including laboratory adverse events, are graded and summarized. Any 
clinically significant abnormalities persisting at the end of the study will be followed by the investigator until 
resolution or until a clinically stable endpoint is reached.
PHARMACOKINETICS EVALUATION
At selected study sites, serial PK blood samples for determination of abiraterone and exemestane concentrations will 
be collected Days 1 and 15 of Cycle 1. Predose samples will also be collected Day 1 of Cycles 2 through 4. From 
PK profiles obtained Days 1 and 15 of Cycle 1, the following parameters will be calculated: Cmax, tmax, AUClast, tlast, 
and AUC24h. Additional PK parameters may be determined and exploratory analyses may be performed, as deemed 
appropriate.
SAMPLE SIZE DETERMINATION
The primary analysis consists of 2 pair-wise comparisons of the experimental treatment groups (abiraterone acetate 
plus prednisone and abiraterone acetate plus prednisone combined with exemestane) with the reference treatment 
group (exemestane alone). For each of the pair-wise comparisons, the statistical tests of treatment effects on primary 
endpoint of PFS will be conducted independently at the 2-sided 0.10 level of significance. This study is event driven 
and will complete for primary analysis after a total of 220 PFS events in the 3 treatment groups have occurred over a 
total study duration of 19 months. It is assumed that the PFS follows an exponential distribution with a constant 
hazard ratio. Assuming an underlying hazard ratio of any pair-wise comparison (abiraterone acetate plus prednisone 
and abiraterone acetate plus prednisone combined with exemestane, each compared with exemestane alone) is 0.65 
(median PFS 6.2 and 4.0 months, respectively), the study has 80% power at a significance level of 0.10 (2-sided) to 
demonstrate a treatment difference with approximately 150 PFS events in each pair-wise comparison. Assuming an
enrollment rate of 20 subjects per month for 15 months, a total sample size of approximately 300 subjects
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Clinical Protocol 212082BCA2001 Amendment INT-7
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Status: Approved Date: 27 April 2015
(100 subjects per group) is planned. In the case that randomization to 1 treatment group is discontinued based on the 
DRC recommendation after the interim analysis, the study may stop randomization when approximately 
200 subjects are enrolled to the remaining 2 treatment groups. The final analysis would then be performed after the 
occurrence of 150 death or progression events within the remaining 2 treatment groups.
STATISTICAL METHODS
An intent-to-treat (ITT) analysis including all randomized subjects will be used to evaluate efficacy. The primary 
efficacy endpoint, PFS, is measured from time of randomization to first occurrence of either disease progression or 
death from any cause. Secondary endpoints include overall survival, overall response rate, PRO scores, and 
biomarkers, and PK. Distributions of time-to-event variables will be estimated using the Kaplan-Meier product-limit 
method. Median times to event with 2-sided 95% confidence intervals will be estimated. The stratified log-rank test 
will be used as the primary analysis for treatment comparison. A Cox proportional-hazards model will provide 
estimates of hazard ratios with 95% confidence intervals. The relative risk of overall response rate 
(treatment:control) will be reported along with the associated 95% confidence interval. Statistical inference will be 
evaluated using the Chi-square statistic. PRO scores and biomarker concentrations will be descriptively summarized 
by treatment group; statistical tests may be carried out as appropriate.
Plasma concentrations of abiraterone and exemestane and PK parameter estimations will be descriptively 
summarized by treatment group. Association of biomarkers with clinical response or time-to-event endpoints will be 
assessed using the appropriate statistical methods (analysis of variance [ANOVA], categorical, or survival model), 
depending on endpoint.
Subjects who receive at least 1 study drug dose will be analyzed for safety. Treatment-emergent adverse events will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) system and graded according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Adverse 
events will be summarized by system organ class and preferred term, and will be presented overall and by treatment 
group. Deaths and other serious adverse events will be provided in a listing. Other safety endpoints, including vital 
signs, clinical laboratory parameters, and ECG, will be summarized descriptively. 
Interim Analysis and Data Review Committee
One interim analysis is scheduled when approximately 110 (50%) of the PFS events have occurred. Gamma-family 
spending functions determined the Type I error rate of 10% (2-sided) and Type II error rate of 20% for each 
pair-wise comparison. After review of interim data, the Data Review Committee (DRC) will make recommendations 
regarding study continuation. In addition to the planned interim analysis, the DRC will meet periodically to review 
the cumulative safety data collected. One DRC safety review will occur after the tenth subject in each treatment 
group (~30 subjects) has received study drug for 28 days (Cycle 1); subject accrual will continue only if no safety 
concerns arise. When baseline and at least 1 posttreatment ECG are available for the first 25 subjects in each 
treatment group (75 subjects total), the DRC will determine if additional ECGs are needed for these and subsequent 
subjects.
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Status: Approved Date: 27 April 2015
TIME AND EVENTS SCHEDULE
The Time and Events Schedule below became obsolete under Amendment INT-6 and has been 
replaced with a new Schedule of Events provided in Attachment 10.
*Except where noted otherwise, study visits/procedures have a 2-day time window.
  PHASE: Screen
Treatment 
Follow-Up
CYCLE (28 days):
1
2
3
4 to disease 
progression a
End
every 3m
*CYCLE DAY:
1
15
1
15
1
15
1
Screening
Informed consent b
X
Inclusion/exclusion criteria
X
Prestudy anticancer therapy c
X
Medical history and 
demographics
X
Urinalysis (dipstick)
X
Immunohistochemistry, FFPE d
X
Study Drug Administration e
Randomization
X
Dispense study drug f
X
X
X
X
Safety 
MUGA (or ECHO) g
X
every 3 cycles
X
Electrocardiogram, 12-lead h
X
every 3 cycles
X
Physical examination i
X
X
X
X
X
Vital signs j
X
X
X
X
X
Efficacy
CT or MRI k
X
X
X k
X
ECOG
X
X
X
X
X
PROs l
X
X
X
X
X
X
Survival status m
X
Clinical Laboratory
Coagulation (PT or INR, and 
PTT)
X
Serology (hepatitis B and C) n
X
LH
X
FSH
X
Lipid profile o
X
every 6 cycles
X
Hematology/Glucose p
X
X
X
X
X
Chemistry with electrolytes p
X
X
X
X
X
X
Liver function tests q
X
X    X
X
X
X
X
X
Circulating tumor cells r
X
X
X
Serum endocrine markers s
X
X
X
every 3 cycles
X
Pharmacogenomics t
X
Ongoing Subject Review
Dosing compliance
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
Adverse events u
X
X
X
X
X
X
X
X
X
Selected Centers Only
Pharmacokinetics v
X
X
X
X
Cycle 4
Tumor biopsy w
X
X
Cycle 5
CT=computed tomography; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; 
FFPE=formalin-fixed paraffin-embedded; FSH=follicle-stimulating hormone; INR=international normalized 
ratio; MRI=magnetic resonance imaging; MUGA=multiple-gated acquisition scan; LH=luteinizing hormone; 
PT=prothrombin time; PRO=patient-reported outcome; PTT=partial thromboplastin time
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a For subjects continuing study drug after 12 months with no disease progression, physical examinations, vital 
signs, CT or MRI, ECOG, fasting glucose, hematology, chemistry with electrolytes, and LFTs to be every 
3 cycles; PROs and lipid profiles to continue every cycle and every 6 cycles, respectively.
b Written informed consent to be obtained within 4 weeks before randomization.
c Potential subjects must not have taken anastrozole, letrozole, fulvestrant, or any chemotherapy for at least 2 weeks 
(bevacizumab for at least 3 weeks) before randomization.
d FFPE tumor tissue to be collected within 7 days before randomization for androgen receptor (AR), ER, 
progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2), CYP17, CYP19, Ki-67, 
3-hydroxysteroid dehydrogenase (HSD), and future molecular analyses.
e At disease progression, subjects randomized to exemestane alone may be switched to abiraterone acetate plus 
prednisone at the discretion of the investigator; if not switched, these subjects must be discontinued from study 
drug. At disease progression, subjects randomized to either abiraterone acetate plus prednisone or abiraterone 
acetate plus prednisone combined with exemestane must be discontinued from study drug. In either case, subjects 
should be evaluated within 30 days during End-of-Treatment visit and entered into the Follow-Up phase.
f Study drug to be dispensed Day 1 of each 282-day cycle and taken outside clinic. Abiraterone acetate must be 
taken on an empty stomach. No food should be consumed for at least 2 hours before the dose of abiraterone 
acetate is taken and for at least 1 hour after the dose of abiraterone acetate is taken. Prednisone (prednisolone 
when prednisone is not available) should be taken daily with abiraterone acetate; if gastric intestinal upset occurs, 
prednisone may be taken with food and separately from abiraterone acetate; exemestane should be taken after a 
meal. Subjects continuing study drug treatment after 12 months without disease progression will be dispensed 
sufficient study drug for visits every 3 cycles. 
g MUGA (ECHO when MUGA unavailable) to be done within 4 weeks before randomization and, using the same 
modality, End-of-Treatment. Subjects with prior anthracycline 350 mg/m2 will have MUGA or ECHO done at 
baseline and every 3 cycles thereafter (eg, Day 1 Cycle 4, Day 1 Cycle 7).
h ECGs to be done within 4 weeks before randomization and every 3 cycles thereafter (eg, Day 1 Cycle 4, Day 1 
Cycle 7), and End-of-Treatment; serum potassium <3.5 mM should be corrected before any ECG. At selected 
study sites, when PK sampling is Day 1 Cycle 1, an ECG will be recorded 2 hours after study drug dose.
i Physical examination to be done within 2 weeks before randomization, Day 1 Cycle 2 and every cycle thereafter 
(eg, Day 1 Cycle 2, Day 1 Cycle 3), and End-of-Treatment; height to be recorded only at baseline.
j Vital signs (upright blood pressure, heart rate, respiratory rate, and oral/aural body temperature) to be done within 
2 weeks before randomization, every cycle thereafter (eg, Day 1 Cycle 2, Day 1 Cycle 3), and End-of-Treatment. 
k Radiographic disease to be measured within 4 weeks before randomization as close as possible to Day 1 Cycle 1 
and, using the same modality (CT or MRI), repeated every 2 cycles (Day 1 Cycle 3, Day 1 Cycle 5, and Day 1 
Cycle 7), and every 3 cycles thereafter (eg, Day 1 Cycle 10, Day 1 Cycle 13), and End-of-Treatment; positron 
emission tomography (PET) not acceptable.
l PROs (EORTC-C30, EQ-5D-5L, BPI-SF pain intensity scale) to be done before any other visit procedure within 
2 days before randomization, repeated every cycle thereafter (eg, Day 1 Cycle 2, Day 1 Cycle 3), 
End-of-Treatment, and every 3 months during Follow-Up.
m Survival status and nonstudy anticancer therapy to be monitored by telephone or chart review during Follow-Up.
n Full hepatitis panel to be done during Screening to include hepatitis B surface antigen and hepatitis C antibody; to 
be repeated during Continuing Treatment only if subject develops Grade 3 or higher LFT increase.
o Lipids to be done within 7 days before randomization, every 6 cycles thereafter (eg, Day 1 Cycle 7, Day 1 
Cycle 13), and End-of-Treatment.
p Fasting glucose, hematology, and chemistry to be done within 7 days before randomization, every cycle thereafter 
(eg, Day 1 Cycle 2, Day 1 Cycle 3), and End-of-Treatment; blood chemistry also to be done Day 15 Cycle 1.
q Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, 
total bilirubin) to be done within 7 days before randomization, every cycle thereafter (eg, Day 1 Cycle 2, Day 1 
Cycle 3), Day 15 of Cycles 1 through 3, and End-of-Treatment.
r At all study sites, blood samples (40 mL where local regulations permit) to be taken Day 1 of Cycles 1 and 2 and 
End-of-Treatment for CTC enumeration and molecular characterization. Circulating tumor cells will be assessed 
in samples from all subjects at baseline. Sites will be notified if a subject’s Day 1 Cycle 1 sample does not meet a 
minimum threshold. If low CTCs are found in the baseline sample, no further CTC sampling should be done for 
the subject. NOTE: CTC samples will not be collected from subjects receiving abiraterone acetate after crossing 
over from exemestane treatment. 
s Endocrine biomarker (estradiol, testosterone, and estrone) blood samples (15 mL) to be taken Day 1 of Cycles 1 
through 3, and every 3 cycles thereafter (eg, Day 1 Cycle 6, Day 1 Cycle 9) up to and including Day 1 Cycle 12, 
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Status: Approved Date: 27 April 2015
and at End-of-Treatment. NOTE: Endocrine biomarker samples will not be collected from subjects receiving 
abiraterone acetate after crossing over from exemestane treatment.
t Where local regulations permit, if separate consent is granted, blood samples (10 mL) to be taken for 
pharmacogenomics research; a sample collected at a later time point will not be a protocol deviation. NOTE: 
Pharmacogenomic samples will not be collected from subjects receiving abiraterone acetate after crossing over 
from exemestane treatment.
u Adverse events will be recorded from time of Consent Form signature until 30 days after last study drug dose.
v At selected study sites, 20 subjects/treatment group to remain overnight Days 1 and 15 of Cycle 1 for blood 
samples (2 mL, abiraterone acetate; 4 mL, exemestane) to be taken before and 1, 1.5, 2, 3, 4, 8, 12, 16, 22, and 
24 hours after study drug dosing; sites that do not have the capability of overnight stays will not collect blood 
samples at 12, 16, and 22 hours after study drug dosing on Days 1 and 15 of Cycle 1; predose samples also to be 
taken Day 1 of Cycles 2 through 4. Study drug will be given at the study site and subjects will be instructed to 
record study drug dosing times and meal times for 2 days before each sampling visit. NOTE: Pharmacokinetic 
samples will not be collected from subjects receiving abiraterone acetate after crossing over from exemestane 
treatment.
w At selected study sites, consent will be sought to biopsy metastasized or primary tumor at screening, Day 1
Cycle 3, and Day 1 Cycle 5 for biomarker studies. Consent should be obtained for a biopsy at baseline and at least 
1 Treatment phase time point; a missing time point will not be considered a protocol deviation.
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ABBREVIATIONS
ALT
alanine aminotransferase (SGPT)
ANOVA
analysis of variance
AR
androgen receptor
AST
aspartate aminotransferase (SGOT)
BPI-SF
Brief Pain Inventory – Short Form
CCO-FA
clinical cutoff for the final analysis
CT
computed tomography
CTC
circulating tumor cells
CYP
cytochrome P450
DHEA
dehydroepiandrosterone
DHEA-S
dehydroepiandrosterone sulphate
DNA
deoxyribonucleic acid
DRC
Data Review Committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
eDC
electronic data capture
EORTC-C30
European Organization for Research and Treatment of Cancer core quality-of-life questionnaire
EQ-5D-5L
Euro-QoL quality-of-life questionnaire
ER+
estrogen receptor positive
EU
European Union
FFPE
formalin-fixed paraffin-embedded
FISH
fluorescence in situ hybridization
GCP
Good Clinical Practice
Her2
human epidermal growth factor receptor 2
HSD
hydroxysteroid dehydrogenase
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
ITT
intent-to-treat 
Ki-67
cellular marker for proliferation
LFT
liver function test
MedDRA
Medical Dictionary for Regulatory Activities
miRNA
microRNA
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition scan
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PQC
product quality complaint
PR+
progesterone receptor positive
PRO
patient-reported outcome
PSA
prostate-specific antigen
PT
prothrombin time
PTT
partial thromboplastin time
RECIST
Response Evaluation Criteria in Solid Tumors
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
U.S.
United States
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1.
INTRODUCTION
Breast cancer is the most frequent cancer among women with an estimated 1.38 million cases 
newly diagnosed worldwide in 2008 (23% of all cancers) (Ferlay 2010); incidence and mortality 
rates per 100,000 person years were 109.4/21.0 (Belgium), 99.7/17.6 (France), 81.8/16.9 
(Germany), 86.3/16.1 (Italy), 82.7/14.7 (Sweden), 96.8/19.6 (Netherlands), and 87.9/18.6 
(United Kingdom). Breast cancer is estimated to account for 28% of newly diagnosed cancers in 
women in the United States (U.S.) and 15% of deaths from cancer in U.S. women in 2010 
(American Cancer Society 2010a). In the U.S. (1999 to 2006), among patients with breast 
cancer, 60% were diagnosed with localized Stage 1 or 2 disease, 33% with Stage 2 or 3, and 5% 
with Stage 4 (National Cancer Institute 2010). About 70% of primary breast cancers are estrogen 
receptor positive (ER+) (National Breast Cancer Coalition 2010), which correlates most often 
with postmenopausal status (Kamangar 2006). Survival rates decrease with stage of disease. The 
5-year survival rate for women with metastatic breast cancer is 15% (American Cancer Society 
2010b), which reflects a substantial unmet medical need for more effective therapy.
Several lines of evidence support investigation of abiraterone acetate (JNJ-212082) for treatment 
of women with ER+ breast cancer. Breast cancers ER+ and progesterone-receptor-positive (PR+) 
positively correlate with circulating levels of adrenal steroids, including dehydroepiandrosterone 
(DHEA) and its sulphate (DHEA-S) (Eliassen 2006; Key 2002) and in vitro data indicate these 
ligands stimulate proliferation of breast cancer cell lines in a low-estrogen environment 
(Maggiolini 1999). Although adrenalectomy and hypophysectomy were effective for treatment 
of ER+ breast cancer, abiraterone acetate is the first compound specifically designed to inhibit 
cytochrome P450 (CYP)17 with resultant inhibition of sex hormone biosynthesis. 
Hypothetically, depletion of androgens and estrogens by abiraterone acetate may inhibit tumor 
growth by disruption of ER-dependent growth signaling. 
The role of androgens and androgen receptor (AR) function in ER+ breast cancer is not entirely 
clear. Proliferation of certain breast tumor cell lines has been suppressed with antiandrogen- and 
androgen-like steroids (Hackenberg 1996). Expression of AR has been correlated with smaller 
tumors, less aggressive disease, and lack of lymph node involvement (Ogawa 2008). However, 
high serum levels of adrenal androgens (DHEA and androstenedione) also have been correlated 
with increased breast cancer risk in postmenopausal women (Hankinson 1998; Kaaks 2005), 
which may result from androgen signaling via either AR or ER (Maggiolini 1999).
Patients with ER+ disease have limited options once disease progresses after treatment with 
available endocrine therapy. Although chemotherapy may be used following progression during 
aromatase inhibitor therapy, toxicities are severe and overall survival is not extended 
substantially. In addition, patients with disease still driven by ER or AR signaling may not yet 
have the extensive visceral disease or the rapid clinical progression requiring immediate therapy 
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Status: Approved Date: 27 April 2015
with systemic chemotherapy. Since CYP17 is upstream from aromatase in the steroid synthesis 
pathway, theoretically, abiraterone acetate more completely inhibits sex steroid synthesis. 
Abiraterone acetate may inhibit synthesis of adrenal sources of hormones (eg, androstenedione) 
whereas other available endocrine therapies may not.
Twenty-five postmenopausal subjects with refractory metastatic breast cancer, who had been 
treated with both tamoxifen and aromatase inhibitors before study entry, have been treated with 
abiraterone acetate in an ongoing Cancer Research Phase 1/2 study sponsored by the United 
Kingdom (CR9304-21). This dose-escalation study has 4 planned dose levels: 250, 500, 1000, 
and 2,000 mg/day with 6 evaluable subjects treated at each dose level; subjects are discontinued 
from study drug and replaced before completion of a 28-day cycle when an event other than 
toxicity occurs. The majority of subjects recruited into the Phase 1 portion of the study are ER+. 
At the time of the poster presentation (Basu 2010), abiraterone acetate at all dose levels resulted 
in suppression of serum testosterone by Day 15 Cycle 1 of study treatment. Serum estradiol also 
declined with treatment but concentrations greater than 15 pmol/L were maintained by 
3 subjects. Mechanism-based toxicities such as hypokalemia were the most frequent adverse 
events and were medically manageable. Preliminary antitumor efficacy in breast cancer was 
observed: of the 6 subjects given 1,000 mg/day, 1 ER+ subject has achieved a partial response 
for more than 8 months with corresponding reduction in breast cancer tumor marker CA 15.3; 
another ER+ subject has had stable disease for more than 11 months.
Exemestane is an oral, irreversible, steroidal aromatase inactivator, structurally related to the 
natural substrate androstenedione, and lowers circulating estrogen concentrations in
postmenopausal women without affecting adrenal biosynthesis of corticosteroids, aldosterone, or 
other enzymes in the steroidogenic pathway (Aromasin 2008, 2009). It is approved in the U.S., 
Europe, and Canada for adjuvant treatment of ER+ early breast cancer in postmenopausal 
women after 2 to 3 years of tamoxifen therapy. Exemestane is commonly prescribed for 
treatment of advanced breast cancer in postmenopausal women whose disease has progressed 
following tamoxifen therapy. As with other estrogen-lowering agents, bone mineral density may 
decrease with exemestane therapy. Patients taking exemestane experienced a significant increase 
in the overall fracture rate when compared with those taking tamoxifen (Lønning 2005). 
The present Phase 2 study is designed to evaluate whether ER signaling remains important to 
breast cancer growth in the setting of aromatase inhibition failure in postmenopausal women 
with ER+ metastatic breast cancer. This study also evaluates if continued aromatase inhibition, 
through the use of exemestane, is required to maximally suppress estrogen biosynthesis when 
abiraterone acetate is used.
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Abiraterone Acetate (JNJ-212082)
Abiraterone acetate is a prodrug of abiraterone [17-(3-pyridyl) androsta-5,16-dien-3-ol], a novel 
selective irreversible inhibitor of cytochrome P450 CYP17, a dual-function enzyme that catalyzes 
2 critical reactions in testosterone synthesis. 
A Phase 3, multinational, randomized, double-blind, placebo-controlled study of oral abiraterone 
acetate and oral prednisone demonstrated that abiraterone acetate 1,000 mg/day was an effective 
therapy for subjects (N=1,195) with metastatic castration-resistant prostate cancer whose disease 
had progressed following treatment with a docetaxel-containing treatment regimen 
(Study COU-AA-301). Compared with placebo-plus-prednisone treatment, abiraterone acetate 
plus prednisone reduced risk of death by 35% and significantly improved time to prostate-
specific antigen (PSA) progression, radiographic progression-free survival (rPFS), and PSA 
response.
This was the first study to demonstrate conclusively the importance of inhibition of CYP17 
targeting 
of 
AR-mediated 
signaling 
persisting 
or 
up-regulated 
after 
conventional 
androgen-deprivation therapy and docetaxel chemotherapy. The results substantiate the 
hypothesis that abiraterone improves survival in patients with metastatic castration-resistant 
prostate cancer by CYP17 inhibition lowering testosterone concentrations below those achieved 
with androgen-deprivation therapies. 
In addition, treatment with abiraterone acetate and prednisone resulted in a highly desirable 
safety profile and benefit/risk ratio, consistent with findings of earlier Phase 1/2 and Phase 2 
studies. Toxicities associated with mineralocorticoid excess secondary to the mechanism of 
abiraterone action were amenable to medical management and resulted in infrequent dose 
interruptions, dose reductions, or treatment discontinuations. Infrequent liver function test (LFT) 
abnormalities were managed with careful laboratory monitoring, treatment interruptions and 
retreatment only after return to baseline values. A daily dose of 1,000 mg was selected for further 
Phase 2 and 3 evaluation based on its consistent pharmacologic and endocrinologic effects. 
For the most accurate and current information regarding the efficacy and safety of abiraterone 
acetate, refer to the latest Investigator Brochure for abiraterone acetate.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
The primary objective is to assess safety and efficacy of abiraterone acetate plus prednisone and 
abiraterone acetate plus prednisone plus exemestane, each compared with exemestane alone, in 
postmenopausal women with ER+ metastatic breast cancer progressing after letrozole or 
anastrozole therapy.
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Secondary objectives are to assess abiraterone acetate plus prednisone and abiraterone acetate 
plus prednisone combined with exemestane, each compared with exemestane alone, in 
postmenopausal women with ER+ metastatic breast cancer progressing after letrozole or 
anastrozole therapy, with respect to the following:

Overall survival 

Overall response rate 

Patient-reported outcomes (PROs) EORTC-C30, EQ-5D-5L, and BPI-SF pain intensity scale

Endocrine markers estradiol, testosterone, estrone, and other biomarkers 

Pharmacokinetic (PK) characterization of abiraterone and exemestane
2.2.
Hypothesis
Abiraterone acetate plus prednisone and abiraterone acetate plus prednisone combined with 
exemestane, each compared with exemestane alone, are safe and prolong PFS in postmenopausal 
women with ER+ metastatic breast cancer still sensitive to treatment with endocrine therapy.
3.
STUDY DESIGN AND RATIONALE
This is a randomized, open-label, parallel-group, multicenter Phase 2 study of abiraterone acetate 
plus prednisone (or prednisolone when prednisone is not available) and abiraterone acetate plus 
prednisone combined with exemestane, each compared with exemestane alone, in 
postmenopausal women with ER+ metastatic breast cancer progressing after letrozole or 
anastrozole therapy. From approximately 65 sites in North America, Europe, and Asia, 
approximately 300 subjects will be randomized to 3 treatment groups (100 subjects per group).
3.1.
Overview of Study Design
This study is divided into 3 phases: Screening, Treatment, and Follow-Up. Timing of study 
assessments and procedures is detailed in the Time and Events Schedule (following the 
Synopsis). The Treatment phase comprises a series of 28-day cycles with continuous study 
treatment until disease progression, when an End-of-Treatment visit is completed before the 
Follow-Up phase begins.
During Screening, potential study subjects are assessed for study eligibility (Section 4) after 
providing signed informed consent. Eligible subjects will be stratified by 2 factors: number of 
prior therapies in the metastatic setting (0 or 1 versus 2); and whether letrozole or anastrozole 
was administered in the adjuvant or metastatic setting. Subjects will be assigned randomly in a 
1:1:1 ratio as follows: 
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Screening
Treatment
Follow-Up
Randomization
AAP
AAP + E
E
30 days
until disease progression↑
up to 36 months
Note: Subjects assigned to exemestane alone may be switched to AAP at disease progression
AAP=abiraterone acetate (1,000 mg/day) + prednisone or prednisolone (5 mg/day); E=exemestane 
(25 mg/day)
During the Treatment phase, study visits and study procedures are scheduled Day 1 of every 
28-day cycle (2 days) as well as Day 15 (2 days) of Cycles 1 through 3. Study drug treatment 
will continue until the earliest of the following events: disease progression, unacceptable toxicity, 
or death. Subjects with no disease progression for 12 treatment cycles may continue study 
treatment at the discretion of the investigator, in which case study visits will continue every 
3 cycles. 
Response Evaluation Criteria in Solid Tumors (RECIST) will define disease progression on 
measurable lesions captured by computed tomography (CT) or magnetic resonance imaging 
(MRI) (Attachment 1). At disease progression, subjects randomized to exemestane alone may be 
switched to abiraterone acetate plus prednisone at the discretion of the investigator; if not 
switched, these subjects must be discontinued from study drug. At disease progression, subjects 
randomized to either abiraterone acetate plus prednisone or abiraterone acetate plus prednisone 
combined with exemestane must be discontinued from study drug. In either case, subjects should 
be evaluated within 30 days during the End-of-Treatment visit and entered into the Follow-Up 
phase. 
Subjects should enter the Follow-Up phase regardless of reason for study drug discontinuation 
and should be monitored every 3 months (7 days) until death, loss to follow-up, consent 
withdrawal, or abiraterone acetate development in this indication is discontinued. The total 
duration of the study will be extended up to September 2018.
Samples to assess circulating tumor cells (CTC) will be collected from all subjects. At selected 
study sites, fresh tumor biopsies and samples to assess pharmacokinetics (PK) will be obtained.
The study will end on the date of the last follow-up of the last subject participating in the study.
The clinical cutoff for the planned interim analysis (110 [50%] of progression or death events) 
occurred on 14 December 2012. At the time of the clinical cutoff, safety data were available for 
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231 subjects. The Data Review Committee (DRC) reviewed the efficacy and safety outcomes of 
the interim analysis. They also reviewed biomarker data in relation to the PFS data. On 
08 March 2013, the DRC recommended the study continue as follows:

abiraterone acetate + exemestane group: The interim analysis criteria were not met for either 
for futility nor efficacy. The DRC therefore recommends that this group continue as 
stipulated in the protocol. 

abiraterone acetate group: The interim analysis criterion for futility was met. The DRC 
therefore recommends that randomized assignment to this group be discontinued. 

exemestane group: Patients with progressive disease in this group are offered crossover to 
abiraterone acetate alone. Given the findings regarding the other 2 groups noted above, the 
study team may consider crossover to the combination of exemestane + abiraterone acetate. 

The biomarker studies should continue as planned.
Protocol Amendment INT-5 incorporates the recommendations of the DRC. The sponsor 
considered the crossover option but decided not to allow crossover and for subjects who progress 
on exemestane to discontinue study treatment. The sponsor also decided that subjects in the 
abiraterone acetate group be informed of the decision to discontinue randomized assignment to 
the abiraterone acetate group and to allow ongoing subjects to make their own decision about 
whether or not to continue further study treatment. The changes in randomization and crossover 
are outlined in Attachment 9 of the protocol.
Post-Clinical Cutoff for the Final Analysis
Based upon the results of the final analysis, the protocol has been amended to allow subjects to 
continue on study medication for up to 2 years from the CCO-FA (ie, up to 20 September 2015), 
at which point the situation will be reassessed for subjects still receiving study medication. 
Subjects who elect not to continue on study medication and those currently in long-term 
follow-up will be discontinued from the study. Since Amendment INT-6, only serious adverse 
event information and drug accountability data will be collected and reported as outlined in 
Attachment 10. Under Amendment INT-7, individual subjects who may continue to derive 
benefit from the treatment they are currently receiving, will be offered the opportunity to 
continue on their existing study medication and followed-up for safety for an additional duration 
of up to 3 years (ie, up to 20 September 2018) from the date previously stated 
(20 September 2015) in the Amendment INT-6. The situation may be reassessed periodically for 
subjects still receiving study medication.
3.2.
Study Design Rationale 
Study Drug Dose
The abiraterone acetate dose in this study is 1,000 mg/day, consistent with the dose 
recommended for Phase 2 by an ongoing Phase 1 study of abiraterone acetate in metastatic breast 
cancer (CR9304-21). Abiraterone acetate was well tolerated at doses ranging from 250-mg to 
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2,000 mg/day. Considering PK, adrenal CYP17 inhibition, and efficacy signal from treatment of 
men with prostate cancer and women with metastatic breast cancer (CR9304-21), abiraterone 
acetate 1,000 mg offers consistent pharmacological effects without additional side effects and is 
the dose chosen for further efficacy and safety evaluation. This study uses the recommended 
dose of exemestane in metastatic breast cancer, 25 mg/day.
Randomization, Comparator, Special Design Considerations
To improve the likelihood that subject attributes are balanced across groups and to enhance 
validity of statistical comparisons across groups, randomization is used in this study. Since 
patients with fewer prior lines of anticancer therapy are likely to be more sensitive to additional 
treatment, subjects are stratified by 2 factors: number of prior therapies in the metastatic setting 
(0 or 1 versus 2) and whether letrozole or anastrozole was administered in the adjuvant or 
metastatic setting (Puente 2010); simultaneous combination treatment is considered 1 line of 
therapy. To help assess abiraterone acetate efficacy, the active comparator (exemestane) in this 
study is the standard of care for postmenopausal women whose disease remains sensitive to 
endocrine therapy following disease progression after treatment with anastrozole or letrozole. To 
manage mineralocorticoid excess, abiraterone acetate is always taken with low-dose prednisone 
(prednisolone when prednisone is not available). To mitigate difficulties managing hypokalemia 
despite optimal potassium supplementation and adequate oral intake, the prednisone dose may be 
increased to 10 mg/day. To understand if continued aromatase inhibition maximally suppresses 
estrogen biosynthesis in the presence of abiraterone acetate plus prednisone, 1 treatment group 
receives combination therapy (abiraterone acetate plus prednisone combined with exemestane). 
To capture time to disease progression, imaging will be done on Day 1 of Cycles 3, 5 and 7, and 
then on Day 1 of every third cycle, thereafter; to facilitate accurate comparisons over time, the 
same modality (CT or MRI) should be used throughout the study; to comply with RECIST, 
positron emission tomography (PET) scans are not allowed. To rule out drug-drug interaction 
due to common abiraterone acetate and exemestane metabolic pathways, potential effects on 
exposure after coadministration of abiraterone acetate and exemestane are assessed in a PK study 
with a subset of subjects. Because almost all plasma concentrations of abiraterone acetate were 
below the limit of quantification in previous clinical studies, only plasma concentrations of 
abiraterone will be measured in this study.
Patient-Reported Outcomes
As metastatic breast cancer progresses, patients often endure painful and debilitating metastases 
that may reduce quality of life. Because health-related quality of life is an important factor when 
evaluating treatment options (Bottomley 2007; Lemieux 2011), standardized PROs are used in 
this study to assess quality of life before, during, and after treatment. Instruments include 
3 questionnaires extensively validated and widely used in breast cancer clinical trials: European 
Organization for Research and Treatment of Cancer Core 30 quality-of-life questionnaire 
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(EORTC-C30) 
(Attachment 
2), 
Euro-QOL
quality-of-life 
questionnaire 
(EQ-5D-5L) 
(Attachment 3), and the pain intensity scale (Attachment 4) from the Brief Pain Inventory-Short 
Form (BPI-SF). 
DNA and Biomarker Collection
Circulating levels of adrenal steroids, including DHEA and its sulphate, DHEA-S, positively 
correlate with ER+/PR+ breast cancers (Eliassen 2006; Key 2002) and in vitro data indicate 
these ligands stimulate proliferation of breast cancer cell lines in a low-estrogen environment 
(Maggiolini 1999). These ligands function as weak ER agonists, indicating that steroidogenic 
enzymes upstream of aromatase may also contribute to disease progression (Chan 2002) by 
activating ER and possibly other steroid hormone receptors. Abiraterone is expected to attenuate 
this activity by suppression of androgenic steroids that may contribute to mitogenesis through 
stimulation of both AR and ER. To demonstrate attenuation on steroidogenic enzyme production 
following abiraterone acetate treatment, CYP17, CYP19, or 3β-hydroxysteroid dehydrogenase 
(HSD) expression levels will be evaluated and compared with baseline expression levels. To 
evaluate the impact of abiraterone on breast cancer subtypes, formalin-fixed paraffin-embedded 
(FFPE) tumor tissue will be evaluated for AR, ER, PR, human epidermal growth factor receptor 
2 (Her2), and other biomarkers. The AR will be fully characterized to identify any anomalies in 
individual subjects and to determine the extent of nuclear localization of the ligand-bound 
complex before and after study drug initiation. Breast cancer subtypes may be further defined by 
characterizing the molecular profile (eg, microRNA [miRNA], mRNA, somatic anomalies) in 
FFPE tumor samples. Fresh tumor biopsies will be taken in a subset of subjects to characterize
AR, ER, PR, CYP17, CYP19, or other candidate markers related to abiraterone or to breast 
cancer. Circulating tumor cell samples will be taken from all subjects to characterize AR, ER, 
PR, CYP17, CYP19, or other candidate markers related to abiraterone or to breast cancer. ER 
mutation analysis and RNA analyses may also be performed, as possible, on CTC and fresh 
biopsy samples. The overall intent is to demonstrate that CTCs can act as surrogates for tumor 
biopsies in future studies and that selected biomarkers will be predictive of response to 
abiraterone in breast cancer subtypes. Future studies will confirm these initial findings.
Genetic variation may be important in understanding individual differences in drug distribution 
and response as well as differential disease susceptibility and prognosis. Therefore, DNA will be 
collected, when separate informed consent is given by the study subject, to identify genetic 
factors that may influence abiraterone efficacy or be associated with metastatic breast cancer.
4.
SUBJECT POPULATION
Entry criteria for enrolling subjects in this study are described in the following 2 subsections. If 
there is a question about any inclusion or exclusion criterion, the investigator should consult the 
appropriate sponsor representative before enrolling a subject in the study. Investigators should 
ensure that all study enrollment criteria have been met during Screening. If a subject’s status 
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changes (including laboratory results) after Screening but before first dose of study drug is taken
such that she now meets an exclusion criterion, she should be excluded from participation in the 
study.
4.1.
Inclusion Criteria
Each potential subject must satisfy all following criteria to be enrolled in this study. If repeated 
clinical laboratory assessments are performed during Screening as part of the patient’s routine 
management, results closest to the date of randomization are used to document study eligibility.
1. Woman 18 years of age and postmenopausal determined by one of the following:

bilateral, surgical oophorectomy

age 60 years 

age <60 years, with amenorrhea 24 months and follicle-stimulating hormone and 
luteinizing hormone concentrations within postmenopausal range 
2. Criterion modified per amendment 
2.1
Subjects with ER+, Her2- metastatic breast cancer, confirmed within 7 days 
before randomization with FFPE tissue from either primary or metastatic breast cancer 
site. In a subject with multiple biopsies of metastatic sites, the most recent biopsy prior to 
study entry should be submitted for evaluation of hormone receptor status.
3. Criterion modified per amendment
3.1
Subjects with disease confined only to bone may be included but subjects with 
purely sclerotic lesions may not participate in the study (see Section 9.2.1)
4. Disease must have been sensitive to anastrozole or letrozole therapy prior to disease 
progression. Sensitivity to anastrozole or letrozole is defined as either stable disease or better 
for 6 months in the metastatic setting or relapse free for 2 years in the adjuvant setting.
5. No more than 2 prior lines of therapy in the metastatic setting, of which no more than 1 was 
chemotherapy [Note: Simultaneous combination treatment is considered one line of therapy.] 
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 1
7. Criterion modified per amendment
7.1
Criterion modified per amendment
7.2
Clinical laboratory values during Screening: 

hemoglobin 10.0 g/dL

neutrophils 1.5 x 109/L

platelets 100 x 109/L
(NOTE: Subjects need to meet the above 3 criteria independent of growth factors 
and transfusions)

total bilirubin 1.5x upper limit of normal (ULN)

alanine (ALT) and aspartate (AST) aminotransferase 2.5xULN
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
alkaline phosphatase 6xULN unless bone metastases with no liver 
disorder

serum creatinine <1.5xULN or creatinine clearance 50 mL/min

serum potassium 3.5 mM

serum albumin 3.0 g/dL

clinically normal prothrombin time (PT) or international normalized ratio 
(INR) and partial thromboplastin time (PTT) per investigator assessment
8. Systolic blood pressure <160 mm Hg and diastolic blood pressure <95 mm Hg 
[Note: Hypertension controlled by antihypertensive therapy is permitted]. 
9. Cardiac ejection fraction 50% measured by MUGA or ECHO done within 4 weeks before 
randomization.
10. Criterion modified per amendment
10.1
A bisphosphonate or denosumab may be initiated on the same day as the assigned 
study treatment
11. Willing and able to adhere to prohibitions and restrictions specified in this protocol
12. Signs an informed consent document within 4 weeks before randomization indicating she 
understands the purpose of and procedures required for the study and is willing to participate 
in the study
13. Signs the informed consent document within 4 weeks before randomization for 
pharmacogenomics research indicating willingness to participate in the pharmacogenomic 
component of the study, where local regulations permit. [Note: Refusal to give consent for 
this component does not exclude a subject from participation in this clinical study.]
4.2
Exclusion Criteria
A potential subject who meets any of the following criteria is excluded from study participation.
1. Criterion modified per amendment
1.1
Prior treatment with exemestane, ketoconazole, aminoglutethimide or a CYP17 
inhibitor. [Note: Prior treatment with ketoconazole for ≤7 days is permitted and topical 
formulations of ketoconazole are permitted]
2. Criterion modified per amendment
2.1
Anticancer immunotherapy or investigational agent within 4 weeks before 
randomization, or anticancer radiotherapy (except palliative) or anticancer endocrine 
therapy within 2 weeks before randomization [Note: Potential subjects must not have 
taken anastrozole, letrozole, fulvestrant, or any chemotherapy for at least 2 weeks 
(bevacizumab for at least 3 weeks) before randomization]
3. Serious or uncontrolled nonmalignant disease, including active or uncontrolled infection
4. Clinical or biochemical evidence of hyperaldosteronism or hypopituitarism
5. Any condition that, in the opinion of the investigator, would compromise the well-being of 
the patient or that could prevent, limit, or confound the protocol-specified assessments
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6. Major thoracic or abdominal surgery or significant traumatic injury with 4 weeks before 
randomization or plans surgery during study participation or within 4 weeks after the last 
dose of study drug [Note: Patients with planned surgical procedures to be conducted under 
local anesthesia are not excluded from the study.]
7. Persistent Grade 2 toxicity from any cause [Note: Chemotherapy-induced alopecia and 
Grade 2 peripheral neuropathy are allowed.]
8. Symptomatic central nervous system disease or leptomeningeal disease 
9. Gastrointestinal disorder interfering with study drug absorption 
10. Criterion modified per amendment
10.1
Active or uncontrolled disease that may require oral corticosteroid therapy
11. Positive serology for hepatitis B surface antigen or hepatitis C antibody
12. Active or symptomatic viral hepatitis or chronic liver disease
13. History of clinically significant heart disease, ie, myocardial infarction or arterial thrombotic 
event within 6 months, severe or unstable angina, or New York Heart Association Class III 
or IV heart disease
14. Known allergies, hypersensitivity, or intolerance to abiraterone acetate, exemestane, 
prednisone, or their excipients
15. Contraindications to the use of exemestane or prednisone per local prescribing information
16. Received an investigational drug (including investigational vaccines) or used an invasive 
investigational medical device within 4 weeks before the planned first dose of study drug or 
is currently enrolled in an investigational study
4.3
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for study participation. The sponsor must 
be notified in advance (or as soon as possible) of any instance in which a prohibited therapy is 
administered. Prestudy and concomitant therapies are detailed in Section 8. Although 
exemestane is metabolized by CYP3A4, ketoconazole showed no significant influence on
exemestane PK in a clinical study (Aromasin 2008). In a PK study in postmenopausal healthy 
volunteers pretreated with rifampicin, a strong CYP3A4 inducer, for 14 days followed by a 
single dose of exemestane, mean exemestane plasma Cmax and AUC0-∞were decreased. 

CYP3A4 inducers listed in Table 1 should be avoided or used with caution. 

No concurrent investigational agent other than abiraterone acetate is permitted.

No concurrent anticancer agent other than exemestane, including megestrol acetate, is 
permitted.

No radiotherapy other than small-field radiotherapy with palliative intent not involving 
response-assessable disease is permitted (unless initiated before study entry).

For subjects participating in the PK study, no food or beverage containing grapefruit juice, 
Seville oranges, or quinine (eg, tonic water) should be consumed from 24 hours (72 hours in 
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the case of grapefruit juice and Seville oranges) before each PK sampling day. On serial PK 
sampling days, these should not be consumed until after the last PK sample is collected.  
Subjects who require any prohibited drug or therapy must be discontinued from study treatment 
and should enter the Follow-Up phase.
Table 1: CYP3A4 Inducers
Inducers
barbiturates
carbamazepine
phenytoin
rifabutin
rifampicin
St. John’s wort
5.
TREATMENT ALLOCATION AND RANDOMIZATION
This is an open-label study using central randomization. Subjects are stratified by 2 factors: 
number of prior therapies in the metastatic setting (0 or 1 versus 2) and whether letrozole or 
anastrozole was administered in the adjuvant or metastatic setting (Puente 2010). On Day 1 
Cycle 1 subjects are randomly assigned by an Interactive Voice Response System to 1 of 3 
treatment groups in a 1:1:1 ratio and must commence study drug treatment within 2 days. 
Subjects withdrawn or discontinued from the study will not be replaced. 
After approval of Amendment INT-6 by the Health Authority (HA) and Independent Ethics 
Committee/Institutional Review Board (IEC/IRB), subjects will be offered the choice of 
continuing on their randomized treatment or discontinuing from the study. Subjects who elect not 
to continue on study medication and those currently in long-term follow-up will be discontinued 
from the study. The procedures for Amendment INT-6 are outlined in Attachment 10. Under 
Amendment INT-7, individual subjects who may continue to derive benefit from the treatment 
they are currently receiving, will be offered the opportunity to continue on their existing study 
medication and followed-up for safety for an additional duration of up to 3 years (ie, up to 20 
September 2018) from the date previously stated (20 September 2015) in the Amendment INT-6. 
The situation may be reassessed periodically for subjects still receiving study medication.
6.
DOSAGE AND ADMINISTRATION
All study drugs are oral and should be taken once daily. Abiraterone acetate 1,000 mg/day must 
be taken as four 250-mg tablets on an empty stomach. No food should be consumed for at least 
2 hours before the dose of abiraterone acetate is taken and for at least 1 hour after the dose of 
abiraterone acetate is taken. Prednisone (prednisolone when prednisone is not available) 
5 mg/day should be taken daily with abiraterone acetate; if gastric intestinal upset occurs, 
prednisone may be taken with food and separately from abiraterone acetate. Exemestane 
25 mg/day should be taken as a single tablet, preferably after a meal.
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Study drugs are dispensed for each 28-day cycle and taken outside the clinic; sufficient study 
drug for 3 cycles will be dispensed when study treatment continues beyond 12 treatment cycles. 
Subjects participating in the PK assessment (selected study sites only) must be administered 
study drug at the study site on PK sampling days.
No dose or dosage adjustment is foreseen but an investigator may make an adjustment for a 
medical emergency, in which case the sponsor must be notified immediately. A missed dose of 
study drug, including prednisone, should be omitted and not made up.
6.1.
Dose Reduction and Toxicity Management
In clinical studies, both abiraterone acetate and exemestane were generally well tolerated. The 
most common abiraterone-acetate-related adverse events included fatigue (cortisol reduced by 
CYP17 inhibition) and mineralocorticoid-related hypertension, fluid retention, and hypokalemia 
(compensatory adrenocorticotropic hormone drive); in this study prednisone is expected to 
mitigate these effects (cortisol supplementation and abrogation of the adrenocorticotropic 
hormone drive). The exemestane-related adverse event experienced by at least 10% of subjects 
was hot flashes (Aromasin 2008). 
Since many adverse events may be related to progressing breast cancer, investigators should 
consider approaches other than dose reduction to address adverse events. Up to 2 dose reductions 
of abiraterone acetate are allowed for adverse events that the investigator attributes to abiraterone 
acetate. At each dose reduction, the dose will be reduced by 1 tablet, eg, 4 tablets (1,000 mg) to 
3 tablets (750 mg), and 3 tablets (750 mg) to 2 tablets (500 mg). After an abiraterone acetate 
dose reduction, the abiraterone acetate dose should not be increased without documentation of 
adverse events resolution and a discussion with the Sponsor’s medical monitor. An abiraterone 
acetate dose of lower than 500 mg/day is not allowed. Study drug should not be resumed until 
resolution of the adverse events is documented.
Based on experience with exemestane at repeated doses up to 200 mg/day, exemestane lower 
than 25 mg/day is not recommended (Aromasin 2008, 2009) and exemestane dose cannot be 
reduced in this study; if interruption is required, exemestane should not be resumed until 
resolution of the adverse event is documented and the medical monitor approves.
During this study, prednisone is taken with abiraterone acetate. Following prolonged 
glucocorticoid therapy, patients may develop Cushing’s syndrome, characterized by central 
obesity, thin skin, easy bruising, bone loss, avascular necrosis of the hip, cataracts, and proximal 
myopathy. With long-term glucocorticoid therapy, a rapid withdrawal may result in symptoms 
that include fever, myalgia, fatigue, arthralgia, and malaise, which may occur even without 
evidence of frank adrenal insufficiency. Discontinuation of prednisone will be individualized 
depending on investigator judgment. Abrupt discontinuation of prednisone after chronic therapy 
may trigger symptoms and signs consistent with adrenal insufficiency.
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6.1.1.
Management of Hypokalemia
At the initial observation of Grade 1 or 2 hypokalemia (serum potassium <lower limit of normal 
(LLN)-3.0 mM; using NCI-CTCAE, Version 4.0), oral potassium supplement should be initiated 
(Table 2). The dose of potassium supplement must be carefully titrated to maintain serum 
potassium between 3.5 and 5.0 mM, inclusive. Any subject with low potassium during the study 
or a history of hypokalemia from a preexisting or concurrent medical condition should undergo 
at least weekly laboratory electrolyte evaluation. The investigator should consider maintaining 
potassium 4.0 mM in these subjects. 
If any subject experiences Grade 3 hypokalemia (serum potassium levels <3.0 to 2.5 mM, 
NCI-CTCAE Version 4.0) or life-threatening hypokalemia with potassium levels <2.5 mM 
(NCI-CTCAE hypokalemia Grade 4), abiraterone acetate plus prednisone treatment should be 
withheld and hospitalization considered for IV potassium replacement and cardiac monitoring. 
Resumption of abiraterone acetate plus prednisone treatment after normalization of potassium 
levels must be approved by the medical monitor.
Table 2: Hypokalemia Management
Serum 
Potassium
Grade of 
Hypokalemia
Action
Further Action
and/or Maintenance
Low K+ and/or 
history of 
hypokalemia
At least weekly laboratory 
electrolyte evaluations
Titrate dose to serum K+ 3.5to 
5.0mM; maintenance at 4.0mM is 
recommended.
<LLN-3.0mM
Grade 1 or 2
Initiate oral K+ supplementation
Titrate dose to serum K+ 3.5 to 
5.0mM; maintenance at 4.0mM is 
recommended.
<3.0 to 2.5mM
Grade 3
Withhold AA treatment and 
initiate i.v. K+ and cardiac 
monitoring
Call medical monitor before re-
initiating AA treatment
<2.5mM
Grade 4
Withhold AAP treatment and 
initiate i.v. K+ and cardiac 
monitoring
Call medical monitor before resuming 
AAP treatment
AA=abiraterone acetate; AAP=AA + prednisone; i.v.=intravenous; K+=potassium; LLN=lower limit of 
normal
If hypokalemia persists despite optimal potassium supplementation and adequate oral intake, the 
dose of prednisone may be increased from 5 to 10 mg/day and documented in the study 
medication electronic case report form (eCRF).
6.1.2.
Management of Hypertension

Grade 1-2:
Management per investigator; 
investigators should 
maintain blood 
pressure <160/95 mm Hg with antihypertensive agents; do not reduce abiraterone acetate 
dose.

Grade 3-4: Withhold abiraterone acetate plus prednisone and adjust/add medications to 
mitigate the toxicity; when resolves to Grade 1, resume abiraterone acetate 1,000 mg/day 
and prednisone.
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
If toxicity recurs, withhold study drug, and adjust or add medications to mitigate the toxicity. 
When toxicity resolves to Grade 1, resume study drug with the first dose level reduction 
(3 tablets, 750 mg of study drug).

If toxicity recurs, withhold study drug, and adjust or add medications to mitigate the toxicity. 
When toxicity resolves to Grade 1, resume study drug with the second dose level reduction 
(2 tablets, 500 mg of study drug).

If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue abiraterone acetate.
6.1.3.
Management of Edema and Fluid Retention

Pedal edema: Supportive management per investigator; do not reduce abiraterone acetate 
dose.

Anasarca or pulmonary edema requiring supplemental oxygen: Withhold abiraterone acetate 
plus prednisone and adjust/add medications to mitigate the toxicity; when resolves to 
Grade 1, resume abiraterone acetate 1,000 mg/day and prednisone. 

If toxicity recurs, withhold study drug, and adjust or add medications to mitigate the toxicity. 
When toxicity resolves to Grade 1, resume study drug with the first dose level reduction 
(3 tablets, 750 mg of study drug).

If toxicity recurs, withhold study drug, and adjust or add medications to mitigate the toxicity. 
When toxicity resolves to Grade 1, resume study drug with the second dose level reduction 
(2 tablets, 500 mg of study drug).

If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue study drug.
6.1.4.
Management of Non-Mineralocorticoid Side Effects

Grade 1-2: Management per investigator; do not reduce abiraterone acetate dose.

Grade 3-4: Withhold abiraterone acetate plus prednisone and adjust/add medications to 
mitigate the toxicity; when toxicity resolves to Grade 1, resume abiraterone acetate 
1,000 mg/day and prednisone. [Note: Toxicities may include headache interfering with daily 
activities, nausea, vomiting (>6 episodes within 24 hours), diarrhea, or other toxicity judged 
related to abiraterone acetate and potentially jeopardizing subject safety.]

If toxicity recurs, withhold study drug, and adjust or add medications to mitigate the toxicity. 
When toxicity resolves to Grade 1, resume study drug with the first dose level reduction 
(3 tablets, 750 mg of study drug).

If toxicity recurs, withhold study drug, and adjust or add medications to mitigate the toxicity. 
When toxicity resolves to Grade 1, resume study drug with the second dose level reduction 
(2 tablets, 500 mg of study drug).

If toxicity recurs despite optimal medical management and 2 dose level reductions, 
discontinue study drug.
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6.1.5.
Management of Abnormal Liver Function Tests

Grade 1 (AST or ALT >ULN- 3xULN; or total bilirubin >ULN-1.5xULN): Increase 
frequency of LFT monitoring if investigator judges the toxicity potentially related to 
abiraterone acetate or exemestane; no dose reductions are required. 

Grade 2 (if asymptomatic, AST or ALT >3 to 5xULN; if symptomatic, AST or ALT 
>3xULN; or total bilirubin >1.5 to 3xULN): Increase frequency of LFT monitoring if 
investigator judges the toxicity potentially related to abiraterone acetate or exemestane. 
Consider withholding study drugs and potentially hepatotoxic concomitant drugs. No dose 
reductions are required, but may be considered.

Grade 3 (AST or ALT >5 to 20xULN or >5x for >2 weeks; or total bilirubin >3 to 10xULN): 
Withhold study drugs and potentially hepatotoxic concomitant drugs. Evaluate LFTs at least 
weekly until values return to baseline or Grade 1. Liver enzyme measurements should be 
made immediately, regardless of when the next study visit is scheduled. If study drug 
resumption is considered (and the medical monitor agrees), resume abiraterone acetate at 
750 mg when toxicity resolves to Grade 1 or baseline. Dose reduction of exemestane is not 
recommended per package insert. If Grade 3 LFT recurs at 750 mg, discontinue study drugs 
and do not rechallenge. Follow subjects until resolution of abnormal LFTs.

Grade 4 (AST or ALT >20xULN; or total bilirubin >10xULN): Discontinue study drugs 
immediately and do not re-challenge. Follow subjects until resolution of abnormal LFTs.
7.
TREATMENT COMPLIANCE
Accurate records of all drug shipments as well as tablets dispensed and returned will be 
maintained. This inventory must be available for inspection by designated sponsor or regulatory 
authority representatives at any time. Drug supplies are to be used only in accordance with this 
protocol and under the supervision of the investigator. Subjects should not miss doses, especially 
during PK sampling periods. Subjects should be instructed on compliance (and diary use, for 
those participating in the PK assessment). During the course of the study, the investigator and 
study personnel will be responsible for providing additional instruction to any noncompliant 
subject. Counts of study drug tablets will be conducted on Day 15 Cycle 1 as well as Day 1 of 
each subsequent treatment cycle. Drug non-compliance is defined as missing 75% of doses in 
2 consecutive cycles or more than 14 days of therapy in 1 cycle.
8.
PRESTUDY AND CONCOMITANT THERAPY
Potential subjects must not have taken anastrozole, letrozole, fulvestrant, or any chemotherapy 
for at least 2 weeks, and bevacizumab for at least 3 weeks, before randomization. Any prestudy 
therapy administered within 30 days before the first dose of study drug must be recorded during 
Screening. Subjects will be allowed to continue their prescribed medications (including vitamins) 
as medically necessary. Any new condition or worsening of an existing condition that requires 
concomitant therapy must be documented on the adverse events section of the eCRF.
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8.1.
Required Study Medication NOT Reported as Concomitant
Throughout the study, prednisone is administered daily with abiraterone acetate, is not 
considered concomitant therapy, and should be documented as a required study medication in the 
eCRF. The use of prednisone for any reason other than required study medication should be 
documented in the eCRF concomitant therapy section.
8.2.
Permitted Supportive Care and Interventions
Subjects may receive supportive care, including transfusions, hematopoietic growth factors, 
antibiotics, analgesics, and antidiarrheal agents during the study per institutional guidelines. No 
other chemotherapy, immunotherapy, hormonal cancer therapy, radiation therapy (except 
small-field radiotherapy with palliative intent, not involving response-assessable disease), or 
experimental medications are permitted during the study. Radiotherapy is permitted if initiated 
before study entry. Supportive therapy should be documented in the concomitant therapy section 
of the eCRF. Any disease progression requiring anticancer therapy other than study-permitted 
drugs will be cause for discontinuation from the study. 
The following supportive-care medications are permitted during the study:

Conventional multivitamins

Additional systemic glucocorticoid administration such as “stress dose” glucocorticoid if 
clinically indicated for a life-threatening medical condition; in such cases, the use of steroids 
should be documented as concomitant drug

Bisphosphonate or denosumab for bone disease [Note: Since all subjects are receiving 
additional anti-estrogen therapy the sponsor suggests investigators follow local protocols, 
practice guidelines, and standard of care for monitoring and treatment of bone health in 
postmenopausal women with breast cancer (Hillner 2003; Reid 2008)]

Transfusions and hematopoietic growth factors per institutional practice guidelines
If the permissibility of a specific drug or treatment is in question, contact the study medical 
monitor.
If progression is not confirmed radiographically or clinically then the following are permitted:

Palliative radiation: one course of involved-field radiation (single- or multi-fraction) to a 
single site; radiation to more than 1 site of disease is NOT permitted

Bisphosphonates: addition of a bisphosphonate or denosumab or changing the type of 
bisphosphonate if a new skeletal related event or bone progression is suspected

Glucocorticoids: an increase in prednisone dose or addition of a more potent glucocorticoid, 
such as dexamethasone, to treat breast-cancer-related signs and symptoms, such as fatigue 
and pain [Note: Prednisone may be increased to 10 mg/day for hypokalemia unmitigated by 
potassium supplementation, Section 6.1.1]
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Only systemic medications (prescription or over-the-counter, including vaccines, vitamins, and 
herbal supplements) taken at least 30 days before randomization and continued or begun during 
the study until 30 days after the final dose of study drug must be documented in the eCRF. 
Occasional steroid use no more than 3 days/month for antiemetic prophylaxis is permitted. 
Treatment consistent with American Society of Clinical Oncology guidelines is recommended. 
Optional treatment with additional antiemetic drugs, such as 5-hydroxytryptomine antagonists or 
additional corticosteroids, is permitted and should be documented on the concomitant therapy 
section of the eCRF. 
8.3
Special Concomitant Therapy
The following concomitant therapies warrant special attention:
CYP2D6 substrates: Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme 
CYP2D6. Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a 
narrow therapeutic index. If an alternative treatment cannot be used, exercise caution and 
consider a dose reduction of the concomitant CYP2D6 substrate.
CYP3A4 inducers: In a clinical pharmacokinetic interaction study of healthy subjects pretreated 
with a strong CYP3A4 inducer (rifampicin, 600 mg daily for 6 days) followed by a single dose 
of abiraterone acetate 1,000 mg, the mean plasma AUC∞ of abiraterone was decreased by 55%. 
Strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, 
phenobarbital) during treatment with abiraterone acetate are to be avoided, or used with careful 
evaluation of clinical efficacy.
Anticoagulant therapy: Subjects taking warfarin may participate in this study but it is 
recommended that PT be monitored at least weekly for the first month and, if the INR is stable, 
monthly thereafter. Subcutaneous heparin is permitted.
For the most accurate and current information regarding potential drug-drug interactions with 
abiraterone acetate, refer to the latest version of the Investigator Brochure for abiraterone acetate.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
Study procedures to be performed under Amendment INT-6 are outlined in Attachment 10. The
Schedule of Events in this Attachment supersedes the Time and Events Schedule in the previous 
version of the protocol (Amendment INT-5).
The Time and Events Schedule summarizes the frequency and timing of all study evaluations. 
When study procedures occur on the same visit day, PROs should be completed before any other 
procedures or consultations for that visit.
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Blood samples (5 mL) are collected to measure coagulation, lipid profile, fasting glucose, 
hematology, chemistry with electrolytes, and LFTs; total blood volume drawn for a subject through 
4 treatment cycles is estimated to be 120 mL (Table 3). Blood samples (2 mL, abiraterone acetate; 
4 mL, exemestane) for PK assessment are collected at selected study sites for 20 subjects/treatment 
group; the approximate total blood volume ranges from 50 to 150 mL, depending on treatment 
group and treatment site. Sites that do not have a capability of overnight stays will not collect PK 
samples at 12, 16, and 22 hours after study drug dosing on Days 1 and 15 of Cycle 1. Blood 
samples (40 mL where local regulations permit) for CTC evaluation are collected at all sites. 
Tumor samples are collected for ER subtyping and other molecular analyses. DNA sampling will 
be completed only where regulations permit for subjects who consent separately to participate in 
the pharmacogenomic component of the study. Repeated or unscheduled blood samples may be 
taken if required for safety reasons.
Instructions for collection and shipment of pharmacogenomics samples are provided in the Study 
Laboratory Manual. In the event of DNA extraction failure, a replacement blood sample may be 
requested. Subjects participating in PK assessment will be provided a diary to record meal and 
dosing times for the 2 days before each PK sampling day. 
Table 3: Approximate Blood Volume Through Four Treatment Cycles
Type of Sample
Volume per 
Sample (mL)
Samples per 
Subject
Volume per 
Subject (mL)
- Coagulation
  5
  2
  10
- Lipid profile
  5
  2
  10
- Hematology
  5
  5
  25
- Chemistry
  5
  6
  30
- Endocrine markers
15
  3
45
- CTCs
40a
  3b
120b
  Without PK, CTC, DNA:
240
- Pharmacokinetics (PK)
  
   - abiraterone group
  2
19 or 25
  38 or 50
   - exemestane group
  4
19 or 25
76 or 100
   - abiraterone + exemestane group
  6
19 or 25
114 or 150
- Pharmacogenomics (DNA)
10
  1
  10
With PK, CTC, DNA:
With safety labs above
48 – 160
288 – 400
PK=pharmacokinetics; CTC=circulating tumor cells
a Where local regulations permit
b If low CTCs are found in the baseline sample, no further CTC sampling should be done 
for the subject.
Note: Approximate total volume for PK analysis ranges from 38 mL (abiraterone acetate + 
prednisone group, sites that do not support overnight stays) to 150 mL (abiraterone acetate 
+ prednisone combined with exemestane group, sites that do support overnight stays).
9.1.2.
Screening Phase
Each subject must satisfy all entry criteria (Sections 4.1 and 4.2) and sign the consent form 
before any study procedure is performed. Potential subjects must not have taken anastrozole, 
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letrozole, fulvestrant, or any chemotherapy for at least 2 weeks, and bevacizumab for at least 
3 weeks, before randomization. Procedures and evaluations should be performed according to the 
Time and Events Schedule.
9.1.3.
Treatment Phase
Subjects should receive study drug until disease progression (Section 9.2.1), when subjects 
randomized to exemestane alone may be switched to abiraterone acetate plus prednisone at the 
discretion of the investigator; if not switched, these subjects must be discontinued from study 
drug. At disease progression, subjects randomized to either abiraterone acetate plus prednisone 
or abiraterone acetate plus prednisone combined with exemestane must be discontinued from 
study drug. Subjects with no disease progression for 12 treatment cycles may continue study 
treatment at the discretion of the investigator, in which case study visits will continue every 
3 cycles for assessment of efficacy (CT or MRI, ECOG) and safety (physical examinations, vital 
signs, fasting glucose, hematology, chemistry with electrolytes, LFTs); PROs and lipid profiles 
will be continued every cycle and every 6 cycles, respectively. Concomitant therapy prohibited 
and allowed is detailed in Sections 4.3 and 8.2, respectively. Procedures and evaluations should 
be performed according to the Time and Events Schedule.
9.1.4.
End-of-Treatment Procedures
The End-of-Treatment visit occurs when the subject has met the criteria for discontinuation of
study drug(s). This should be scheduled within 30 days after the final dose of study drug to 
collect posttreatment safety and efficacy data as well as a biomarker sample, as specified in the 
Time and Events Schedule.
9.1.5.
Follow-Up Phase
Subjects should enter the Follow-Up phase regardless of reason for study drug discontinuation 
and should be monitored every 3 months (7 days) until death, loss to follow-up, consent 
withdrawal, or abiraterone acetate development in this indication is discontinued. Nonstudy 
anti-breast-cancer therapies (with start and stop dates) and survival status may be collected by 
telephone or chart review. PROs also should be completed. The total study duration will be 
extended up to September 2018.
Under Amendment INT-6, the follow-up phase will be stopped, and subjects currently in long-
term follow up will be discontinued from the study.
9.2.
Efficacy Evaluation
9.2.1.
Progression-Free Survival
Determination of PFS will use radiographic progression defined by RECIST (Attachment 1) on 
measurable lesions captured by CT or MRI at baseline and, using the same modality, repeated 
every 2 cycles initially (Day 1 Cycle 3, Day 1 Cycle 5, and Day 1 Cycle 7) and every 3 cycles 
thereafter (eg, Day 1 Cycle 10, Day 1 Cycle 13) until, and including, the End-of-Treatment visit. 
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The baseline image should be taken within 4 weeks before randomization as close as possible to 
Day 1 Cycle 1. Every effort must be made to ensure the same radiographic method (CT or MRI) 
is used before and throughout the study. 
Since disease progression should be documented by CT or MRI, imaging with whichever 
modality was used at baseline should be completed as soon as possible if a new 
breast-cancer-related symptom appears that requires medical intervention, such as initiation of 
chemotherapy, palliative radiotherapy, or opiate therapy (or dose increase). When clinical 
progression cannot be confirmed by CT or MRI, such as when the disease site is skin, bone 
marrow, or central nervous system, the corresponding clinical examination finding will be 
recorded in the source documents and in the eCRF. See the Time and Events Schedule for 
frequency of physical examinations.
Disease progression should not be based on assessments of new sclerotic bone lesions. When 
bone disease is the only basis for determination of progression or response, only lytic bone 
lesions should be used.
All disease progressions should be confirmed by the sponsor company via a faxed confirmation 
form (Attachment 5).
9.2.2.
Long-Term Benefit
Survival status will be determined throughout the study and during Follow-Up. Survival status, 
including nonstudy anticancer therapy, may be monitored by telephone or chart review during 
Follow-Up.
The following PROs are self-administered, health-related quality-of-life questionnaires that 
assess subject-perceived disease burden, including pain, and should be conducted according to 
the Time and Events Schedule. 
EORTC-C30
The EORTC-C30 (Attachment 2) is a 30-item questionnaire validated for clinical research in 
oncology (Aaronson 1993; Bottomley 2007; Fayers 2002) and is specifically validated and 
responsive in breast cancer patients (McLachlan 1998; Osoba 1994). The EORTC-30 comprises 
scales in function, symptoms, a global health subscale, as well as single items to assess specific 
symptoms.
EQ-5D-5L
The EQ-5D-5L (Attachment 3) is a 5-item instrument measuring mobility, self-care, usual 
activities, pain, discomfort, and anxiety/depression (EuroQol Group 1990) that generates a single 
utility score commonly used to calculate quality-adjusted life years, an outcome measure of cost 
effectiveness (Drummond 2005; Weinstein 1996).
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Pain Intensity Scale of BPI-SF
Of the BPI-SF instrument, only the 4-item pain intensity scale (Attachment 4) is used in this 
study (Cleeland 1994).
9.3.
Safety Evaluation
All study subjects who received any dose of study drug will be evaluable for safety. Adverse 
events, including laboratory adverse events, will be graded and summarized according to the 
NCI-CTCAE (Attachment 6). Any clinically significant abnormalities persisting at the end of the 
study will be followed by the investigator until resolution or until a clinically stable endpoint is 
reached. The following evaluations of safety will be performed at time points specified in the 
Time and Events Schedule.
Cardiac Function
The cardiac left ventricular ejection fraction should be evaluated by MUGA (ECHO if MUGA 
unavailable) before and after study treatment using the same assessment modality; subjects with 
prior anthracycline 350 mg/m2 will have evaluations at baseline and every 3 cycles thereafter 
(eg, Day 1 Cycle 4, Day 1 Cycle 7). ECGs should be done within 4 weeks before randomization 
and Day 1 Cycle 4 and every 3 cycles thereafter (eg, Day 1 Cycle 4, Day 1 Cycle 7), and 
End-of-Treatment (see Section 11.9 for details); serum potassium <3.5 mM should be corrected 
before any ECG is recorded. At selected study sites, when PK sampling is Day 1 Cycle 1, an 
ECG should be recorded 2 hours after study drug dose. ECGs (12-lead) should be recorded at a 
paper speed of 25 mm/sec until 4 regular consecutive complexes are available. 
Computer-generated interpretations of ECGs should be reviewed for data integrity and 
reasonableness by the investigator. 
Physical Examination
Physical examinations, including weight, should be conducted at every visit; height will be 
recorded at baseline only. Subject weight will be measured with the subject lightly clothed and 
without shoes. Any clinically significant change in physical findings noted during the study 
should be reported as an adverse event. Any clinically significant abnormalities persisting at the 
end of the study should be followed by the investigator until resolution or until reaching a 
clinically stable endpoint. 
Vital Signs 
Upright sitting blood pressure, heart rate, respiratory rate, and oral or aural body temperature, 
should be recorded. 
Clinical Laboratory Tests 
Blood samples for hematology and chemistry will be taken for evaluation of laboratory safety 
parameters (Attachment 7). The investigator must review the laboratory report, document this 
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review, and record any clinically relevant changes during the study in the adverse event section 
of the eCRF. Baseline values, including Screening coagulation and dipstick urinalysis, should be 
measured within 7 days before randomization.
All laboratory test results should be classified according to NCI-CTCAE criteria. Standard 
reference ranges will be used for missing or discrepant normal ranges. Baseline laboratory test 
values will be the results from the last blood samples drawn on or before the first day of study 
treatment. On-study laboratory test values will be those results from blood samples drawn 1 day 
after the first study treatment until 30 days after the last dose of study treatment.
9.4.
Biomarker Evaluation
Circulating levels of adrenal steroids, including DHEA and its sulphate, DHEA-S, positively 
correlate with ER+/PR+ breast cancers (Eliassen 2006; Key 2002) and in vitro data indicate 
these ligands stimulate proliferation of breast cancer cell lines in a low-estrogen environment 
(Maggiolini 1999). These ligands function as weak ER agonists, indicating that steroidogenic 
enzymes upstream of aromatase may also contribute to disease progression (Chan 2002) by 
activating ER and possibly other steroid hormone receptors. Abiraterone is expected to attenuate 
this activity by suppression of androgenic steroids that may contribute to mitogenesis through 
stimulation of both AR and ER.
9.4.1.
Formalin-Fixed Paraffin-Embedded Tumor Tissue
To determine study eligibility, prior to randomization an FFPE tumor sample will be assessed for 
ER, PR, and Her2. In addition to these markers, samples may also be analyzed for expression 
levels 
of 
intratumoral 
nuclear 
AR, 
CYP17, 
CYP19, 
Ki-67, 
and 
3-HSD 
by 
immunohistochemistry or fluorescence in situ hybridization (FISH). Samples may also be 
analyzed for miRNA expression levels to define molecular subtypes of breast cancer or for 
mutations or amplification of the ERα gene, K303R or for other biomarkers (e.g. mRNA, 
somatic anomalies). 
9.4.2.
Endocrine Markers
For every subject, blood samples (15 mL) for assessment of endocrine biomarkers will be taken 
Day 1 of Cycles 1 through 3, and every 3 cycles thereafter (eg, Day 1 Cycle 6, Day 1 Cycle 9) up 
to, and including Day 1 Cycle 12, and at the End-of-Treatment visit. Estradiol, testosterone, and 
estrone levels will be evaluated for all subjects. Additional androgens or estrogens may also be 
evaluated. 
9.4.3.
Circulating Tumor Cells 
Blood samples (40 mL where local regulations permit) will be taken Day 1 of Cycles 1 and 2 and 
during the End-of-Treatment visit for enumeration and characterization of CTCs and biomarkers 
such as AR, ER, PR, Her2, CYP17, CYP19, or other candidate markers. Other molecular 
analyses (eg, RNA or DNA based) may also be conducted. Sites will be notified when a subject’s 
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Day 1 Cycle 1 baseline sample does not meet a minimum threshold and no further CTC sampling 
should be done for the subject.
9.4.4.
Fresh Tumor Biopsies (Selected Study Sites)
Consent to biopsy metastasized or primary tumor will be sought from subjects with superficial 
disease easily and safely amenable to successive tumor biopsies at selected study sites. Consent 
will be obtained for a biopsy at baseline and at least 1 treatment phase time point. If consent is 
granted for 3 time points, biopsies will be taken at screening, Day 1 Cycle 3, and Day 1 Cycle 5; 
missing time points will not be considered protocol violations. Biomarker studies may include 
global 
miRNA 
and 
gene-expression 
profiling,
somatic 
mutational 
profiling,
immunohistochemistry or FISH analyses of AR, ER, PR, Her2, CYP17, CYP19, Ki-67, and 
3β-HSD. Additional androgens and estrogens also may be evaluated.
9.5.
Pharmacogenomics Evaluation
There are 2 parts to the optional pharmacogenomics component of this study. The first part 
enables analysis of genes that may be relevant to abiraterone acetate or breast cancer. Candidate 
genes will be genotyped only if it may help resolve issues with clinical data. Genotyping of 
candidate genes related to abiraterone or breast cancer would be performed on identifiable 
samples. Additional genes may be added as more knowledge related to abiraterone or breast 
cancer becomes available.
The second part of the pharmacogenomics research allows for storage of DNA samples for future 
genetic research related to abiraterone acetate or breast cancer. Stored DNA samples will be 
double-coded and stored for a period of 5 years after the Clinical Study Report is issued. 
Subjects may participate in either part, neither part, or both parts, where local regulations permit.
9.6.
Pharmacokinetics Evaluation (Selected Study Sites)
Evaluations
The twenty (20) subjects/treatment group will participate in PK assessments on Days 1 and 15 of 
Cycle 1 for collection of serial venous blood samples (2 mL, abiraterone acetate; 4 mL, 
exemestane). On Days 1 and 15 of Cycle 1, PK samples will be collected before and 1, 1.5, 2, 3, 
4, 8, 12, 16, 22, and 24 hours after study drug dosing. Sites that do not have the capability of 
overnight stays will not collect PK samples at 12, 16, and 22 hours after study drug dosing on 
Days 1 and 15 of Cycle 1. Predose samples only will also be collected Day 1 of Cycles 2 through 
4. Study drug will be given at the study site on these days and subjects will be instructed to 
record study drug dosing times and meal times for 2 days before each PK sampling visit. 
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Analytical Procedures
Plasma abiraterone and exemestane concentrations will be determined using a validated liquid 
chromatography-mass spectrometry/mass spectrometry method under the supervision of the 
sponsor Bioanalytical Laboratory. 
Pharmacokinetics Parameters
PK analysis will be the responsibility of the sponsor in accordance with the current Clinical 
Pharmacokinetics Guideline. PK parameters to be estimated for abiraterone and exemestane from 
plasma data include the following:
Cmax
maximum plasma concentration
tmax
time to reach the maximum plasma concentration
AUClast
area under the plasma concentration-time curve from time 0 to time of 
last quantifiable plasma concentration
tlast
time to last quantifiable plasma concentration
AUC24h
area under the plasma concentration-time curve from time 0 to 24 hours
Additional PK parameters will be calculated if deemed appropriate.
9.7.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded on the laboratory requisition 
forms. If an indwelling catheter is used for sample collection, saline flushes (no heparin) should 
be used. PK sample collection, processing, storage, and shipping instructions are detailed in the 
Study Laboratory Manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered as having completed the Treatment phase if she completes 
assessments until experiencing disease progression or unacceptable toxicity or medical condition 
that precludes further study treatment. A subject will be considered as having completed the 
study if she completes Treatment and Follow-Up phases (total study duration will be extended up 
to September 2018).
Under Amendment INT-6, the long-term follow-up phase will be stopped, and subjects in long-
term follow up will be discontinued from the study (see Attachment 10).
10.2.
Discontinuation of Study Drug
Notification of study drug discontinuation for disease progression should be made to the sponsor 
by fax before treatment discontinuation and clearly documented on the appropriate eCRF. Once 
the sponsor has been notified of an acceptable reason for study treatment discontinuation, the 
subject can be discontinued from study drug(s) and entered into the Follow-Up phase after the 
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End-of-Treatment visit. An exception to the discontinuation rule can be made if the treatment 
discontinuation is being made for safety reasons. The End-of-Treatment visit should be 
scheduled within 30 days after the final dose of study drug. When a subject withdraws consent 
for study treatment but is willing to continue in the study, posttreatment follow-up should report 
overall survival, subsequent non-study anti-breast-cancer therapies (with start and stop dates), 
and PRO score.
At disease progression, subjects randomized to exemestane alone may be switched to abiraterone 
acetate plus prednisone at the discretion of the investigator after notifying the sponsor; if not 
switched, these subjects must be discontinued from study drug after notifying the sponsor. Those 
subjects who cross-over to abiraterone acetate from exemestane will complete study visits 
starting again with Day 1 Cycle 1. However, the subjects that cross-over will not be required to 
provide additional samples for the sub-studies (i.e., PK, biopsy), or have further samples 
collected for biomarker, endocrine, CTCs and pharmacogenomic evaluations. At disease 
progression, subjects randomized to either abiraterone acetate plus prednisone or abiraterone 
acetate plus prednisone combined with exemestane must be discontinued from study drug. 
In addition, an investigator may discontinue study drug for any of the following reasons:

Dosing noncompliance

Unacceptable toxicity

Medical condition not served by continuing study drug treatment 

Administration of prohibited therapies or medications
10.3.
Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:

Loss to follow-up

Withdrawal of consent

Death
If a subject is lost to follow-up, every reasonable effort must be made by study site personnel to 
contact the subject to determine the reason for withdrawal and the measures taken to follow up 
must be documented. If a subject withdraws consent, the End-of-Treatment study visit should be 
completed within 30 days of the last dose of study drug. 
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn
subject may not be assigned to another subject. Subjects who withdraw will not be replaced.
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A subject who withdraws from the study will have the following options regarding 
pharmacogenomic research:

The DNA extracted from the subject's blood will be retained and used in accordance with the 
subject's original pharmacogenomic informed consent.

The subject may withdraw consent for pharmacogenomic research, in which case the DNA 
sample will be destroyed and no further testing will take place. To initiate the sample 
destruction process, the investigator must notify the sponsor site contact to request sample 
destruction. The sponsor site contact will, in turn, contact the biomarker/pharmacogenomics 
representatives to execute sample destruction. If requested, the investigator will receive 
written confirmation from the sponsor that the sample has been destroyed.
Withdrawal From Pharmacogenomics Research Only
A subject may withdraw consent for pharmacogenomic research while remaining in the clinical 
study. In such a case, any DNA extracted from the subject’s blood will be destroyed. The sample 
destruction process will proceed as described above. 
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the supervision of the sponsor. A general 
description of the statistical methods to be used to analyze efficacy and safety data is outlined 
below. Specific details are provided in the Statistical Analysis Plan.
Unless otherwise specified, continuous endpoints will be summarized using descriptive statistics, 
which will include subject number, mean, standard deviation, median, minimum, and maximum. 
Categorical endpoints will be summarized using frequencies and percentages. The baseline 
measurement will be the last value on or before the first dose of study medication. 
11.1.
Sample Size Determination
The primary analysis consists of 2 pair-wise comparisons of the experimental treatment groups 
(abiraterone acetate plus prednisone and abiraterone acetate plus prednisone combined with 
exemestane) with the reference treatment group (exemestane alone). For each of the pair-wise 
comparisons, the statistical tests of treatment effects on primary endpoint of PFS will be 
conducted independently at the 2-sided 0.10 level of significance. No multiplicity adjustment to 
the Type I error will be made. A log-rank test will be used in the testing of the primary endpoint 
PFS. This study is event driven and will complete for primary analysis after a total of 220 PFS 
events in the 3 treatment groups have occurred over a total study duration of 19 months. It is 
assumed that PFS follows an exponential distribution with a constant hazard ratio. Assuming an 
underlying hazard ratio of any pair-wise comparison (abiraterone acetate plus prednisone and 
abiraterone acetate plus prednisone combined with exemestane, each compared with exemestane 
alone) is 0.65 (median PFS 6.2 and 4.0 months, respectively), the study has 80% power at a 
significance level of 0.10 (2-sided) to demonstrate a treatment difference with approximately 150 
PFS events in each pair-wise comparison. Assuming an enrollment rate of 20 subjects per month 
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for 15 months, a total sample size of approximately 300 subjects (100 subjects per group) is 
planned. In the case that randomization to 1 treatment group is discontinued based on the DRC 
recommendation after the interim analysis, the study may stop randomization when 
approximately 200 subjects are enrolled to the remaining 2 treatment groups. The final analysis 
would then be performed after the occurrence of 150 death or progression events within the 
remaining 2 treatment groups.
11.2.
Analysis Populations 
Subject disposition and efficacy analyses will be performed on data from the intent-to-treat (ITT) 
population. All randomized subjects included in the ITT analysis will be classified according to 
assigned treatment group, regardless of actual treatment received. The primary efficacy analyses 
will be on the ITT population. 
All subjects who receive at least 1 dose of study drug will be included in the analysis of safety 
(Safety Population).
11.3.
Demographics and Baseline Characteristics
Demographic variables will include age, race, ethnicity, height, and weight. Baseline disease 
characteristics (documented in the source documents and eCRF) will include time since 
diagnosis, disease sites, prior therapies (how many and whether nonsteroidal aromatase inhibitor 
was given in adjuvant or metastatic setting), duration of stable disease during prior aromatase 
inhibitor therapy, and hormone receptor status. 
11.4.
Efficacy Analyses
11.4.1.
Primary Efficacy Endpoint
The primary efficacy endpoint, PFS, is measured from time of randomization to first occurrence 
of one of the following:

Disease progression as defined in Section 9.2.1

Death from any cause
11.4.2.
Secondary Efficacy Endpoints

Overall survival will be measured from date of randomization to date of death from any 
cause. Survival time of living subjects will be censored on the last date a subject is known to 
be alive or lost to follow-up.

Overall response rate is defined as the proportion of subjects fulfilling respective criteria for 
response over the total number of subjects in the ITT population. Overall response for 
measurable disease is defined as a subject having a best overall response of either complete 
response or partial response based on RECIST (Attachment 1). 

PROs: EORTC-C30, EQ-5D-5L, and BPI-SF pain intensity scale scores (Attachment 2, 
Attachment 3, Attachment 4)
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
Change in endocrine marker concentrations (estradiol, testosterone, estrone, and other 
biomarkers)

PK characterization of abiraterone and exemestane
Other efficacy endpoints include ECOG (Attachment 8), pharmacogenomics evaluations, CTC 
characterization, and biomarker evaluations in fresh tumor biopsies.
11.4.3.
Analyses Methods
Distributions of time-to-event variables will be estimated using the Kaplan-Meier product-limit 
method. Median times to event with 2-sided 95% confidence intervals will be estimated. The 
stratified log-rank test will be used as the primary analysis for treatment comparison. A Cox 
proportional-hazards model will be used to provide estimates of hazard ratios with 95% 
confidence intervals.
The relative risk (treatment:control) will be reported along with the associated 95% confidence 
interval. Statistical inference will be evaluated using Chi-square statistic; the Fisher’s exact test 
may be used if the expected counts in some cells are small.
Scores from EORTC-C30, EQ-5D-5L, and BPI-SF pain intensity scale will be descriptively 
summarized by treatment group. Longitudinal analysis with repeated measures may be used as 
appropriate.
11.5.
Biomarker Analyses  
Biomarker studies are designed to identify markers predictive of response (or resistance) to 
abiraterone. The following biomarkers may be analyzed: 

protein levels quantified by immunohistochemistry and FISH (AR, ER, PR, Her2, CYP17, 
CYP19, Ki-67, and 3β-HSD)

serum endocrine biomarkers (estradiol, testosterone, and estrone)

CTCs

gene expression, miRNA or somatic mutation profiling
The associations of the above biomarkers with clinical response or time-to-event endpoints will 
be assessed using the appropriate statistical methods (analysis of variance [ANOVA], 
categorical, or survival model), depending on the endpoint.
Analyses will be performed within each treatment group and difference by race will be explored. 
Correlation of baseline expression levels or changes in expression levels with response or 
time-to-event endpoints will identify responsive (or resistant) subgroups. For expression-related 
analyses, evaluations will determine whether patterns of expression change with acquired 
resistance to treatment. 
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11.6.
Pharmacokinetics Analyses
The PK population will include all subjects with sufficient and interpretable PK assessments to 
estimate the noncompartmental PK parameters. PK parameter estimations of abiraterone and 
exemestane will be summarized by descriptive statistics by treatment group. The plasma 
abiraterone and exemestane concentrations of at each time point will be summarized by 
descriptive statistics by treatment group. Individual and mean plasma concentration-time profiles 
of abiraterone and exemestane will be plotted by treatment group. All subjects and samples 
excluded from analysis will be clearly documented in the study report. Further exploratory PK 
analyses may be performed, as deemed appropriate.
11.7.
Safety Analyses
All subjects who receive at least 1 dose of study drug will be analyzed for safety. 
Treatment-emergent adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) system and graded according to the NCI-CTCAE. Adverse events will be 
summarized by system organ class and preferred term, and will be presented overall and by 
treatment group. Deaths and other serious adverse events will be provided in a listing. 
Treatment-emergent adverse events resulting in study drug discontinuation, dose modification, 
and dose interruption or delay will also be listed and tabulated by preferred term. Other safety 
endpoints, including vital signs, clinical laboratory parameters, and ECG, will be summarized 
descriptively. Shift tables for select laboratory parameters will be presented. No formal statistical 
analyses are planned.
11.8.
Interim Analysis
One interim analysis is scheduled when a total of approximately 110 (50%) of the PFS events 
have occurred. The interim analysis is expected to occur after approximately 75 PFS events in 
each of the 2 pair-wise comparisons: 1) abiraterone acetate plus prednisone versus exemestane 
alone, 2) abiraterone acetate plus prednisone combined with exemestane versus exemestane 
alone. The stopping boundaries for PFS-based futility and efficacy were calculated using East®
software. Gamma-family spending functions determined the Type I error rate of 10% (2-sided) 
and Type II error rate of 20% for each comparison. After the review of interim data, the Data 
Review Committee (DRC) will make recommendations regarding the continuation of the study.
11.9.
Data Review Committee
A DRC will be formed to monitor data on a regular basis to ensure the safety of the subjects 
enrolled in this study and to meet efficacy objectives. The DRC will consist of at least 1 medical 
expert in breast cancer and at least 1 statistician. Details regarding DRC responsibilities and 
interim analysis procedures will be provided in a separate DRC charter.
In addition to the planned interim analysis (Section 11.8), the DRC will meet periodically to 
review the cumulative safety data collected. One safety review by DRC will occur after the tenth 
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subject in each treatment group (~30 subjects) has received study drug for 28 days (Cycle 1); 
subject accrual will continue only if no safety concerns arise. When the baseline and at least 
1 posttreatment ECG are available for the first 25 subjects in each treatment group (75 subjects 
total), the DRC will determine if additional ECGs are needed for these and subsequent subjects.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or noninvestigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can, therefore, be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non-investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) product. 
Note: Definition is according to the International Conference on Harmonisation (ICH).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the informed consent form 
(refer to Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event, based on ICH and EU Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use, is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity
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
Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent 1 of the outcomes listed in the definition above. These 
should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For an investigational product, the expectedness 
of an adverse event will be determined by whether or not it is listed in the Investigator’s 
Brochure. For a non-sponsor investigational medicinal product (eg, a comparator product) with a 
marketing authorization, the expectedness of an adverse event will be determined by whether or 
not it is listed in the package insert. 
Adverse Event Associated with the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2. 
12.1.2.
Attribution Definitions
Not related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, eg, concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
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Very likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria 
The NCI-CTCAE Version 4.0 will be used to grade the severity of adverse events. Adverse 
events not listed in the NCI-CTCAE Version 4.0 will be graded as follows.

Grade 1: Mild adverse event; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated

Grade 2: Moderate adverse event; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living

Grade 4: Life-threatening consequences; urgent intervention indicated

Grade 5: Death related to the adverse event
12.2.
Special Reporting Situations
Safety events of interest on a sponsor medicinal product that may require expedited reporting 
and/or safety evaluation include, but are not limited to:

Overdose of a sponsor medicinal product

Suspected abuse/misuse of a sponsor medicinal product

Inadvertent or accidental exposure to a sponsor medicinal product

Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor medicinal product, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All adverse events, whether serious or non-serious, will be reported from the time a signed and 
dated informed consent form is obtained until 30 days after the last dose of study drug. Serious 
adverse events, including those spontaneously reported to the investigator within 30 days after 
the last dose of study drug, must be reported using the Serious Adverse Event Form. The sponsor 
will evaluate any safety information that is spontaneously reported by an investigator beyond the 
time frame specified in the protocol.
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Disease progression will not be reported as an adverse event, as this information will be used for 
assessment of efficacy endpoints. However, the signs and symptoms of clinical sequelae 
resulting from disease progression will be reported if they fulfill the serious adverse event 
definition (see Section 12.1.1, Adverse Event Definitions and Classification). All adverse events, 
regardless of seriousness, severity, or presumed relationship to study therapy, must be recorded 
using medical terminology in the source document and the eCRF. Whenever possible, diagnoses 
should be given when signs and symptoms are due to a common etiology (eg, cough, runny nose, 
sneezing, sore throat, and head congestion should be reported as “upper respiratory infection”). 
Investigators must record in the eCRF their opinion concerning the relationship of the adverse 
event to study therapy. All measures required for adverse event management must be recorded in 
the source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
Subjects (or their designees, if appropriate) must be provided with a “study card” indicating the 
name of the investigational study drug, the study number, the investigator’s name, a 24-hour 
emergency contact number, and, if applicable, excluded concomitant medications.
12.3.2.
Serious Adverse Events
All serious adverse events occurring during clinical studies must be reported to the appropriate 
sponsor contact person by investigational staff within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious 
Adverse Event Form, which must be completed and signed by a member of the investigational 
staff, and transmitted to the sponsor within 24 hours. The initial and follow-up reports of a 
serious adverse event should be made by facsimile (fax).
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject’s participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value is available

The event can be attributed to agents other than the study drug or to factors unrelated to study 
conduct
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
It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration of 
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product should be reported as a 
serious adverse event. Any event requiring hospitalization (or prolongation of hospitalization) 
that occurs during the course of a subject’s participation in a clinical study must be reported as a 
serious adverse event, except hospitalizations for the following:

Reasons described in the protocol, eg, drug administration, protocol-required testing

Prolonged hospitalization for technical, practical or social reasons, in the absence of an 
adverse event

Preplanned reasons (ie, planned prior to the start of treatment on study – must be documented 
in the eCRF). Prolonged hospitalization for a complication considered to be at least possibly 
related to the study medication remains a reportable serious adverse event

As part of a standard procedure for protocol therapy administration will not be reported as a 
serious adverse event. Hospitalization or prolonged hospitalization for a complication of 
therapy administration will be reported as a serious adverse event

For the administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious adverse 
event As part of a procedure for protocol- or disease-related investigations (eg, surgery, 
scans, endoscopy, sampling for laboratory tests, bone marrow sampling), or hospitalization 
or prolonged hospitalization for a complication of such a procedure
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
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13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, reliability of a product, including its labeling or package integrity. PQCs may have an 
impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and 
analysis of PQC information from clinical studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor 
has established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information; all clinical studies conducted by the sponsor or its 
affiliates will be conducted in accordance with those procedures.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the investigational staff within 24 hours after 
being made aware of the event.
If the defect is combined with a serious adverse event, the investigational staff must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (Section 12.3.2,
Serious Adverse Events). A sample of the suspected product should be maintained for further 
investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drugs
Abiraterone acetate 250-mg tablets are oval, white to off-white, and contain abiraterone acetate 
and compendial-grade (USP/NF/EP) lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, and colloidal 
silicon dioxide. Additional information is in the Investigator Brochure.
Exemestane is provided as 25-mg tablets.
Prednisone is provided as 5-mg tablets.
14.2.
Packaging
Study medication is provided to each site in bulk form. The study site pharmacist dispenses study 
medication to each subject in accordance with this protocol under the guidelines of the site’s 
dispensation standard operating procedure.
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14.3.
Labeling
Study drug labels contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling, and Storage
Study drugs must be stored in a secure area and administered only to study subjects in 
accordance with conditions specified in this protocol. Abiraterone acetate and exemestane should 
be stored at room temperature (15 to 30°C; 59 to 86°F) in the original container. Prednisone 
should be stored at 20 to 25°C (68 to 77°F) and prednisolone should be stored below 25°C.
Subjects should be instructed to keep medications out of reach and sight of children. 
Abiraterone is contraindicated in women who are pregnant or may be pregnant. There are no 
human data on the use of abiraterone acetate in pregnancy. To avoid inadvertent exposure, 
women who are pregnant or may be pregnant should not handle abiraterone acetate without 
protection, eg, gloves. It is not known if either abiraterone acetate or its metabolites are excreted 
in human breast milk. 
Additional information is provided in the abiraterone acetate Investigator’s Brochure.
14.5.
Drug Accountability
The investigator is responsible for ensuring all study drug received at the site is inventoried and 
accounted for throughout the study. Dispensing of study drug to subjects and return of study drug 
from subjects must be documented on the drug accountability form and eCRF. Subjects must be 
instructed to return all original containers, whether empty or containing study drug. Study drug 
returned by study subjects will be stored and disposed of according to sponsor's instructions. Site 
staff must not combine contents of study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and 
should be stored in a limited-access area or in a locked cabinet under appropriate environmental 
conditions. Unused study drug and study drug returned by subjects must be available for 
verification by the sponsor site monitor during on-site monitoring visits. Return to the sponsor of 
unused study drug, or used returned study drug for destruction, will be documented on the Drug 
Return Form. When the site is an authorized destruction unit and study drug supplies are 
destroyed on site, this must also be documented on the Drug Return Form.
Study drug should be dispensed under the supervision of the investigator, a qualified member of
the investigational staff, or by a hospital/clinic pharmacist. Study drug will be supplied only to 
subjects participating in the study. Returned study drug must not be dispensed again, even to the 
same subject. Whenever a subject brings her study drug to the site for pill count, this is not seen 
as a return of supplies. Study drug may not be relabeled or reassigned for use by other subjects.
The investigator agrees neither to dispense the study drug from, nor store it at, any site other than 
the study sites agreed upon with the sponsor.
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15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the follow supplies:

Investigator Brochure for abiraterone acetate

eCRFs

Study Pharmacy Manual

Study Laboratory Manual

Study PRO Booklets 

Subject diaries for subjects participating in PK assessment

Collection tubes, labels, and other supplies required for collection and shipment of blood 
samples for PK and pharmacogenomic assessments 

Collection and shipping supplies for biomarker samples
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Ongoing medical review by sponsor and DRC occurs as soon as a subject is enrolled in the study. 
Study recruitment will be on hold until the DRC reviews safety data from the first 30 subjects. The 
safety profile and dosing compliance of abiraterone acetate plus prednisone or abiraterone acetate 
plus prednisone combined with exemestane, compared with exemestane alone, must be 
comparable for recruitment to continue. An interim analysis reviewed by the DRC for safety and 
efficacy will occur when 110 events have occurred.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable 
regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the clinical study data are credible.
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16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved informed consent form (and any other written materials to be provided to 
the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as documented 
by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), informed consent form, applicable recruiting 
materials, and subject compensation programs, and the sponsor has received a copy of this 
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study, the investigator (or sponsor, where required) will send the following 
documents and updates to the IEC/IRB for its review and approval, where appropriate:

Protocol amendment(s) (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to informed consent form and any other written materials provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
investigational drug

New information that may adversely affect subject safety or study conduct 
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
Deviations from or changes to the protocol to eliminate immediate hazards to subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or trial conduct), the amendment and applicable informed 
consent form revisions must be submitted promptly to the IEC/IRB for review and approval 
before implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this clinical study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The consent form must be signed before performance of any 
study-related activity. Results from laboratory tests, medical procedures and imaging or scans
done as part of standard of care that have been performed before the consent form signature date
may be used for the study. The consent form used must be approved by both sponsor and 
reviewing IEC/IRB and be in a language the subject can read and understand. Informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current 
ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the investigational 
staff must explain to potential subjects the aims, methods, reasonably anticipated benefits, and 
potential hazards of the study, and any discomfort participation in the study may entail. Subjects 
will be informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. They will be informed that choosing not to participate will not affect the 
care the subject will receive for her disease. Subjects will be told that alternative treatments are 
available if they refuse to take part and that such refusal will not prejudice future treatment. 
Finally, they will be told that the investigator will maintain a subject identification register for 
purposes of long-term follow-up, if needed, and that their records may be accessed by health 
authorities and authorized sponsor staff without violating the confidentiality of the subject, to the 
extent permitted by applicable laws or regulations. By signing the informed consent form the 
subject is authorizing such access and allows the study physician to re-contact the subject for the 
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purpose of obtaining consent for additional safety evaluations, subsequent disease-related 
treatments, or survival status and any new antitumor therapies.
The subject will be given sufficient time to read the informed consent form and the opportunity 
to ask questions. After this explanation and before entry into the study, consent should be 
appropriately recorded by means of the subject's personally dated signature. After having 
obtained the consent, a copy of the informed consent form must be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the informed consent form after the oral consent of the subject is 
obtained.
When prior consent of the subject is not possible, enrollment procedures should be described in 
the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights, 
safety, and well-being of the subject and to ensure compliance with applicable regulatory 
requirements. The subject must be informed about the study as soon as possible and give consent 
to continue.
In accordance with local regulations, subjects will be required to sign an updated informed 
consent form to continue in the study under Amendment INT-6. Subjects who elect not to 
continue in the study and those in long-term follow up will be discontinued from the study.
Under Amendment INT-7, individual subjects who may continue to derive benefit from the 
treatment they are currently receiving, will be offered the opportunity to continue on their 
existing study medication and followed-up for safety for an additional duration of up to 3 years 
(ie, up to 20 September 2018) from the date previously stated (20 September 2015) in the 
Amendment INT-6. The situation may be reassessed periodically for subjects still receiving 
study medication.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of study subjects confidential.
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The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator to allow direct access to his or her original medical records
(source data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory 
inspection. This consent also addresses the transfer of the data to other entities and to other 
countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Pharmacodynamics, biomarker, and PK research is not conducted under standards appropriate 
for the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment. 
All protocol amendments must be issued by the sponsor, and signed and dated by the 
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or 
when the relevant competent authority has raised any grounds for non-acceptance, except when 
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be 
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of 
amendment approval by the investigator and IEC/IRB must be provided to the sponsor or its 
designee. When the change(s) involves only logistic or administrative aspects of the study, the 
IEC/IRB only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information pages provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the eCRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
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17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
investigational site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed written IEC/IRB approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, subject compensation 
programs. This approval must clearly identify the specific protocol by title and number and 
must be signed by the chairman or authorized designee.

Name and address of the IEC/IRB including a current list of the IEC/IRB members and their 
function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the investigational staff is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the vote/opinion 
of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all clinical subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by assigned number.
The investigator must also complete a subject-screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all adverse events; and follow-up of adverse events; 
concomitant medication; drug receipt/dispensing/return records; study drug administration 
information; and date of study completion, and reason for early discontinuation of study drug or 
withdrawal from the study, if applicable. 
It is recommended that the author of an entry in the source documents be identifiable.
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care. Specific 
details required as source data for the study will be reviewed with the investigator before the 
study and will be described in the monitoring guidelines (or other equivalent document).
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study personnel from the source documents onto an eCRF, and transmitted in a secure manner to 
the sponsor within the timeframe agreed upon between the sponsor and the site. The electronic 
file will be considered to be the eCRF. Worksheets may be used for the capture of some data to 
facilitate completion of the eCRF. Any such worksheets will become part of the subjects’ source 
documentation. All data relating to the study must be recorded in eCRFs prepared by the 
sponsor. Data must be entered into eCRFs in English. Designated site personnel must complete 
eCRFs as soon as possible after a subject visit, and the forms should be available for review at 
the next scheduled monitoring visit.
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Every effort should be made to ensure that all subjective measurements (eg, pain scale 
information or other questionnaires) to be recorded in the eCRF are completed by the same 
individual who made the initial baseline determinations. The investigator must verify that all data 
entries in the eCRFs are accurate and correct.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. The 
investigator or an authorized member of the investigational staff must adjust the eCRF (if 
applicable) and complete the query. 
If corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 3 
different ways:

Site personnel can make corrections in the eDC tool at their own initiative or as a response to 
an auto query (generated by the eDC tool)

Site manager can generate a query for resolution by the investigational staff

Clinical data manager can generate a query for resolution by the investigational staff
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigator 
and associated personnel before the study, and periodic monitoring visits by the sponsor, and 
direct transmission of clinical laboratory data from a central laboratory into the sponsor’s data 
base. Written instructions will be provided for collection, preparation, and shipment of blood, 
plasma, and urine samples. 
Guidelines for eCRF completion will be provided and reviewed with study personnel before the 
start of the study. The sponsor will review eCRFs for accuracy and completeness during on-site 
monitoring visits and after transmission to the sponsor; any discrepancies will be resolved with 
the investigator or designee, as appropriate. After upload of the data into the clinical study
database they will be verified for accuracy.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing
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applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator must permit access to such reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study center visit log that will be kept at the site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known to the sponsor and 
investigational staff and are accessible for verification by the sponsor site contact. If electronic 
records are maintained at the investigational site, the method of verification must be discussed 
with the investigational staff. 
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the eCRF are consistent with the original source data. Findings 
from this review of eCRFs and source documents will be discussed with the investigational staff. 
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last visit of the last subject participating in the study.
The final data from the investigational site will be sent to the sponsor (or designee) after 
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial 
Agreement.
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17.9.2.
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed.
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of an investigational site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the sponsor’s procedures, or GCP 
guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further drug development
17.10.
On-Site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the site at any 
time during or after completion of the study to conduct an audit of the study in compliance with 
regulatory guidelines and company policy. These audits will require access to all study records, 
including source documents, for inspection and comparison with the eCRFs. Subject privacy 
must, however, be respected. The investigator and staff are responsible for being present and 
available for consultation during routinely scheduled site audit visits conducted by the sponsor or 
its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
17.11.
Use of Information and Publication
All information, including but not limited to information regarding abiraterone acetate or the 
sponsor’s operations (eg, patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, formulation information) supplied by the sponsor to the investigator and 
not previously published, and any data, including pharmacogenomic research data, generated as 
a result of this study, are considered confidential and remain the sole property of the sponsor. 
The investigator agrees to maintain this information in confidence and use this information only 
to accomplish this study, and will not use it for other purposes without the sponsor’s prior 
written consent.
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The investigator understands that the information developed in the clinical study will be used by 
the sponsor in connection with the continued development of abiraterone acetate, and thus may 
be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all investigational sites that participated in the study. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Study subject identifiers will not be 
used in publication of pharmacogenomic results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work. 
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such data and information without 
approval from the investigator. If an investigator wishes to publish information from the study, a 
copy of the manuscript must be provided to the sponsor for review at least 60 days before 
submission for publication or presentation. Expedited reviews will be arranged for abstracts, 
poster presentations, or other materials. If requested by the sponsor in writing, the investigator 
will withhold such publication for up to an additional 60 days to allow for filing of a patent 
application. In the event that issues arise regarding scientific integrity or regulatory compliance, 
the sponsor will review these issues with the investigator. The sponsor will not mandate 
modifications to scientific content and does not have the right to suppress information. For
multicenter study designs and substudy approaches, results may need to be published in a given 
sequence (eg, substudies) should not generally be published before the primary endpoints of a 
study have been published. Similarly, investigators will recognize the integrity of a multicenter 
study by not publishing data derived from the individual site until the combined results from the 
completed study have been published in full, within 12 months after conclusion, abandonment, 
or termination of the study at all sites, or the sponsor confirms there will be no multicenter study 
publication. Authorship of publications resulting from this study will be based on the guidelines 
on authorship, such as those described in the Uniform Requirements for Manuscripts Submitted 
to Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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Attachment 1: 
Response Evaluation Criteria in Solid Tumors (RECIST)
Eligibility

RECIST criteria will be used on measurable soft tissue and visceral lesions.
–
Measurable disease is the presence of at least one measurable lesion. If the measurable disease is restricted 
to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
–
Measurable lesions: Visceral or extranodal lesions need to be 10 mm in one dimension using spiral CT; 
however, lymph nodes need to be 20 mm in at least one dimension to be considered as target or evaluable 
lesions to assess changes in size.
–
Non-measurable lesions are all other lesions, including small lesions (longest diameter <20 mm), 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by imaging 
techniques. 

All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 
14 days before the beginning of the treatment; nodal and visceral/extranodal disease will be recorded separately.

The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. 

Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules and palpable 
lymph nodes). For the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
Methods of Measurement

CT and MRI are the best currently available and reproducible methods to measure target lesions selected for 
response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 

Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by
aerated lung. However, CT is preferable. 

Ultrasound, endoscopy and laparoscopy should not be used to measure tumor lesions. 

Cytology and histology can be used to differentiate between Partial Response and Complete Response in rare 
cases (eg, after treatment to differentiate between residual benign lesions and residual malignant lesions).
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Attachment 1: (Continued)
Response Evaluation Criteria in Solid Tumors (RECIST)
Baseline Documentation of TARGET and NON-TARGET Lesions

All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all 
involved organs should be identified as target lesions and recorded and measured at baseline. 

Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repeated measurements (either by imaging techniques or clinically). 

A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. 
The baseline sum LD will be used as reference to characterize the objective tumor.

All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at 
baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up. 
Evaluation of Target Lesions
Complete Response:
Disappearance of all target lesions
Partial Response:
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD
Progressive Disease:
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started 
or the appearance of one or more new lesions
Stable Disease:
Neither sufficient shrinkage to qualify for Partial Response nor 
sufficient increase to qualify for Progressive Disease, taking as 
reference the smallest sum LD since the treatment started
Evaluation of Non-Target Lesions
Complete Response:
Disappearance of all non-target lesions and normalization of tumor 
marker level
Incomplete Response/ 
Stable Disease: 
Persistence of one or more non-target lesion(s) or/and maintenance 
of tumor marker level above the normal limits
Progressive Disease:
Appearance of new lesions and/or unequivocal progression of 
existing non-target lesions a
a Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail. 
Confirmations of PR and CR will be documented by a second CT or MRI at least 4 weeks 
after the initial response.
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
78
Status: Approved Date: 27 April 2015
Attachment 1: (Continued)
Response Evaluation Criteria in Solid Tumors (RECIST)
Evaluation of Best Overall Response
The Best Overall Response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for Progressive Disease the smallest measurements recorded since the 
treatment started). In general, the subject’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
RESPONSE CRITERIA
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
Complete Response
Complete Response
No
Complete Response
Complete Response
Incomplete response/
Stable Disease
No
Partial Response
Partial Response
Non- Progressive Disease
No
Partial Response
Stable Disease
Non- Progressive Disease
No
Stable Disease
Progressive Disease
Any
Yes or No
Progressive Disease
Any
Progressive Disease
Yes or No
Progressive Disease
Any
Any
Yes
Progressive Disease

Subjects with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be classified as having “symptomatic deterioration.” Every 
effort should be made to document the objective progression even after discontinuation of treatment. 

In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation 
of complete response depends on this determination, it is recommended that the residual lesion be investigated 
(fine needle aspirate/biopsy) to confirm the complete response status.
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
79
Status: Approved Date: 27 April 2015
Attachment 2: 
European Organization for Research and Treatment of Cancer Core 30
We are interested in some things about you and your health. Please answer all of the questions yourself by circling 
the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will 
remain strictly confidential.
Please fill in your initials:
Your birth date (Day, Month, Year):
Today's date (Day, Month, Year):
Not 
at All
A 
Little
Quite 
a Bit
Very 
Much
 1. Do you have any trouble doing strenuous activities, like carrying a heavy shopping bag or a suitcase?
1
2
3
4
  2. Do you have any trouble taking a long walk?
1
2
3
4
  3. Do you have any trouble taking a short walk outside of the house?
1
2
3
4
  4. Do you need to stay in bed or a chair during the day?
1
2
3
4
  5. Do you need help with eating, dressing, washing yourself or using the toilet?
1
2
3
4
During the past week:
  6. Were you limited in doing either your work or other daily activities?
1
2
3
4
  7. Were you limited in pursuing your hobbies or other leisure time activities?
1
2
3
4
  8. Were you short of breath?
1
2
3
4
  9. Have you had pain?
1
2
3
4
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things, like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that best applies to you.
29. How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30. How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
80
Status: Approved Date: 27 April 2015
Attachment 3: 
Euro-QoL (EQ-5D-5L)
Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking 

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
81
Status: Approved Date: 27 April 2015
Attachment 3: (Continued) 
Euro-QoL (EQ-5D-5L)

We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the box below. 
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health
you can imagine
The worst health    
you can imagine
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
82
Status: Approved Date: 27 April 2015
Attachment 4: 
Pain Intensity Scale (of Brief Pain Index–Short Form)
Please rate your pain by circling the one number that best describes your pain at its worst in the last 
24 hours.
0
1
2
3
4
5
6
7
8
9
10
No
Pain
Pain as 
bad as 
you can 
imagine
Please rate your pain by circling the one number that best describes your pain at its least in the last 
24 hours.
0
1
2
3
4
5
6
7
8
9
10
No
Pain
Pain as 
bad as 
you can 
imagine
Please rate your pain by circling the one number that best describes your pain on the average.
0
1
2
3
4
5
6
7
8
9
10
No
Pain
Pain as 
bad as 
you can 
imagine
Please rate your pain by circling the one number that tells how much pain you have right now.
0
1
2
3
4
5
6
7
8
9
10
No
Pain
Pain as 
bad as 
you can 
imagine
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
83
Status: Approved Date: 27 April 2015
Attachment 5:
Progressive Disease Notification Fax
FAX       Protocol no.:  212082BCA2001
Progressive Disease Notification Fax
Fax details
To:
Dr. 
*
From:
Include investigator name
Fax no. :
Site no.:
Include investigator site no.
Cc:
Janssen LTM (include name)
Fax no.: 
Include investigator fax no.
Fax: 
Include fax no.
*in case of emergencies please contact 
 (fax no.: Janssen LTM include 
number) or 
(fax no.: Janssen 
LTM include number) if 
cannot 
be contacted
Tel no:
Include investigator tel no.
Instructions
Please complete this form as soon as the patient is documented to have progressive disease and FAX this form to the Sponsor Medical 
Representative and Local Trial Manager mentioned above.
Patient details [please complete]
SUBJECT ID: ___ ___ ___ ___ ___ ___ ___  ___
Date of PD: _____ / _____ / _______
dd
mmm
yyyy
Disease Progression should be confirmed by CT or MRI ideally (option 1 below).  If clinical 
progression is confirmed please tick option 2 below:
1.
Please, indicate the Radiological basis for diagnosis of progressive disease (per RECIST)
Target lesions
At least a 20% increase in the sum of longest diameter of target lesions, taking as reference the smallest sum long diameter recorded 
since the treatment started 
Appearance of any new lesion
Non-target lesions
Unequivocal progression of existing lesion
Appearance of any new lesion
Please note - in bone only disease PD cannot be based on assessment of new sclerotic lesions 
(only lytic lesions can be used)
The sponsor representative will complete and sign the lower part of this form and return it by fax.
Retain this fax as part of the subject’s study records
Version 12OCT2011
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
84
Status: Approved Date: 27 April 2015
Attachment 5: (Continued)
Progressive Disease Notification Fax
FAX       Protocol no.:  212082BCA2001
Progressive Disease Notification Fax
2. Clinical progression
When CT or MRI could not be used and symptoms indicate signs of disease progression 
Please indicate all sites of involvement:
CNS
Bone marrow 
Skin
Pulmonary
GI
Cardiac
Head and neck
Symptomatic deterioration caused by cancer
Other
Investigator Name: ________________________________________
Investigator Signature:
Date:
__________________________________________
____ / ____ / _______
  
  
dd      mmm      yyyy
For Sponsor medical representative use only:
Agree, basis for diagnosis of PD is consistent with protocol criteria
Disagree: Specify: _________________________________________________________________________________
__________________________________________________________________________________________________
Sponsor Medical Representative Signature:
Date:
__________________________________________
____ / ____ / _______
    
dd      mmm      yy
The sponsor representative will complete and sign the lower part of this form and return it by fax.
Retain this fax as part of the subject’s study records
Version 12OCT2011
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
85
Status: Approved Date: 27 April 2015
Attachment 6: 
National Cancer Institute Common Terminology Criteria for Adverse Events
The descriptions and grading scales found in the revised NCI-CTCAE, Version 4.0 (published 28 May 2009) will be 
utilized for adverse event reporting. A copy of the NCI-CTCAE Version 4.0 can be downloaded from the Cancer 
Therapy Evaluation Program web site (http://ctep.cancer.gov).
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
86
Status: Approved Date: 27 April 2015
Attachment 7: 
Laboratory Tests
Local Laboratory Tests
Hematology:

Hemoglobin

Platelet count

White blood cell count:
o absolute neutrophil count
o absolute lymphocyte count
o absolute eosinophil count
Coagulation Factors: 

Prothrombin time (PT)

Partial thromboplastin time (PTT)

International normalized ratio (INR)
Urinalysis dipstick for:

Blood

Protein

Glucose
(Microscopic examination if abnormal)
Clinical Laboratory:

Luteinizing hormone (LH)

Follicle stimulating hormone (FSH)
Serum Chemistry and Electrolytes:

Albumin

Amylase

Blood urea nitrogen

Calcium

Creatinine

Glucose (fasting)

Lactate dehydrogenase

Liver Function Tests:
o
alkaline phosphatase
o
alanine aminotransferase (ALT; SGPT)
o
aspartate aminotransferase (AST; SGOT)
o
total bilirubin
o
direct bilirubin

Lipids (fasting):
o
cholesterol
o
low-density lipoprotein
o
high-density lipoprotein
o
triglycerides

Magnesium

Phosphorus

Potassium

Sodium

Total protein
Central Laboratory Tests

Immunohistochemistry (FFPE for AR, ER, PR, Her2, CYP17, CYP19, Ki-67, 3β-HSD)

Endocrine markers (estradiol, testosterone, estrone)

Pharmacokinetics (PK)

Circulating tumor cells (CTC)

miRNA, gene expression arrays

Pharmacogenomics
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
87
Status: Approved Date: 27 April 2015
Attachment 8: 
Eastern Cooperative Oncology Group
0
Fully active, able to carry on all pre-disease performance without restriction  
(Karnofsky 90-100)
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work on a light or sedentary nature, eg, light housework, office work  
(Karnofsky 70-80)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours  (Karnofsky 50-60)
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours  (Karnofsky 30-40)
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair  (Karnofsky 10-20)
5
Dead
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
88
Status: Approved Date: 27 April 2015
Attachment 9: 
Amendment INT-5 Changes to Randomization and Crossover
Based on the DRC recommendations as described in Section 3.1 of the protocol, the following 
changes are being implemented with Amendment INT-5:

The randomization ratio will now be 1:1 with randomization to the abiraterone acetate plus 
prednisone plus exemestane group or the exemestane only group. There will no longer be 
randomization to the abiraterone acetate plus prednisone group.

No crossover is permitted. Subjects with disease progression must discontinue study drug.

Subjects who were randomized to the abiraterone acetate plus prednisone group before 
implementation of Amendment INT-5 can decide whether or not to continue study drug.  
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
89
Status: Approved Date: 27 April 2015
Attachment 10: 
Modified Schedule of Events for Subjects Continuing to Receive Study Medication Under Amendment 
INT-6 (after the Clinical Cut Off Date for Final Analysis)
The final analysis of Study 212082BCA2001 occurred as planned. The results did not show a 
significant benefit in PFS (the primary endpoint of the study) of adding abiraterone acetate to 
exemestane. Furthermore, there was a slight increase in reported adverse events for the 
abiraterone acetate group and the abiraterone acetate plus exemestane group compared with
exemestane alone. This was most notable for hypokalemia, hypertension, and infections and 
infestations. No drug-related deaths were observed.
However, individual subjects might derive benefit from their current treatment with continued 
control of disease in the absence of significant toxicity. Therefore, the study has been amended 
to allow subjects to continue to receive their current study medication. As well, the number of 
required study-related procedures and amount of data to be collected have been reduced. 
For subjects continuing on study medication, a final study follow-up visit will occur within 
30 days after the last dose of study medication is administered. Subjects who elect not to 
continue on study medication and those currently in long-term follow-up will be discontinued 
from the study. At that time final patient disposition for these subjects will be recorded in the 
eCRF.
The study will be considered completed when the last subject completes the last study visit.
The following outlines instructions for the follow-up of subjects who continue to receive study 
medication under Amendment INT-6.
Study Evaluations to be Performed Under Amendment INT-6
Only serious adverse event information will be collected and drug accountability performed
according to the Schedule of Events below. However, no further data will be collected in the 
eCRF. Assessments not specified in the Schedule of Events are at the discretion of the 
investigator. Investigators should monitor and assess the subjects according to routine practice. 
No further efficacy data are being collected by the sponsor.
Information regarding serious adverse events (as defined in Section 12.3.2) will be transmitted to 
the sponsor using the Serious Adverse Event Form, which must be completed and signed by a 
member of the investigational staff, and transmitted to the sponsor within 24 hours. The initial 
and follow-up reports of a serious adverse event should be made by facsimile (fax). No other 
safety data will be collected by the sponsor. An End-of-Treatment Visit or phone call for a safety 
assessment should take place within 30 days after the last dose of study medication is 
administered.
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
90
Status: Approved Date: 27 April 2015
Attachment 10: (Continued)
Modified Schedule of Events for Subjects Continuing to Receive Study Medication Under Amendment 
INT-6 (after the Clinical Cut Off Date for Final Analysis)
Treatment Phase Under Amendment INT-6
Subjects must sign an updated informed consent form to continue in the study under 
Amendment INT-6. Subjects who elect to remain in the study will continue to receive study
medication. Treatment may continue for up to 2 years from the date of the CCO-FA (ie, up to 
20 September 2015) as long as the subject, in the opinion of the investigator, is receiving benefit 
and not experiencing unacceptable toxicity; or until such time that the subject needs to start other 
anti-cancer treatment, withdraws consent, or at the investigator’s/subject’s decision. At the end 
of the 2-year period, the situation will be reassessed for subjects still receiving study medication. 
During the treatment phase, subjects will continue to receive daily treatment with abiraterone 
acetate plus prednisone/prednisolone and/or exemestane as they were up to the time of this 
amendment and according to the dosing regimens outlined in Section 6 Dosage and 
Administration. Subject’s visits will be registered in the interactive voice response system, and 
the dispensing of study medication and drug accountability will occur every 3 months. Subjects 
will be supplied with 3 months of study drug at each visit. For consistency, the subjects will not 
restart their cycle number. Cycle “X” will be the first cycle under Amendment INT-6.
Efficacy Evaluations to be Performed Under Amendment INT-6
Investigators should monitor and assess the subjects for response to treatment or disease 
progression according to routine practice. No efficacy data will be collected by the sponsor under 
Amendment INT-6.
Safety Evaluations to be Performed Under Amendment INT-6
Safety assessments as outlined in the Schedule of Events provided in this Attachment will be 
performed while continuing treatment and for up to 30 days after the last dose of study 
medication. Only serious adverse events will be collected and reported. Any serious adverse 
event occurring during the study must be reported to the sponsor by investigational staff within 
24 hours of their knowledge of the event. The sponsor will only collect serious adverse event 
data by the serious adverse event reporting process as described above in this attachment. No 
other safety data will be collected by the sponsor.
Study Drug Preparation and Dispensing Instructions
Study drug administration and dosing compliance should be assessed every 3 months. A count of 
all study drug provided by the sponsor will be conducted in the Treatment Phase.
The study site must maintain accurate drug accountability records including dates and amount of 
study drug received, to whom dispensed (subject by subject accounting), and accounts of any 
study drug accidentally or deliberately destroyed. Reconciliation must be made between the 
amount of study drug supplied, dispensed, and subsequently destroyed or returned to sponsor or 
its representative.
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
91
Status: Approved Date: 27 April 2015
Attachment 10: (Continued)
Modified Schedule of Events for Subjects Continuing to Receive Study Medication Under Amendment 
INT-6 (after the Clinical Cut Off Date for Final Analysis)
End-of-Treatment Visit Under Amendment INT-6
This visit can take place as a scheduled visit or a phone call at the discretion of the investigator.
Subject Completion
A subject is considered to have completed the study after discontinuing treatment for any reason 
and having had a follow-up safety assessment within 30 days after the last dose of study 
medication is administered or the subject is lost to follow-up.
Subject Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
•
Lost to follow-up
•
Withdrawal of consent
•
Discontinuation of study treatment
•
Investigator’s decision
A subject's study treatment will be discontinued if:
•
The investigator or sponsor believes (eg, for safety or tolerability reasons such as an adverse 
event) that it is in the best interest of the subject to stop treatment
•
The investigator believes the subject is no longer receiving clinical benefit from continued 
abiraterone acetate and/or exemestane treatment
•
The sponsor terminates the study
Source Documentation
At a minimum, the type and level of detail of source data available for a study subject should be 
consistent with that commonly recorded at the site as a basis for standard medical care.  This 
should also include: subject identification and study identification; study discussion and date
of updated informed consent; dates of visits; serious adverse event information; drug receipt/ 
dispensing/ return records and study drug administration information. (See Section 17.4)
Study Completion
The study is considered completed with the last End-of-Treatment safety assessment for the last 
subject receiving study medication under Amendment INT-6 or upon a decision by the sponsor 
to terminate the study.
Study Termination
The sponsor reserves the right to close the investigational site or terminate the study at any time 
or any reason at the sole discretion of the sponsor.  Investigational sites will be closed
upon study completion. 
An investigational site is considered closed when all required
documents and study supplies have been collected and a site closure visit has been performed.
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
92
Status: Approved Date: 27 April 2015
Attachment 10: (Continued)
Modified Schedule of Events for Subjects Continuing to Receive Study Medication Under Amendment 
INT-6 (after the Clinical Cut Off Date for Final Analysis)
Schedule of Events for Subjects Continuing to Receive Study Medication Under 
Amendment INT-6
Phase 2
Treatment Phase
End of Treatment
Amendment INT-6
Cycle X1
Every Third Cycle 
Until Treatment 
Discontinuation
End-of-Treatment 
Visit
Study 
Procedures2
Informed 
consent3
X
Dispense/ 
administer study 
drug4
X
X
Drug 
accountability
X
X
X
Serious Adverse 
Events5
X
X
X6
1
Cycle X will be the first cycle under Amendment INT-6.
2
Response and safety evaluations (other than serious adverse event reporting) are to be performed at the discretion of the 
investigator according to routine practice.
3
At the time of signing the informed consent for Amendment INT-6, only patient disposition information will be recorded for 
subjects in the eCRF.
4
Subject’s visits will be registered in an interactive voice response system. Subjects will be supplied with 3 months of study 
drug at each visit.
5
Information regarding serious adverse events will be transmitted to the sponsor using the Serious Adverse Event Form, 
which must be completed and signed by a member of the investigational staff, and transmitted to the sponsor within 
24 hours. The initial and follow-up reports of a serious adverse event should be made by facsimile (fax). No other safety 
data will be collected by the sponsor.
6
An End-of-Treatment Visit (or phone call) for a safety assessment should take place within 30 days after the last dose of 
study medication is administered.
NCT01381874


Abiraterone acetate:  Clinical Protocol 212082BCA2001 – Amendment INT-7
93
Status: Approved Date: 27 April 2015
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
LAST PAGE
NCT01381874

SAP_001.pdf: 
1
Statistical Analysis Plan
Randomized, Open-Label Study of Abiraterone Acetate (JNJ-212082) plus Prednisone 
with or without Exemestane in Postmenopausal Women with ER+ Metastatic Breast 
Cancer Progressing after Letrozole or Anastrozole Therapy
Protocol 212082BCA2001; Phase 2
JNJ-212082 (Abiraterone Acetate)
Issue/Report Date:
30-July-2013
Document No.: EDMS-ERI-68198934: 0.1
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP)
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged 
or confidential.
NCT01381874


212082 (Abiraterone Acetate)
Statistical Analysis Plan [Protocol 212082BCA2001]
2
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Trial Objectives ................................................................................................................................ 6
1.1.1
Primary Objective ......................................................................................................................... 6
1.1.2
Secondary Objectives................................................................................................................... 6
1.2.
Study Design.................................................................................................................................... 6
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 7
1.4.
Sample Size Justification ................................................................................................................. 8
1.5.
Randomization and Blinding ............................................................................................................ 8
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 8
2.1.
Population Analyzed ........................................................................................................................ 8
2.1.1.
Intention-to-Treat (ITT) Population ............................................................................................... 8
2.1.2.
Safety Population.......................................................................................................................... 9
2.2.
Baseline Definitions or Conventions ................................................................................................ 9
2.3.
Study Day and Visit Windows .......................................................................................................... 9
2.4.
Missing and Partial Dates .............................................................................................................. 10
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE ............................................................... 10
3.1.
Interim Analysis .......................................................................................................................... 10
3.1.1
Stopping Boundary ..................................................................................................................... 11
3.1.2
Conditional Power....................................................................................................................... 14
3.2.
Data Review Committee............................................................................................................. 14
3.3.
Protocol Amendment and Final Analysis.................................................................................... 14
4.
SUBJECT AND TREATMENT INFORMATION................................................................................ 15
4.1.
Subject Disposition......................................................................................................................... 15
4.2.
Demographics and Baseline Characteristics ................................................................................. 15
4.3.
Prior and Concomitant Medications ............................................................................................... 17
4.4.
Protocol Deviations ........................................................................................................................ 17
4.5.
Treatment Compliance................................................................................................................... 18
4.6.
Extent of Exposure......................................................................................................................... 18
5.
EFFICACY ......................................................................................................................................... 18
5.1.
Analysis Specifications................................................................................................................... 19
5.2.
Primary Efficacy Endpoint.............................................................................................................. 20
5.2.1.
Progression Free Survival (PFS)................................................................................................ 20
5.2.2.
Analysis Methods........................................................................................................................ 20
5.2.3.
Disease Progression and Censoring Rules................................................................................ 21
5.2.4.
Impact of Potential Factors on PFS Analysis ............................................................................. 21
5.2.5.
Subgroup Analysis...................................................................................................................... 22
5.3.
Secondary Endpoints..................................................................................................................... 23
5.3.1.
Overall Survival........................................................................................................................... 23
5.3.1.1.
Definition.................................................................................................................................. 23
5.3.1.2.
Analysis Method ...................................................................................................................... 23
5.3.1.3.
Censoring and Impact of Crossover........................................................................................ 23
5.3.2.
Overall Response Rate............................................................................................................... 24
5.3.2.1.
Definition.................................................................................................................................. 24
5.3.2.2.
Analysis Method ...................................................................................................................... 24
5.3.3.
Duration of Response................................................................................................................. 24
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5.3.4.
Endocrine Markers...................................................................................................................... 24
5.4.
Other Endpoints.......................................................................................................................... 25
6.
SAFETY............................................................................................................................................. 25
6.1.
Clinical Adverse Events.............................................................................................................. 25
6.2.
Clinical Laboratory Tests ............................................................................................................ 27
6.3.
Vital Signs and Physical Examination Findings.......................................................................... 27
6.4.
Electrocardiogram....................................................................................................................... 28
6.5.
Echocardiogram/MUGA (ECHO/MUGA) .................................................................................... 29
7.
PATIENT REPORTED OUTCOMES................................................................................................. 29
7.1.
Primary PRO Analysis Endpoints .................................................................................................. 29
7.1.1.
Time to Progression or Deterioration Analysis........................................................................... 30
7.1.2.
Proportion of Subjects Experiencing Progession or Deterioration Analysis .............................. 30
7.2.
Secondary PRO Analysis Endpoints ..............................................................................................31
7.3.
Compliance with PRO Assessment Form .......................................................................................32
8.
PHARMACOKINETICS ..................................................................................................................... 32
REFERENCES............................................................................................................................................ 33
ATTACHMENTS......................................................................................................................................... 33
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AMENDMENT HISTORY
NA
ABBREVIATIONS
AA
abiraterone acetate
AAP
abiraterone acetate plus prednisone 
AAPE
abiraterone acetate plus prednisone combined with exemestane
AE
adverse event
ALT
alanine aminotransferase (SGPT)
AR
androgen receptor
AST
aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical
BPI-SF
Brief Pain Inventory – Short Form
CBC
complete blood count
CI
confidence interval
CT
computed tomography
CTC
circulating tumor cells
CR
complete response
CRF
case report form
DRC
Data Review Committee
E
exemestane 
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
EMEA
European Medicines Agency
EORTC-C30
European Organization for Research and Treatment of Cancer core quality-of-life questionnaire
EQ-5D-5L
Euro-QoL quality-of-life questionnaire
EQ-VAS
EQ visual analogue scale
ER+
estrogen receptor positive
FDA
Food and Drug Administration
HDL
High density lipoprotein
ICH
International Conference on Harmonisation
INR
international normalized ratio
IPCW
inverse probability of censoring weighted
ITT
intent-to-treat 
IVRS/IWRS
interactive voice/web response system 
LFT
liver function test
LDL
Low density lipoprotein
LVEF
Left Ventricular Ejection Fraction
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition scan
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events, version 4
OS
Overall survival
PFS
progression-free survival
PK
Pharmacokinetics
PR
Partial response
PR+
progesterone receptor positive
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
Qol
Quality of life
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RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SOC
System Organ Class
WHO
World Health Organization
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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of the analysis populations, derived 
variables and statistical methods to be used in the analyses of efficacy and safety for the study 
Protocol 212082BCA2001, titled “Randomized, Open-Label Study of Abiraterone Acetate (JNJ 
212082) plus Prednisone/ Prednisolone with or without Exemestane in Postmenopausal Women 
with ER+ Metastatic Breast Cancer Progressing after Letrozole or Anastrozole Therapy”.
1.1.
Trial Objectives
1.1.1 Primary Objective
The primary objective is to assess the safety and efficacy of abiraterone acetate plus prednisone 
and abiraterone acetate plus prednisone combined with exemestane, each compared with 
exemestane alone, in postmenopausal women with estrogen receptor positive (ER+) metastatic 
breast cancer progressing after letrozole or anastrozole therapy.
1.1.2 Secondary Objectives
Secondary objectives are to assess abiraterone acetate plus prednisone (AAP) and abiraterone 
acetate plus prednisone combined with exemestane (AAPE), each compared with exemestane (E)
alone, in postmenopausal women with ER+ metastatic breast cancer progressing after letrozole 
or anastrozole therapy, with respect to the following:
Overall survival (OS);
Overall response rate;

Patient-reported outcome (PRO) from the following three instruments: European Organization for 
Research and Treatment of Cancer core quality-of-life questionnaire (EORTC-C30), Euro-QoL 
quality-of-life questionnaire (EQ-5D-5L), and Brief Pain Inventory-Short Form (BPI-SF) pain 
intensity scale;
Endocrine markers estradiol, testosterone, estrone, and other biomarkers;
Pharmacokinetics (PK) characterization of abiraterone and exemestane.
1.2.
Study Design
Abiraterone, the active metabolite of abiraterone acetate (AA) (JNJ 212082), is a novel selective 
cytochrome P450 CYP17 enzyme inhibitor being developed for treatment of patients with 
advanced metastatic castration-resistant prostate cancer and breast cancer.
This is a randomized, open-label, parallel-group, multicenter Phase 2 breast cancer study. From 
approximately 65 sites, approximately 300 subjects will be randomized in a 1:1:1 ratio to one of 
the three treatment groups: AAP, AAPE, or E. Subjects are stratified by two factors: number of 
prior therapies in the metastatic setting (0 or 1 versus 2) and setting of prior letrozole or 
anastrozole treatment (adjuvant versus metastatic).
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This study is divided into three phases: Screening, Treatment, and Follow-Up. During Screening, 
potential study subjects are assessed for study eligibility after providing signed informed 
consent. 
The Treatment phase comprises a series of 28-day cycles with continuous study treatment. 
Determination of progression free survival (PFS) will use radiographic progression defined by 
Response Evaluation Criteria in Solid Tumors (RECIST) on measurable lesions captured by 
computed tomography (CT) or magnetic resonance imaging (MRI) at baseline and, using the 
same modality, repeated every 2 cycles initially (Cycle 3, 5, and 7) and every 3 cycles thereafter 
(e.g., Cycle 10 and 13) until, and including, the End-of-Treatment visit. Treatment will continue 
until the earliest of the following events: disease progression, unacceptable toxicity, or death. At 
disease progression, subjects randomized to exemestane alone may be switched to abiraterone 
acetate plus prednisone at the discretion of the investigator; if not switched, these subjects must 
be discontinued from study drug. 
Subjects will enter the Follow-Up phase regardless of reason for study drug discontinuation and 
will be monitored every 3 months until death, loss to follow-up, consent withdrawal, or 
abiraterone acetate development in this indication is discontinued. Survival status and non study 
anti-breast-cancer therapies will be collected by telephone or chart review. Patient-reported 
outcomes also will be completed per protocol. The total study duration is for approximately 
36 months (3 years).  
1.3.
Statistical Hypotheses for Trial Objectives
The primary efficacy endpoint is PFS. For the experimental treatment groups AAP and AAPE,
each is compared with the control group (E) in postmenopausal women with ER+ metastatic 
breast cancer.
For each of the pair-wise comparison, the statistical hypotheses are as follows:
H0: The PFS distributions of experimental treatment group, ST(t), and the control group, SC(t), 
are equal at all time points t:
ST(t) = SC(t), for all t > 0
versus
H1: The PFS distributions are not equal at least one time point t:
ST(t) ≠SC(t), for some t > 0
These hypotheses will be tested using log-rank test and assessed within the context of a group 
sequential testing design as described in Sections 3. Each pair-wise testing will be conducted 
independently, no adjustment to the Type I error will be made.
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1.4.
Sample Size Justification
Recent publication in a similar patient population treated with exemestane (Chia 2008) suggests
that the estimated median PFS for the control exemestane alone group (E) is approximately 
4 months. For sample size calculation, it is assumed that PFS follows an exponential distribution 
with a constant hazard ratio.
Assuming an underlying hazard ratio of any pair-wise comparison (AAP or AAPE, each 
compared with E) is 0.65 (median PFS 6.2 and 4.0 months, respectively), the study has 80% 
power at a significance level of 0.10 (two-sided) to demonstrate a treatment difference with 
approximately 150 PFS events. Assuming an enrollment rate of 20 subjects/month for 
15 months, sample size of approximately 300 subjects (100 subjects/group) is planned for this 
study to achieve 220 PFS events over a study duration of 19 months. 
1.5.
Randomization and Blinding
This is an open-label study. Eligible subjects will be randomized in a 1:1:1 ratio to one of three 
treatment groups: AAP, AAPE, or E. Randomization is stratified based on two factors: number 
of prior therapies in the metastatic setting (0 or 1 versus 2), and setting of prior letrozole or 
anastrozole treatment (adjuvant versus metastatic). Randomization will be implemented by an 
Interactive Voice/Web Response System (IVRS/IWRS).
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Population Analyzed
2.1.1.
Intention-to-Treat (ITT) Population
The intent-to-treat (ITT) population is defined as all subjects randomized into the study and who 
will be classified according to assigned treatment group, regardless of the actual treatment 
received. This population will be used for all efficacy analyses including PFS and overall 
survival (OS), and all analyses of disposition, demographic, and baseline disease characteristics. 
Analysis of select secondary efficacy endpoints will be based on the ITT principle with 
following modifications:

Overall response rate analysis will include all ITT subjects with measurable disease at 
baseline. Subjects with missing post-randomization measures will be considered 
nonresponders. 

Analysis of endocrine markers will include all ITT subjects who have a valid baseline 
and at least 1 post-randomization value.

PK analysis will include all ITT subjects with sufficient and interpretable PK assessments 
to estimate the noncompartmental PK parameters.

Analysis population for PRO endpoints will be detailed in Section 7.
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2.1.2.
Safety Population 
Safety population is defined as all randomized subjects who receive at least one dose of study 
drug. This population will be used for all safety analyses and all analyses of treatment 
compliance and exposure. All subjects will be analyzed according to the treatment which they 
actually received.
2.2.
Baseline Definitions or Conventions
Unless specified otherwise, the baseline value is defined as the last available value collected on 
or prior to the first dose of study drug. 
2.3.
Study Day and Visit Windows
The protocol allows a 2 day window between randomization and first dose. For analyses on 
efficacy endpoints, e.g. time-to-event endpoints and PRO endpoints, the randomization day is 
considered as the Day 1. For analyses on safety, drug exposure and compliance, the first day of 
dosing is considered as Day 1. Subjects’ time on study will be determined in study days. Study 
day is defined as follows:
Study Day = the current date – Day 1 + 1, if the current date ≥date of Day 1; 
Study Day = the current date – Day 1, if current date < date of Day 1.
The study date and corresponding study visit/cycle will be captured on each case report form 
(CRF). Visit windows will be created around the study day of each scheduled visit. It will be 
used to aggregate data, which are to be summarized by visit, e.g. clinical laboratory, vital signs, 
and PRO assessments. The visit windows and the targeted study day are indicated in Table 1. If 
more than one assessment falls within the same visit window, then the assessment that occurred 
first will be used in the analysis. If an assessment is not scheduled for every visit, windows will 
be combined so that the interval between targeted study days is split evenly and consistently 
between visits. Any cycles beyond Cycle 12 will have the windows similarly constructed.
Table 1. Visit Windows
Scheduled Study Day 
Visit Window 
Scheduled Study Day 
Visit Window 
Cycle 1 Day 1* 
1, 7 
Cycle 6 (Day 140) 
127, 154 
Cycle 1 Day 15 
8, 22 
Cycle 7 (Day 168) 
155, 182 
Cycle 2 Day 1 (Day 28) 
23, 35 
Cycle 8 (Day 196) 
183, 210 
Cycle 2 Day 15 (Day 42 ) 
36, 49 
Cycle 9 (Day 224) 
211, 238 
Cycle 3 Day 1 (Day 56) 
50, 63 
Cycle 10 (Day 252) 
239, 266 
Cycle 3 Day 15 (Day 71) 
64, 78 
Cycle 11 (Day 280) 
267, 294 
Cycle 4 (Day 84) 
79, 98 
Cycle 12 (Day 308) 
295, 322 
Cycle 5 (Day 112) 
99, 126 
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* For safety, drug exposure and compliance, Study Day 1 begins on the day of first dose. For efficacy endpoints, Study Day 
1 begins on the day of randomization.  
Each cycle consists of 28 days.
Baseline value is defined as the last available value collected on or prior to the first dose of study drug.
2.4.
Missing and Partial Dates
For missing and incomplete dates during the study, the following imputation rule serves as a 
general guideline for imputation in the assessment of an event:
1. If the date is completely missing or the year is missing, no imputation will be made.
2. Missing Start Day, and only day is missing:

If it has the same month or year as the start of treatment, then Day = day of start of 
treatment.

Otherwise,   Day = 01, e.g. November 1990 is imputed as 01NOV1990.
3. Missing Start Month and Day:  

If it has the same year as the start of treatment, then Month and Day = month and day 
of start of treatment.

Otherwise, Month = 01 and Day=01, e.g. 1990 is imputed as 01JAN1990.
4. Missing Stop Day, and only day is missing:

If it has the same month or year as the end of treatment, then Day = day of end of 
treatment.

Otherwise,   Day = 30 or 31 (or 28 or 29 for February), depending on the month and 
the year, e.g. November 1990 is imputed as 30NOV1990.
5. Missing Stop Month and Day:  

If it has the same year as the end of treatment, then Month and Day = month and day 
of end of treatment.

Otherwise, Month = 12 and Day= 31, e.g. 1990 is imputed as 31DEC1990
3.
INTERIM ANALYSIS AND DATA REVIEW COMMITTEE 
3.1.
Interim Analysis 
One interim analysis is planned. Key efficacy analyses as indicated in Table 4 below will be 
performed together with primary safety analyses. It is scheduled when 50% of the PFS events 
have occurred, or approximately 75 PFS events have occurred in any of the two pair-wise 
comparisons: AAP versus E, and AAPE versus E. This is anticipated to be approximately 110 
PFS events across all the three treatment groups, and projected to be approximately 12 months 
after first subject has been randomized. 
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3.1.1 Stopping Boundary 
The purpose of the interim analysis is to investigate if AAP or AAPE demonstrate efficacy 
improvement over E based on PFS. A significant efficacy finding in PFS at interim analysis will 
allow planning of a Phase 3 confirmatory study. The study may drop one or both experimental 
treatment groups for futility or for superiority.
Gamma-family spending functions (Huang 1990) were used to control the Type I error of 0.05
(one-sided) and Type II error of 0.20 for each comparison. Figure 1 shows the shape of the Type 
I error (alpha) and Type II error (beta) spending functions for the PFS endpoint. 

Alpha spending: a Gamma-family spending function with parameter rho=1 is used to be 
similar to Pocock spending function. Figure 1 shows that it allocates cumulative alpha 
0.031 (62% of total spending) at the interim (50% of information), and cumulative alpha 
0.05 (one-sided) at the final analysis. 

Beta spending: a Gamma-family spending function with parameter rho=-2 is used. Figure 
1 shows it allocates cumulative beta 0.054 (27% of total spending) at the interim (50% of 
information), and cumulative beta 0.20 at the final analysis. 
The stopping boundaries for PFS-based futility and efficacy were calculated using East®
software v5.2. Table 2 summarizes the efficacy and futility monitoring plan for each pair-wise 
comparison. The corresponding estimated hazard ratio for cutoff values are approximates.
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Figure 1. Cumulative Error Spending Function for Alpha and Beta
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Table 2. Stopping Boundaries and Corresponding Minimal
Observed Difference for Each Pair-wise Comparison
Analysis
PFS Events 
(information)
Cumulative Error
Stopping Boundary
Observed Hazard Ratio
Alpha
Beta
Z score
p-value (one-sided)
Efficacy
Futility
Efficacy
Futility
Efficacy
Futility
Efficacy
Futility
Interim
75 (50%)
0.031
0.054
1.865
0.286
<0.031
≥ 0.388
<0.650
≥ 0.936
Final
150 (100%)
0.05
0.20
1.887
1.887
<0.030
≥ 0.030
<0.735
≥ 0.735
Type I error of 0.05 (one-sided), efficacy boundary is based on Gamma family spending function with rho=1, similar to Pocock.
Power of 80%, futility boundary is based on Gamma family spending function with rho=-2
Observed hazard ratio are approximates.
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3.1.2 Conditional Power   
Conditional power is the probability that the study will demonstrate statistical significance at the 
end of the study (i.e. final analysis to claim superiority on PFS), conditioning on the data 
observed in the study thus far, and an assumption about the trend of the data to be observed in 
the remainder of the study. Two assumptions about the trend of the data were presented below:
The futility boundary corresponds to a conditional power of approximately 39% if the original 
hazard ratio assumption is true, while only 4% conditional power will be achieved if the 
observed hazard ratio at interim is true for the remainder of the study.
The efficacy boundary corresponds to a conditional power of approximately 90% if the original 
hazard ratio assumption is true, and 92% conditional power will be achieved if the observed 
hazard ratio at interim is true for the remainder of the study.
The conditional power of stopping boundaries was computed using method of Lan (2009).
3.2.
Data Review Committee
A Data Review Committee (DRC) will be formed to monitor data on a regular basis to ensure the 
safety of the subjects in this study, assess the evidence of benefit or adverse effects of 
abiraterone acetate, and to monitor the overall conduct of the study. The DRC is comprised of 
experts in breast cancer, medical safety, and biostatistical aspects of clinical studies. Details 
regarding DRC responsibilities and activities will be provided in a separate DRC Charter.
In addition to the planned interim analysis, the DRC will meet periodically to review the 
cumulative safety data. The first safety review meeting will be held approximately after the 10th
subject in each treatment group (~30 subjects total) has received study drug for 28 days 
(Cycle 1). The DRC will review unblinded reports for safety, to identify any potential added 
toxicity when abiraterone acetate is combined with exemestane. Subject accrual will continue 
only if no safety concerns arise. The second safety review meeting will be held when baseline 
and at least one post-treatment ECG are available for approximately the first 25 subjects in each 
treatment group (~75 subjects total). The DRC will review unblinded reports for safety and
determine if additional ECGs are needed for these and subsequent subjects.
3.3.
Protocol Amendment and Final Analysis
The DRC reviewed the unblinded efficacy, safety, and biomarker outcomes of the interim 
analysis after the clinical cutoff (110 [50%] of progression or death events) occurred. The 
clinical cutoff date was December 14, 2012. On 08 March 2013, the DRC recommended 
discontinuing the enrollment to the AAP group because the interim analysis criterion for futility 
was met. The study protocol was amended accordingly and the following changes were 
implemented with the new protocol (Amendment INT-5):

The randomization ratio will now be 1:1 with randomization to the AAPE group or the E 
only group. There will no longer be randomization to the AAP group.
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
No crossover is permitted. Subjects with disease progression must discontinue study 
drug.

Subjects who were randomized to the AAP group before implementation of Amendment 
INT-5 can decide whether or not to continue study drug.
The final analysis will be conducted when 150 progression or death events occurred in the AAPE
group and the E alone group. Although the enrollment to AAP group has been discontinued per 
DRC recommendation, the data display will present all the 3 treatment groups. However, the 
statistical inference will be focused on the comparison between the AAPE group and the E only 
group.
4.
SUBJECT AND TREATMENT INFORMATION
All statistical analyses will be performed using SAS®. Analyses of disposition, demographic, 
baseline disease characteristics, and prior and concomitant therapy will be conducted on the ITT 
population. Analyses on treatment compliance and extent of exposure will be conducted on the 
Safety Population. No statistical testing is planned.
Unless otherwise specified, all continuous endpoints will be summarized using descriptive 
statistics, which will include the number of subjects with a valid measurement (n), mean, 
standard deviation (SD), median, minimum, and maximum. All categorical endpoints will be 
summarized using frequencies and percentages. Percentages will be calculated by dividing the 
number of subjects with the characteristic of interest by the number of subjects with non-missing 
value in the analysis population, unless otherwise specified.
4.1.
Subject Disposition
Distribution of subjects by treatment group for each of the analysis population will be provided. 
The number of subjects enrolled, dosed, and discontinued will be summarized. Treatment 
discontinuation will be summarized according to reasons of discontinuation as documented in the 
CRF. 
In addition, study enrollment by country and study site will be summarized for each randomized 
treatment group and for the 3 groups combined. 
4.2.
Demographics and Baseline Characteristics
Subject demographics and baseline disease characteristics as described in Table 3 will be 
summarized using descriptive statistics.
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Table 3.   Demographics and Baseline Characteristics
Variable
Description
Demographics
Continuous Variables:

Age (yr)
Categorical Variables:

Age group (<65, 65 to 69, 70 to 74, ≥ 75)

Sex (Female)

Race 

Ethnicity
(n, mean, SD, median, minimum, and 
maximum)
(n, %)
Baseline Vital Signs
Continuous Variables:

Weight (kg)

Height (cm)

Systolic and Diastolic Blood Pressure (mmHg)

Heart Rate (beats/min)

Respiratory Rate (breaths/min)

Body Temperature (oC)
(n, mean, SD, median, minimum, and 
maximum)
Baseline Disease Characteristics
Continuous Variables:

Time from initial diagnosis to first dose

Time from initial breast cancer diagnosis to diagnosis 
of metastatic disease

Time from diagnosis of metastatic disease to first dose

Time from end of letrozole/anastrazole to first dose

Time from most recent progression to first dose

Time from surgical removal of primary tumor to 
diagnosis of metastatic disease

Time from end of last endocrine therapy to first dose
Categorical Variables

Subject status at initial diagnosis (post-menopausal, 
pre-menopausal)

Sites of metastatic disease (visceral, visceral only , 
lymph nodes, bone, bone only, skin, muscle, bone and 
lymph nodes without visceral, other)

Number of sites of metastatic disease (1,2,3,>=4)

Determination of recent progression (radiological, 
clinical)

ECOG PS Score (0, 1)

PR status (positive, negative)
(n, mean, SD, median, minimum, and 
maximum)
(n, %)
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
ER status (positive, negative)
Baseline LDH (high, normal or low)
Prior Therapies

Type of prior cancer therapy: surgery, radiotherapy, 
hormonal, chemotherapy, other

Subjects with adjuvant prior chemotherapy (Yes/No)

Best response of prior therapy (complete response, 
partial response, stable disease)

Subjects with measurable disease at baseline (Yes/No)
(n, %)
Stratification Factors

Prior therapies in the metastatic setting (0 or 1 versus 
2) 

Prior letrozole or anastrozole treatment (adjuvant 
versus metastatic)
(n, %)
ER=estrogen receptor;  PR=progesterone receptor; ECOG PS=Eastern Cooperative Oncology Group
Performance Status; LDH=lactate dehydrogenase; , 
4.3.
Prior and Concomitant Medications
For summarization purposes, medications will be coded to a generic term based on the World 
Health Organization (WHO) dictionary. Medications administered prior to the first dose of study 
drug will be considered prior medications. Concomitant therapies include those taken on or after 
first dose date through 30 days after the last dose.
Incidence of prior and concomitant medications will be summarized by Anatomical Therapeutic 
Chemical (ATC) class and drug generic term. Summary of subjects’ prior anti-cancer therapy 
including radiotherapy, surgery, hormone therapy, and chemotherapy will each be presented.
4.4.
Protocol Deviations
In general, subjects who do not meet the inclusion/exclusion criteria are not allowed to be 
randomized into the study.  
Protocol deviations will be captured in the CRF and reviewed by a medical monitor. Major 
protocol deviations will be summarized by the following categories:

Subjects entering study although entrance criteria not met;

Subjects developing withdrawal criteria during the study, but who were not withdrawn;

Subjects receiving the wrong treatment or incorrect dose;

Subjects receiving an excluded concomitant treatment;

Abiraterone acetate not taken in the fasted state;

Other major non-compliance.
Individual subjects with protocol deviations will be listed.
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4.5.
Treatment Compliance
Drug compliance is estimated by the percent of number of tablets actually taken during the 
course of study while the subject is on active treatment. Specifically, for subject i
For each drug, the number and percentage of subjects who completed the specified range of 
compliance rate, starting at ≤ 75% compliance to a maximum of 100% in increments of 5% will 
be summarized by treatment as appropriate. 
The period after discontinuation (of study 
medication or from the study itself) will not be considered in the compliance rate calculation. 
The Medication Kit form in the CRF will serve as the source data for drug amount actually 
taken, based on tablet counts.  The Treatment Exposure form of the CRF will serve as the source 
data for drug amount that should be taken. 
4.6.
Extent of Exposure
Treatment duration is defined as number of weeks between the first dose date and last dose date. 
Subjects will be classified into the following categories by the amount of time on study drug: 0
to 3 months, 3 to 6 months, 6-9 months, 9 to 12 months, 12 to 15 months, 15 to 18 months, and
≥ 18 months (the cutoff values are subject to change if warranted to better represent the exposure 
data). The number of subjects in each category will be reported. Number of weeks on study drug
and the number of cycles the subject started treatment will be summarized as well. The 
cumulative distribution of treatment duration by cycle or time will also be summarized and 
presented graphically.
The number and percentage of subjects with dose increases, dose decreases, and dose 
interruption will be summarized. In addition, subjects with dose modifications and reasons for 
dose modifications will be listed.
5.
EFFICACY
Analysis of efficacy endpoints will be conducted on the ITT Population. Table 4 summarizes the 
efficacy endpoints and analysis methods to be performed. The analyses on PROs and PK 
characterization abiraterone acetate and exemestane are detailed in Section 7 and 8, respectively.
100
 taken
be
 to
supposed
 tablets
of
number 
Total
 taken 
 tablets
of
number 
Actual








i
Compliance
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Table 4. Summary of Efficacy Analyses to be Performed
Endpoint
Analysis
Analysis Method
Population
Primary
Progression-Free-Survival 
Primary*
Stratified log rank test, Cox regression model
ITT
Sensitivity
Non-stratified log rank test; Multivariate Cox 
regression model;
Alternate censoring rules
Subgroup*
Non-stratified log rank test, Cox regression model 
within each subgroup
Secondary
Overall Survival
Primary*
Stratified log rank test, Cox regression model
ITT
Sensitivity
Alternate censoring rules
Subgroup 
Non-stratified log rank test, Cox regression model 
within each subgroup
Overall Response Rate*
Chi-square test or Fisher’s Exact test as 
appropriate
ITT  with measurable 
disease at baseline
Duration of Response*
Stratified log rank test, Cox regression model
ITT with CR or PR
Change from baseline in 
endocrine markers
Descriptive summary
ITT with a valid baseline 
and at least 1 post-
randomization value
Exploratory
Clinical Benefit Rate
Chi-square test or Fisher’s Exact test as 
appropriate
ITT  with measurable 
disease at baseline
Subsequent Therapy
Descriptive summary
ITT
ECOG PS Score*
Descriptive summary, shift table
ITT
CR=complete response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; ITT=intent-to-treat; 
PR=partial response
Abiraterone acetate plus prednisone (AAP) or abiraterone acetate plus prednisone plus exemestane (AAPE) will be 
compared with exemestane (E).  Nominal p-values will be presented for these comparisons.
*Performed during interim analysis 
.
5.1.
Analysis Specifications
For each of the pair-wise comparison, the statistical tests of treatment effects on primary 
endpoint of PFS will be conducted independently at the two-sided 0.10 level of significance. No 
multiplicity adjustment to the Type I error will be made. The alpha (Type I error) spending at 
interim and final analyses is specified in Section 3.1.1.
No adjustment for multiplicity testing will be performed for secondary efficacy endpoints. All 
interval estimations will be reported using two-sided 95% confidence intervals.
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5.2.
Primary Efficacy Endpoint
5.2.1.
Progression Free Survival (PFS)
The primary efficacy endpoint, PFS, is defined as the time from randomization to first 
occurrence of disease progression (radiographic or clinical), or death from any cause. 
Radiographic disease progression is defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) on measurable lesions captured by CT or MRI. Clinical disease progression is 
considered only when disease progression cannot be confirmed by CT or MRI, such as when the 
disease site is skin, bone marrow, or central nervous system.
5.2.2.
Analysis Methods
The PFS distribution and median PFS with its 95% confidence interval will be estimated using 
the Kaplan-Meier product-limit method. The stratified log-rank test accounting for number of 
prior therapies in the metastatic setting (0 or 1 versus 2) and setting of prior letrozole or 
anastrozole treatment (adjuvant versus metastatic) will be used as the primary analysis for 
treatment comparison. A stratified Cox proportional hazards model will be used to assess the 
magnitude of treatment effect.  The model will include stratification factors and will provide 
estimates of hazard ratio with 95% confidence intervals. The validity of the proportional hazards 
assumptions will be explored. The following sample SAS code will be used for stratified log-
rank test and Cox regression model in the primary analysis.
PROC LIFETEST DATA=dataset;
   TIME pfstime*censor(0);
   STRATA stratum1 stratum2;
   TEST trt;
RUN;
PROC PHREG DATA=dataset;
    STRATA stratum1 stratum2;
    MODEL pfstime*censor(0)=trt / RL;
RUN;
The non-stratified log-rank test will be conducted as sensitivity analysis. Multivariate Cox 
proportional hazards model including an independent variable for treatment groups and 
covariates for the 2 stratification factors will also be conducted. Estimates of hazard ratio with 
95% confidence intervals for each covariate will be provided. This analysis is used as sensitivity 
analysis and to confirm the prognostic effect of stratification factors on PFS. The following 
sample SAS code will be used for non-stratified log-rank test and multivariate Cox regression 
model in the sensitivity analysis.
PROC LIFETEST DATA=dataset ;
   TIME pfstime*censor(0);
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   TEST trt;
RUN;
PROC PHREG DATA=dataset;
    MODEL pfstime*censor(0)=trt statum1 stratum2/ RL;
RUN;
5.2.3.
Disease Progression and Censoring Rules
The date of progression is the earliest date of documented progressive disease based on 
radiographic assessment, clinical evaluation, and discontinuation due to disease progression. 
Subjects who were discontinued due to progressive disease will be considered to have disease 
progression at the date of last dose of study treatment. Death from any cause at any time will also 
be considered as an event. A listing of tumor assessment will be provided.
The data for subjects who were alive and did not have progression will be censored at the date of 
the last adequate radiologic assessment which has sufficient evidence to correctly indicate that 
progression has or has not occurred. The censoring rules for primary analysis of PFS are
summarized in Table 5.
Table 5. Censoring Rules for Primary PFS Analysis
Situation
Outcome
Date
Progression 
PFS event
Earliest date of documented progression 
Death from any cause at any time 
PFS event
Date of death 
No on-study tumor assessment
Censored 
Date of randomization  
No progression 
Censored 
Date of last adequate radiologic assessment
New anti breast cancer treatment started 
before progression
Censored 
Date of last adequate radiologic assessment before 
subsequent therapy
PFS=progression-free survival
5.2.4.
Impact of Potential Factors on PFS Analysis
Adequacy of Follow-Up
Adequacy of follow-up in each treatment group will be evaluated. The number (%) of subjects 
who have missed two or more follow-up visits will be tabulated by treatment group. An 
imbalance in deaths in such subjects could bias the measurement of PFS, because PFS will be 
artificially prolonged on the group with less adequate follow-up. The number of deaths occurring 
after 2 or more missing follow-up visits will be tabulated by treatment group. 
In case of a large number of subjects having 2 or more missing follow-up visits, a supportive 
PFS analysis may be preformed to include only well-documented radiographic progression 
events and deaths for subjects with scheduled follow-up visits. Specifically, the deaths occurring 
after 2 or more missed follow-up visits will be censored at the last visit when the subjects are still 
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alive. The deaths occurring before the first progressive disease (PD) assessment planned, or 
between adequate assessment visits, or after 1 missed visit will be considered as PFS events.
Missing Tumor Assessments
Number (%) of subjects with missing lesion measurements (target lesion or non-target lesion) 
among the ITT population will be tabulated by cycles for each treatment group. In case of 
substantial missing data (e.g. 30% or more of lesions), the impact of the missing data on the 
analysis of PFS will be explored.  
Assessment Bias
Tumor assessments will be performed by CT or MRI at baseline and repeated every 2 cycles 
initially (Day 1 Cycle 3, Day 1 Cycle 5, and Day 1 Cycle 7), and every 3 cycles thereafter (e.g.
Day 1 Cycle 10, Day 1 Cycle 13) until, and including, the End-of-Treatment visit. Unscheduled 
assessments can occur for many reasons (including tumor-related symptoms, drug toxicity). In 
this open-label study, differences between study groups in the frequency or reason for 
unscheduled assessments are likely to introduce bias. On the other hand, scheduled visits and 
radiological assessments in the study are symmetric across the three groups, systematic bias is 
prevented. To evaluate the effects of bias due to unscheduled assessments, number of subjects 
with disease progression will be tabulated by assessment (scheduled vs. unscheduled) and 
treatment groups.
In case of substantial assessment bias due to missing data and unscheduled visit, it may not be 
appropriate to treat PFS data solely as right censored data. The data for PFS can be better 
presented and analyzed as interval-censored data. A likelihood based score test developed by 
Finkelstein (1986) for interval-censored data may be explored to test the difference between 
treatment groups. 
5.2.5.
Subgroup Analysis
Subgroup analysis is planned for the primary endpoint PFS to investigate whether treatment 
effects are consistent within subgroups. Subgroups are formed based on the following subject
characteristics and baseline variables for those subjects whose data are available:
1. Number of prior therapies in the metastatic setting (0 or 1 versus 2);
2. Setting of prior letrozole or anastrozole treatment (adjuvant versus metastatic);
3. ECOG PS score (0  versus 1 );
4. Number of lines of prior chemotherapy in the metastatic setting (0 versus 1);
5. Age (below median versus above median);
6. Geographic regions (North America, Western Europe, Eastern Europe, others);
7. Sites of metastatic disease (visceral, non-visceral, bone only);
8. PR status (positive vs negative);
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9. Time from initial diagnosis to first dose (< median versus >= median);
10. Time from diagnosis of metastatic disease to first dose (< median versus >= median);
11. Time from surgery of removing primary tumor to diagnosis of metastatic disease (<
median versus >= median)
The non-stratified log rank test and Cox proportional hazard regression model for PFS will be
used for each of the subgroup analysis. Median PFS with 95% confidence interval and hazard 
ratio with 95% confidence interval (CI) will be provided by treatment group within each 
subgroup. Subgroup analysis will be presented graphically in forest plot.  No formal testing for 
treatment-by-subgroup interaction will be performed.
5.3.
Secondary Endpoints
5.3.1.
Overall Survival
5.3.1.1.
Definition 
Overall survival is defined as from date of randomization to date of death from any cause.
5.3.1.2.
Analysis Method 
Overall survival will be analyzed using the same analysis methods as used for PFS. The OS 
distribution and median OS with its 95% confidence interval will be estimated using the Kaplan-
Meier product-limit method. The stratified log-rank test and estimates of hazard ratio with 95% 
confidence intervals from stratified Cox proportional hazards model will be provided.
The same subgroup analysis for PFS may be performed for overall survival if the number of 
events within each subgroup is sufficient to provide a meaningful interpretation.
5.3.1.3.
Censoring and Impact of Crossover 
In this study, at disease progression, subjects randomized to the E group may be switched to 
AAP at the discretion of the investigator.
For primary analysis of OS, survival time of living subjects will be censored on the last date a 
subject is known to be alive or lost to follow-up. In this ITT estimate of OS, subjects are 
categorized by their assigned treatment, and subjects’ survival after crossover from E to AAP is 
credited to the E treatment.
As a sensitivity analysis, data from subjects in the E group who crossover to receive AAP will be 
censored at the date of crossover.
In case of a large amount of treatment crossover and a substantial number of subjects have data 
that are censored, the following analysis may be explored to correct for dependent censoring:

Iterative Parameter Estimate (IPE) method as described by Branson (2001) under an 
accelerated failure time model with the Weibull distribution;

Rank preserving failure time model described by Robins(1991);
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
Weighted log-rank test by the inverse probability of censoring weighted (IPCW) method 
(Robins 2000, Finkelstein 2011).
5.3.2.
Overall Response Rate
5.3.2.1.
Definition 
Overall response rate is defined as the proportion of subjects with measurable disease achieving 
a best overall response of either complete response (CR) or partial response (PR) based on 
RECIST.
5.3.2.2.
Analysis Method 
All randomized subjects who have a valid baseline value will be included in this analysis. 
Subjects with missing post-randomization data are considered non-responders. Overall response 
rate will be summarized using descriptive statistics for categorical data by treatment group. For 
each pair-wise comparison, the relative risk (AAP vs E, or AAPE vs E) will be reported along 
with the associated 95% confidence interval. Statistical inference will be evaluated using Chi-
square statistic, or Fisher’s exact test if the expected counts in some cells are small. The 
following sample SAS code format will be used:
PROC FREQ DATA=dataset;
TABLE trt* response / CHISQ RELRISK;
RUN;
Note: CMH option may be used to replace RELRISK option if any cell in the 2 by 2 
table has zero count to get the relative risk.
5.3.3.
Duration of Response 
This analysis will include all randomized subjects with a CR or PR. Duration of Response is 
measured from the first time that the CR or PR is achieved to the first observation of disease 
progression based on the RECIST criteria.  The same analysis methods used for PFS will be used 
for duration of response.
5.3.4.
Endocrine Markers
Change from baseline in serum endocrine biomarkers (progesterone, estradiol, testosterone, and 
estrone) will be summarized by treatment at each scheduled post-baseline assessment visit. The 
analysis will include all ITT subjects who have a valid baseline and at least 1 post-randomization 
value. Correlation of biomarker levels with clinical response to abiraterone acetate may be 
explored.
Circulating tumor cells (CTC) and other tumor biopsy biomarkers are optional data collected at 
some of the investigational sites. Exploratory analysis may be performed separately if there is 
sufficient data. 
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Except for the descriptive summary, all the exploratory biomarker analysis will be performed by 
the J&J Biomarkers Oncology Function and will be reported separately.
5.4.
Other Endpoints
Clinical benefit rate is defined as the proportion of subjects with measurable disease achieving a 
best overall response of a complete response (CR), partial response (PR), or stable disease (SD) 
based on RECIST. The same analysis methods used for overall response rate will be used for 
clinical benefit rate.
Number of subjects receiving subsequent anti-cancer therapy will be summarized by therapy 
type. Listing of subjects with subsequent anti-cancer therapy will also be provided.
Mean values in ECOG values will be summarized by descriptive statistics at each scheduled 
visit. Minimum and maximum shifts in ECOG performance status score during the study will
also be presented.
6.
SAFETY
Analysis of safety data will be conducted on the Safety Population, which includes subjects 
randomized who receive any study medication. The safety variables to be analyzed include 
adverse events (AEs), electrocardiograms (ECGs), multiple uptake gated acquisition scan 
(MUGA)/echocardiogram (ECHO), routine hematology such as the complete blood count (CBC) 
with differential and platelet count, coagulation factors, serum chemistry panel, serum lipids, 
vital sign measurements, and deaths. Safety variables are to be tabulated by descriptive statistics
(n, mean, median, standard deviation, minimum, and maximum; or n and percent). No formal 
statistical testing is planned.
6.1.
Clinical Adverse Events
Adverse events are coded to System Organ Class (SOC) and preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA)coding system, version 13.1 or greater.  For 
summary purposes, AEs refer to treatment emergent AEs, which is defined as all reported 
adverse events with a start date between first dose date and 30 days after last dose date.
The severity of AEs will be graded on a scale of 1 to 5 according to the adult NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE version 4.0) where higher grades 
indicate events of higher severity.  Adverse events will be summarized by grade 1-4 according to 
the worst grade experienced. Grade 5 AEs (deaths) will be summarized separately.
All AEs will have their relationship to study drug recorded as not related, doubtful, possible, 
probable, or very likely on eCRF.  Adverse events will be categorized and summarized according 
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to their highest relationship to study drug.  Adverse events reported as possible, probable, or very 
likely will be classified as drug-related AEs.
Table 7 describes the summaries of AEs that will be provided as incidence tables (number of 
subjects experiencing an event). A summary of reasons for discontinuation will be provided 
summarizing the number and percentage of subjects for each reason indicated. Listings of 
premature discontinuations due to AEs, SAEs, and deaths will be provided. Listings of SAEs and 
deaths will also be provided.   
Table 7.  Summary of Adverse Events 
Summary
Sorted By
AEs
SOC, PT
SOC, PT, toxicity grade (1 to 4)
Drug-related AEs
SOC, PT
SAE 
SOC, PT
SOC, PT, toxicity grade (1 to 4)
Drug-related SAE
SOC, PT
Grade 3 or 4 AEs
SOC, PT
Drug-related Grade 3 or 4 AEs
SOC, PT
Most common AEs (≥ 5%a of the subjects
in any of the 3 treatment groups) 
SOC, PT
AE leading to death
SOC, PT
AEs leading to dose modification or 
interruption for abiraterone acetate
SOC, PT
AEs leading to dose modification or 
interruption for prednisone/prednisolone
SOC, PT
AEs leading to dose modification or 
interruption for exemestane
SOC, PT
AEs leading to hospitalization
SOC, PT
AEs leading to treatment discontinuation
SOC, PT
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AEs of special interest (Selected AEs 
including osteoporosis and osteoporosis-
related fractures, cataract formation, 
hypokalemia, hypertension, fluid 
retention/edema, hepatotoxity, anemia, 
and cardiac Disorders)
PT, severity grade (1 to 4)
Deaths during treatment or within 30 days 
of last dose
Reason for death
a the 5% cutoff is subject to change if warranted to better represent the safety data
AE=adverse event; SAE=serious adverse event; PT=preferred term; SOC = System organ 
class
6.2.
Clinical Laboratory Tests
Laboratory tests will be summarized by hematologic, non-hematologic, and urinalysis, 
separately. 
Selected hematologic laboratory parameters include: hemoglobin, platelet count, white blood cell
count (neutrophil, lymphocyte, eosinophil), and coagulation factors (PT, PTT, INR).
Selected non-hematologic lab parameters include: albumin, amylase, blood urea nitrogen, 
calcium, creatinine, glucose (fasting), lactate dehydrogenase, liver function tests (alkaline 
phosphatase, AST, ALT, bilirubin), lipids (cholesterol, LDL, HDL, triglycerides), magnesium, 
phosphorus, potassium, sodium, and total protein.  
Descriptive statistics will be provided for the values of selected clinical laboratory tests at each 
scheduled on-treatment evaluation including the final value (defined as the last observation 
obtained in the treatment phase) by treatment group. Changes from baseline to each scheduled 
on-treatment evaluation and to the final value will also be summarized. 
A summary of the shifts in selected laboratory hematology and serum chemistry parameters from 
baseline to the worst toxicity grade during the study will be provided.
6.3.
Vital Signs and Physical Examination Findings
Vital sign measurements collected will include blood pressure, heart rate, respirations, weight 
and body temperature.  Mean values and change from baseline in vital signs will be summarized
by descriptive statistics at each scheduled visit. The course of blood pressure over time will be 
presented graphically. 
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Incidence of abnormalities in vital signs, as categorized in Table 8, will be summarized for safety 
population who had a baseline assessment and at least one post-baseline assessment for that vital 
sign.
Table 8.  Vital signs abnormality categories
Vital sign
Criteria
Temperature
>38 oC and with >=1 oC increase from baseline 
Pulse
>120 bpm and with >30 bpm increase from baseline
<50 bpm and with >20 bpm decrease from baseline
Systolic blood pressure
>180 mmHg and with >40 mmHg increase from baseline
<90 mmHg and with >30 mmHg decrease from baseline
Diastolic blood pressure
>105 mmHg and with >30 mmHg increase from baseline
<50 mmHg and with >20 mmHg decrease from baseline
Respiratory rate
<8 breaths/min and >25% decrease from baseline
>22 breaths/min and >50% increase from baseline
>100% increase from baseline
>100% decrease from baseline
No quantitative post baseline physical examination data are collected in this study. A listing by 
subject for abnormal physical examination data will be presented with subject ID, treatment, 
time point, body system, and verbatim examination findings.
6.4.
Electrocardiogram
Selected ECG variables include but may not be limited to QTc, PR interval, and QRS. 
Descriptive statistics will be presented at each scheduled evaluation. A shift table will be 
generated to indicate the number of subjects who shift categories (normal, clinically non-
significant abnormal, and clinically significant abnormal) from baseline to post-baseline. 
Subjects will be classified into the following categories by the maximum change from baseline 
of QTc interval: ≤ 30 msec, 30 to 60 msec, and > 60 msec. Subjects will also be classified into 
the categories by the maximum absolute values of QTc interval:  ≤  450 msec  , 450 to 480 msec, 
480-500 msec, and > 500 msec. The number and percentage of subjects in each category will be 
summarized by treatment groups. Subjects whose QTc increases > 60 msec, or who have QTc > 
500 msec on study will be listed. For all tables and summaries on QTc, both the Fredericia and 
Bazett corrections will be reported.
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6.5.
Echocardiogram/MUGA (ECHO/MUGA)
Left Ventricular Ejection Fraction (LVEF) will be measured at screening and the End-of 
Treatment visit. Mean values and change from baseline will be descriptively summarized. A 
summary table will be generated to indicate the number of subjects in following categories: no
change, improved from baseline evaluation, and worsening from baseline evaluation. Number of 
subjects with absolute decrease from baseline ≥15% and number of subjects with LVEF<50% at 
the end of treatment will be summarized by treatment group.
7.
PATIENT REPORTED OUTCOMES 
The following three PRO instruments that assess subject-perceived disease burden, including 
pain will be collected throughout the study and analyzed at the end of the study. 
EORTC-QLQ C30 is a 30-item questionnaire and incorporates a global health status / QoL scale, 
5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, 
pain, nausea and vomiting), and 6 single items assessing additional symptoms and perceived 
financial impact of the disease. Scores will be derived using validated scoring algorithms 
according to EORTC QLQ-C30 Scoring Manual.  
Pain intensity domain of BPI-SF consists of 4 items that report the severity dimension of pain 
over time: pain at its ‘worst’, ‘least’, ‘average’, and ‘now’ (current pain).  Each item is assessed 
in a 0–10 numerical rating scale where 0 is no pain and 10 is pain as bad as you can imagine.
EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ-
VAS).  EQ-5D descriptive system assesses 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression). Each dimension is measured on a 5-point ordinal scale 
ranging between 1 (no limitation) and 5 (greatest limitation) where a higher score corresponds to 
a worse health state. The EQ-VAS records the respondent’s self-rated health on a 100 mm VAS 
where 0 is ‘worst imaginable health state’, and 100 is ‘best imaginable health state’. The higher 
scores in VAS reflect a ‘better’ health state. 
PROs will be collected before any other visit procedure within 2 days before randomization (Day 
1 Cycle 1, defined to be baseline), repeated every cycle thereafter (e.g., Day 1 Cycle 2, Day 1 
Cycle 3), End of Treatment, and every 3 months during Follow-Up.
The PRO data from all the visits including follow-up and cross-over visits will be included for 
analyses.
7.1.
Primary PRO Analysis Endpoints
The PRO measures for primary analysis are listed below:
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
BPI-SF: ‘Worst’ Pain Intensity 

EORTC:  global health status/QoL scale; scales of physical, role, emotional, cognitive, 
and social
For each of the PRO scales, descriptive statistics (number of observations, mean, standard 
deviation, median, minimum, maximum) of scores at baseline and post-baseline assessments will 
be reported by treatment groups. The following three analyses will be conducted for each of the 
PRO scales.
7.1.1.
Time to Progression or Deterioration Analysis
Using a pre-defined definition (see Table 9 below) for progression or deterioration specific to 
each PRO scale, time to progression or deterioration will be compared between treatment groups.
Distributions of time-to-event variables will be estimated using the Kaplan-Meier product-limit 
method. Median times to event with two-sided 95% confidence intervals will be estimated. 
The stratified log-rank test accounting for number of prior therapies in the metastatic setting (0 
or 1 versus 2) and setting of prior letrozole or anastrozole treatment (adjuvant versus metastatic) 
will be used for treatment comparison. A stratified Cox proportional-hazards model will provide 
estimates of hazard ratios with 95% confidence intervals.
7.1.2.
Proportion of Subjects Experiencing Progression or Deterioration 
Analysis
Using the same threshold value to each PRO scale, the proportion of subjects experiencing 
progression or deterioration will be compared between treatment groups, using Chi-square test or 
Fisher’s exact test if appropriate.  Table 9 summarizes the definition of primary PRO endpoints
and analysis methods to be used.
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Table 9. Summary of Selected PRO Endpoints of Interest and Analysis Methods
PRO Endpoints
Definition
Analysis Method
Population
Time to pain progression
The time interval from randomization to the first date 
a subject experiences pain progression. Two 
definitions will be used separately: 
(1) the ‘worst’ pain intensity in the last 24 hours  
increased by ≥30% from baseline at 2 consecutive 
evaluations ≥4 weeks apart; 
(2): an increase from baseline of ≥2 points (in 11-
point scale) in the BPI-SF worst pain intensity score 
in the last 24 hours observed at 2 consecutive visits 
≥4 weeks apart.
Subjects who have not experienced pain progression 
at the time of analysis will be censored on the last 
known date a subject was known to have not 
progressed.  Subjects with no on-study assessment or 
no baseline assessment will be censored at date of 
randomization.
Stratified log 
rank test, Cox 
regression model
ITT
Proportion of subjects with 
pain progression
Proportion of subjects experiencing pain progression.
Subjects with no post-baseline will be included in the 
denominator for the proportion calculation.
Chi-square test, 
or Fisher’s exact 
test if appropriate
ITT 
subjects 
with a 
baseline 
value  
Time to EORTC Deterioration 
(global QoL, physical, role, 
emotional, cognitive, and 
social)
The time interval from randomization to the first date 
a subject experiences a deterioration, defined as 
change from baseline ≤-5 (decreased at least 5) in 
EORTC scale (in a 0-100 scale).
Subjects who have not experienced EORTC 
deterioration at the time of analysis will be censored 
on the last known date a subject was known to have 
not deteriorated.  Subjects with no on-study 
assessment or no baseline assessment will be 
censored at date of randomization.
Stratified log 
rank test, Cox 
regression model
ITT 
Proportion of subjects with 
EORTC Deterioration (global 
QoL, physical, role, 
emotional, cognitive, and 
social)
Proportion of subjects experiencing a deterioration.
Chi-square test, 
or Fisher’s exact 
test if appropriate
ITT 
subjects 
with a 
baseline 
value 
7.2.
Secondary PRO Analyses Endpoints 
For all the other PRO measures in the three instruments (EORTC-QLQ C30, BPI-SF, and EQ-
5D-5L), descriptive statistics (number of observations, mean, standard deviation, median, 
minimum, maximum) of scores at baseline and post-baseline assessments will be reported by 
treatment groups.

Score values in EORTC-QLQ C30
o
3 symptom scales: fatigue, nausea and vomiting, pain
NCT01381874


212082 (Abiraterone Acetate)
Statistical Analysis Plan [Protocol 212082BCA2001]
32
o
6 single items: dyspnea, insomnia, appetite loss, constipation, diarrhea, 
financial difficulties

Score values in BPI-SF: 
o
Least pain
o
Average
o
Current pain

Score values in EQ-5D-5L:
o
5 
dimensions: 
mobility, 
self-care, usual activities, pain/discomfort, 
anxiety/depression
o
EQ-VAS
7.3.
Compliance with PRO Assessment Form
Compliance with PRO assessment form will be evaluated by summarizing the numbers of 
expected, received, and missing forms. Missing PRO assessments defined as the expected 
number of assessments for a particular visit minus the actual number of assessments for that visit 
may be tabulated by treatment group and overall for each visit (baseline and post-baseline 
including end of treatment visit). Expected number of assessments per visit will be determined 
by the number of expected subjects and forms to be completed in each group at each visit.
Separate tables may be constructed for each instrument. 
8.
PHARMACOKINETICS (PK) Analyses
At selected study sites, twenty (20) subjects/treatment group will participate in PK assessments. 
The PK population will include all subjects with sufficient and interpretable PK assessments to 
estimate the noncompartmental PK parameters. 
The plasma abiraterone and exemestane concentrations of at each time point will be summarized 
by descriptive statistics by treatment group. PK parameters to be estimated for abiraterone and 
exemestane include Cmax, tmax, AUClast, tlast, and AUC24h, and will be descriptively summarized
by treatment group. Individual and mean plasma concentration-time profiles of abiraterone and 
exemestane will be plotted by treatment group. All subjects and samples excluded from analysis 
will be clearly documented in the study report. Further exploratory PK analyses may be 
performed, as deemed appropriate.
The PK analyses will be performed by J&J Clinical Pharmacology Function.
NCT01381874


212082 (Abiraterone Acetate)
Statistical Analysis Plan [Protocol 212082BCA2001]
33
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ATTACHMENTS
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NCT01381874