Conditions: Metastatic Prostate Cancer
Keywords: Metastatic Castrate-Resistant Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1101
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of ipatasertib plus abiraterone and prednisone/prednisolone compared with placebo plus abiraterone and prednisone/prednisolone in participants with metastatic castrate-resistant prostate cancer (mCRPC).

Detailed description:

Arms:
arm 1: Participants received Placebo plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles. arm 2: Participants received Ipatasertib plus Abiraterone (along with Prednisone/Prednisolone), administered orally in 28-day cycles.

Interventions: intervention 1: Ipatasertib intervention 2: Abiraterone intervention 3: Placebo intervention 4: Prednisone/Prednisolone
Intervention descriptions: intervention 1: Oral tablets, 400 mg, given once daily (QD) beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity. intervention 2: Oral tablets of abiraterone, 1000 mg QD, taken on an empty stomach and swallowed whole with water. intervention 3: Oral tablets (matched to ipatasertib appearance), given QD beginning on Day 1 of Cycle 1 until disease progression or intolerable toxicity. intervention 4: Oral tablets of 5 mg, taken twice daily (BID) until disease progression or intolerable toxicity.

Protocol document:
Prot_002.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Trial Testing Ipatasertib Plus Abiraterone Plus 
Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone Plus 
Prednisone/Prednisolone in Adult Male Patients With Asymptomatic 
or Mildly Symptomatic, Previously Untreated, Metastatic Castrate-
Resistant Prostate Cancer 
NCT Number: 
NCT03072238 
Document Date: 
Protocol Version 8: 15-Nov-2022  
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from persons 
to whom the drug may be administered. 
Ipatasertib—F. Hoffmann-La Roche Ltd 
Protocol CO39303, Version 8 
PROTOCOL 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER TRIAL TESTING 
IPATASERTIB PLUS ABIRATERONE PLUS 
PREDNISONE/PREDNISOLONE, RELATIVE TO PLACEBO 
PLUS ABIRATERONE PLUS PREDNISONE/PREDNISOLONE 
IN ADULT MALE PATIENTS WITH ASYMPTOMATIC OR 
MILDLY SYMPTOMATIC, PREVIOUSLY UNTREATED, 
METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 
PROTOCOL NUMBER: 
CO39303 
VERSION NUMBER: 
8  
TEST COMPOUND: 
Ipatasertib (RO5532961) 
STUDY PHASE:
III 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
IND Number:  130663
EudraCT Number:  2016-004429-17 
EU Trial Number:  To be determined 
NCT Number:  NCT03072238
SPONSOR’S NAME
AND LEGAL 
REGISTERED 
ADDRESS:
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124 
4070 Basel, Switzerland
APPROVAL: 
See electronic signature and date stamp on the final page 
of this document. 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
2/Protocol CO39303, Version 8 
VHP Protocol  
Associated Global Protocol 
Version 
Date Final 
Version 
Date Final 
8  
See electronic date stamp 
on the final page of this 
document. 
 
 
7 (VHP) 
24 December 2020 
7 
23 December 2020 
6 (VHP) 
30 April 2019 
6 
13 February 2019 
5 (VHP) 
14 August 2018 
5 
19 October2018 
 
 
4 
1 June 2018 
 
 
3 
7 March 2018 
 
 
2 
9 November 2017 
 
 
1 
21 December 2016 
 
 
 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
3/Protocol CO39303, Version 8 
PROTOCOL AMENDMENT, VERSION 8: RATIONALE 
The intent of this amendment is to simplify the protocol assessments after the final 
overall survival (OS) analysis, which is the last efficacy analysis planned for the study.  
The primary goals of the amendment have been to reduce the number of study visits 
and limit assessments in support of efficacy analyses after the final OS analysis. 
With the Clinical Trials Regulation (CTR) entering into application on 31 January 2022 
and the retirement of the Voluntary Harmonization Procedure (VHP) in European 
countries, the Sponsor has decided to consolidate the former CO39303 VHP and 
CO39303 non‑VHP protocol versions into one protocol with this protocol amendment.  
The countries which have been following the VHP protocol are Austria, Belgium, 
Denmark, Hungary, Ireland, Italy, Norway, Poland, Portugal, Spain, and the United 
Kingdom.  All other countries have been following the non-VHP protocol.  
The VHP protocol is different from the non‑VHP protocol in its requirement for daily 
glucose self-monitoring at home.  Mandatory self-monitoring of glucose was 
implemented with Protocol Version 5 VHP dated 14 August 2018 in response to a health 
authority requirement issued via VHP to implement minimum once daily post-prandial 
home glucose monitoring for the entire duration of study treatment to monitor the risk of 
hyperglycemia. 
In addition, safety requirements for hyperglycemia Grade 1 are different between the 
two protocol versions.  Home glucose monitoring is already performed daily for patients 
from VHP countries whereas, for patients from non-VHP countries, home glucose 
monitoring should only be considered.  For hyperglycemia Grade 2 and above, home 
glucose monitoring is mandatory for all patients.  The differences between the 
two protocol versions are highlighted in Sections 4.5.7 and 5.1.1.2 as well as in 
Appendix 1.  Of note, the differential requirements regarding glucose monitoring were 
already described in previous VHP and non-VHP protocol versions, and there were 
no changes introduced related to this aspect as part of this amendment.  Therefore, 
the countries should continue with country‑specific requirements for home glucose 
monitoring without introducing any changes. 
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
Personal identifiable information (i.e., name and telephone number) for the 
Medical Monitors has been removed from the protocol (front matter and 
Section 5.4.1).  Medical Monitor contact information has been replaced with a 
sentence indicating that this information will be provided separately to sites. 
 
The synopsis has been simplified to align with CTR, TransCelerate, and the Clinical 
electronic Structured Harmonised Protocol (CeSHarP) M11s. 
 
Updates to indicate that after the final OS analysis, study visits will be performed 
every 3 months instead of monthly for patients who are still on ipatasertib treatment.  
Only safety data will be collected at study visits.  Tumor assessments will continue 
to be performed as per local practice and at the investigator’s discretion, but these 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
4/Protocol CO39303, Version 8 
data will not be collected.  Patients who have already discontinued from study 
treatment and patients who are in the placebo arm and are receiving abiraterone 
only will no longer be followed after the final OS analysis, and no data will be 
collected from these patients (Sections 3.1, 4.5.6, and Appendix 1). 
 
Updates to indicate that, after the final OS analysis, the following assessments are 
no longer required were made (Sections 3.1, 4.5.6, 4.5.7, 4.5.10, 4.5.11, 
Appendix 1, and Appendix 2): 
– 
All patient-reported outcome (PRO) assessments 
– 
Consumption of analgesics information (including opioids) 
– 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
– 
Symptomatic skeletal event 
– 
Optional blood for RBR (for DNA extraction) 
– 
Plasma samples for somatic tumor mutations and exploratory biomarkers 
analysis 
– 
Subsequent line of prostate cancer therapy and outcome 
– 
Disease Follow up and Post-Treatment Follow up visits for patients who have 
discontinued from study treatment 
– 
Study visits for patients who are in the placebo arm and are still receiving 
abiraterone after the final OS analysis 
– 
Serum testosterone and PSA samples for the central laboratory should no 
longer be collected since no additional analysis will be performed after this 
analysis 
 
A section describing duration of participation has been added to align with CTR 
requirements (Section 3.2.1) 
 
The responsibilities of the investigator and the role of the Medical Monitor in 
determining patient eligibility and during study conduct have been clarified 
(Sections 4.1.1, 4.3.2.1, 4.4.2, 4.5.7, Appendix 1). 
 
Clarified that after the final OS analysis, investigators and patients will be unblinded 
about the treatment that the patient has been receiving in the study because 
efficacy analysis will be completed and blinding will no longer be required 
(Section 4.2) 
 
Clarified that after the patients’ unblinding, the patients who are on placebo and 
abiraterone will continue receiving abiraterone only.  These patients will no longer 
be required to attend study visits.  The only patients that will continue to be followed 
via regular 3-mothly study visits are those that are receiving ipatasertib 
(Section 4.3.1.1) 
 
Update to indicate that after the patients’ unblinding, home glucose monitoring will 
be performed in countries with mandatory self‑monitoring of glucose only for 
patients who are receiving ipatasertib (Section 4.5.7, Appendix 1) 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
5/Protocol CO39303, Version 8 
 
Clarified that the post-trial access to ipatasertib may be provided through the 
extension study or post-trial access program for patients who are still receiving 
ipatasertib after the final OS analysis (Section 4.3.5). 
 
The email address for withdrawal from the Research Biosample Repository after site 
closure has been corrected (Section 4.5.12). 
 
Update to reflect guidelines provided to VHP and non‑VHP countries regarding 
home-glucose monitoring in case of hyperglycemia (Section 5.1.1.2). 
 
A description of the technical and organizational security measures taken to protect 
personal data has been added to align with CTR requirements (Section 8.4). 
 
Due to certain local requirements and an alignment of Sponsor process, it has been 
clarified that summaries of clinical study results may be available in health authority 
databases for public access in addition to redacted Clinical Study Reports 
(Section 9.6). 
 
A comprehensive list of investigational medicinal products and auxiliary medicinal 
products (non-investigational medicinal product) has been added to align with 
CTR requirements (Section 4.3 and Appendix 14). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 15 
PROTOCOL SYNOPSIS .................................................................................... 16 
1. 
BACKGROUND .......................................................................................... 22 
1.1 
Background on Metastatic Castrate-Resistant 
Prostate Cancer ..................................................................... 22 
1.2 
Background on Ipatasertib ..................................................... 23 
1.3 
Study Rationale and Benefit−Risk Assessment ..................... 23 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 25 
3. 
STUDY DESIGN ......................................................................................... 27 
3.1 
Description of the Study......................................................... 27 
3.2 
End of Study and Length of Study ......................................... 33 
3.2.1 
Duration of Participation ........................................................ 33 
3.3 
Rationale for Study Design .................................................... 33 
3.3.1 
Dose Rationale for the Combination ...................................... 33 
3.3.2 
Rationale for Patient Population ............................................ 33 
3.3.3 
Rationale for Control Group ................................................... 34 
3.3.4 
Rationale for Double-Blind Design ......................................... 34 
3.3.5 
Rationale for China Extension Cohort ................................... 34 
3.3.6 
Rationale for Pharmacokinetic Sampling and 
Schedule ................................................................................ 34 
3.3.7 
Rationale for Patient-Reported Outcomes 
Assessments ......................................................................... 35 
3.3.8 
Tissue and Blood-Based Biomarker 
Assessments ......................................................................... 35 
3.3.8.1 
PTEN Expression Analysis by IHC ........................................ 36 
3.3.8.2 
RNA and DNA Sequencing Analysis ..................................... 36 
3.3.8.3 
Plasma Sample for Somatic Tumor Mutation 
Analysis ................................................................................. 36 
3.3.8.4 
Blood Sample for the Detection of Plasma 
Protein Biomarkers ................................................................ 36 
3.3.8.5 
Blood Sample for Next-Generation Sequencing .................... 37 
4. 
MATERIALS AND METHODS .................................................................... 37 


 
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4.1 
Patients .................................................................................. 37 
4.1.1 
Inclusion Criteria .................................................................... 37 
4.1.1.1 
General Inclusion Criteria ...................................................... 37 
4.1.1.2 
Disease-Specific Inclusion Criteria ........................................ 38 
4.1.2 
Exclusion Criteria ................................................................... 39 
4.1.2.1 
General Exclusion Criteria ..................................................... 39 
4.1.2.2 
Disease-Specific Exclusion Criteria ....................................... 40 
4.1.2.3 
Abiraterone-Specific Exclusion Criteria.................................. 42 
4.1.2.4 
Ipatasertib-Specific Exclusion Criteria ................................... 42 
4.2 
Method of Treatment Assignment and Blinding ..................... 42 
4.3 
Study Treatment .................................................................... 43 
4.3.1 
Formulation, Packaging, and Handling .................................. 43 
4.3.1.1 
Ipatasertib and Placebo ......................................................... 43 
4.3.1.2 
Abiraterone Acetate ............................................................... 43 
4.3.1.3 
Prednisone/Prednisolone ....................................................... 43 
4.3.2 
Dosage, Administration, and Compliance .............................. 44 
4.3.2.1 
Ipatasertib, Placebo, and Abiraterone Acetate ...................... 44 
4.3.3 
Dosage Modifications ............................................................ 45 
4.3.3.1 
Ipatasertib/Placebo ................................................................ 45 
4.3.3.2 
Abiraterone ............................................................................ 46 
4.3.3.3 
Prednisone/Prednisolone ....................................................... 46 
4.3.4 
Investigational Medicinal Product Accountability ................... 46 
4.3.5 
Post-Trial Access to Ipatasertib ............................................. 47 
4.4 
Concomitant Therapy, Prohibited Therapy, and 
Excluded Drugs ..................................................................... 48 
4.4.1 
Permitted Therapy ................................................................. 48 
4.4.2 
Prohibited Therapy ................................................................ 49 
4.4.2.1 
Protocol-Specific Guidance on CYP450Drug 
Interactions ............................................................................ 49 
4.5 
Study Assessments ............................................................... 50 
4.5.1 
Informed Consent Forms and Screening Log ........................ 51 
4.5.2 
Medical History and Demographic Data ................................ 51 
4.5.3 
Physical Examinations ........................................................... 51 
4.5.4 
Vital Signs .............................................................................. 52 


 
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4.5.5 
ECOG Performance Status ................................................... 52 
4.5.6 
Tumor and Response Evaluations ......................................... 52 
4.5.7 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 54 
4.5.8 
Assay Methods for Biomarker Samples ................................. 56 
4.5.8.1 
Ventana PTEN IHC ............................................................... 56 
4.5.8.2 
Foundation Medicine Next-Generation 
Sequencing ............................................................................ 56 
4.5.8.3 
Circulating-Tumor DNA and RNA Analysis ............................ 57 
4.5.8.4 
Messenger RNA Expression Profiling .................................... 57 
4.5.8.5 
Copy Number Analysis .......................................................... 58 
4.5.8.6 
Plasma Biomarker Analyses .................................................. 58 
4.5.8.7 
Plasma Pharmacokinetic Assay ............................................ 58 
4.5.8.8 
Pharmacogenetic Polymorphism Assay ................................ 58 
4.5.9 
Electrocardiograms and Multigated Acquisition 
Scan/Echocardiogram ........................................................... 58 
4.5.10 
PROs ..................................................................................... 59 
4.5.10.1 
EORTC QLQ-C30 and Urinary Scale from QLQ-
P25 ........................................................................................ 60 
4.5.10.2 
Pain Assessments ................................................................. 60 
4.5.10.3 
Medication Log ...................................................................... 61 
4.5.10.4 
PRO-CTCAE ......................................................................... 61 
4.5.10.5 
EQ-5D-5L .............................................................................. 62 
4.5.11 
Survival Follow-Up ................................................................. 62 
4.5.12 
Optional Samples for Research Biosample 
Repository ............................................................................. 62 
4.5.12.1 
Overview of the Research Biosample Repository .................. 62 
4.5.12.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 63 
4.5.12.3 
Sample Collection .................................................................. 63 
4.5.12.4 
Confidentiality ........................................................................ 63 
4.5.12.5 
Consent to Participate in the Research 
Biosample Repository ............................................................ 64 
4.5.12.6 
Withdrawal from the Research Biosample 
Respository ............................................................................ 64 


 
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4.5.12.7 
Monitoring and Oversight ....................................................... 65 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 65 
4.6.1 
Patient Discontinuation .......................................................... 65 
4.6.2 
Study Treatment Discontinuation ........................................... 65 
4.6.3 
Study and Site Discontinuation .............................................. 66 
5. 
ASSESSMENT OF SAFETY ....................................................................... 66 
5.1 
Safety Plan ............................................................................ 66 
5.1.1 
Management of Selected Identified and Potential 
Risks of Ipatasertib and Abiraterone ...................................... 67 
5.1.1.1 
Diarrhea ................................................................................. 67 
5.1.1.2 
Fasting Hyperglycemia .......................................................... 68 
5.1.1.3 
Nausea and/or Vomiting ........................................................ 70 
5.1.1.4 
Rash ...................................................................................... 71 
5.1.1.5 
Pneumonitis ........................................................................... 72 
5.1.1.6 
Hepatotoxicity ........................................................................ 73 
5.2 
Safety Parameters and Definitions ........................................ 74 
5.2.1 
Adverse Events ..................................................................... 74 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 75 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................... 75 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 76 
5.3.1 
Adverse Event Reporting Period ........................................... 76 
5.3.2 
Eliciting Adverse Event Information ....................................... 77 
5.3.3 
Assessment of Severity of Adverse Events ........................... 77 
5.3.4 
Assessment of Causality of Adverse Events ......................... 78 
5.3.5 
Procedures for Recording Adverse Events ............................ 78 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 79 
5.3.5.2 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 79 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 79 
5.3.5.4 
Abnormal Laboratory Values ................................................. 80 


 
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5.3.5.5 
Abnormal Vital Sign Values ................................................... 80 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 81 
5.3.5.7 
Deaths ................................................................................... 81 
5.3.5.8 
Preexisting Medical Conditions .............................................. 82 
5.3.5.9 
Lack of Efficacy or Worsening of mCRPC ............................. 82 
5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 82 
5.3.5.11 
Patient-Reported Outcome Data ........................................... 83 
5.3.5.12 
Cases of Accidental Overdose, Medication Error, 
Drug Abuse, or Drug Misuse ................................................. 83 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 85 
5.4.1 
Emergency Medical Contacts ................................................ 86 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest ..................... 86 
5.4.2.1 
Events That Occur before Study Drug Initiation ..................... 86 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 86 
5.4.3 
Reporting Requirements for Pregnancies .............................. 86 
5.4.3.1 
Pregnancies in Female Partners of Male Patients ................. 86 
5.4.3.2 
Congenital Anomalies/Birth Defects ...................................... 87 
5.5 
Follow-Up of Patients after Adverse Events .......................... 87 
5.5.1 
Investigator Follow-Up ........................................................... 87 
5.5.2 
Sponsor Follow-Up ................................................................ 87 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 87 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 88 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 88 
6.1 
Determination of Sample Size ............................................... 88 
6.1.1 
Type I Error Control ............................................................... 88 
6.1.2 
Co-Primary Endpoint:  Progression-Free Survival ................. 90 
6.1.3 
Key Secondary Endpoint:  Overall Survival ........................... 90 
6.1.4 
China Extension Cohort ......................................................... 91 
6.2 
Summaries of Conduct of Study ............................................ 92 


 
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6.3 
Summaries of Demographic and Baseline 
Characteristics ....................................................................... 92 
6.4 
Efficacy Analyses .................................................................. 92 
6.4.1 
Primary Efficacy Endpoint ...................................................... 92 
6.4.2 
Key Secondary Efficacy Endpoints ........................................ 93 
6.4.2.1 
Overall Survival ..................................................................... 93 
6.4.2.2 
Time to Pain Progression ...................................................... 94 
6.4.2.3 
Time to Initiation of Cytotoxic Chemotherapy ........................ 95 
6.4.2.4 
Time to Function Deterioration .............................................. 95 
6.4.2.5 
Time to Prostate-Specific Antigen Progression ..................... 95 
6.4.2.6 
Time to First Opioid Use ........................................................ 96 
6.4.2.7 
Time to Symptomatic Skeletal Events ................................... 96 
6.4.2.8 
Objective Response Rate ...................................................... 96 
6.4.2.9 
Prostate-Specific Antigen Response Rate ............................. 96 
6.4.2.10 
Investigator-Assessed rPFS in Patients with 
PTEN-Loss Tumors by NGS .................................................. 96 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 97 
6.5 
Safety Analyses ..................................................................... 97 
6.6 
Pharmacokinetic Analyses ..................................................... 97 
6.7 
Biomarker Analyses ............................................................... 98 
6.8 
Interim Analyses .................................................................... 98 
6.8.1 
Planned Interim Safety Analyses ........................................... 98 
6.8.2 
Planned Interim Efficacy Analyses ........................................ 99 
6.8.3 
Optional Interim Analysis ..................................................... 100 
6.9 
China Subgroup Analyses ................................................... 100 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 101 
7.1 
Data Quality Assurance ....................................................... 101 
7.2 
Electronic Case Report Forms ............................................. 101 
7.3 
Electronic Patient-Reported Outcome Data ......................... 102 
7.4 
Source Data Documentation ................................................ 102 
7.5 
Use of Computerized Systems ............................................ 102 
7.6 
Retention of Records ........................................................... 103 
8. 
ETHICAL CONSIDERATIONS .................................................................. 103 


 
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8.1 
Compliance with Laws and Regulations .............................. 103 
8.2 
Informed Consent ................................................................ 103 
8.3 
Institutional Review Board or Ethics Committee .................. 105 
8.4 
Confidentiality ...................................................................... 105 
8.5 
Financial Disclosure ............................................................ 106 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 106 
9.1 
Study Documentation .......................................................... 106 
9.2 
Protocol Deviations .............................................................. 106 
9.3 
Management of Study Quality ............................................. 107 
9.4 
Site Inspections ................................................................... 107 
9.5 
Administrative Structure....................................................... 107 
9.6 
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 107 
9.7 
Protocol Amendments ......................................................... 108 
10. REFERENCES ......................................................................................... 109 


 
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LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 26 
Table 2 
Dose Reductions for Ipatasertib/Placebo .................................... 46 
Table 3 
Diarrhea Management Guidelines .............................................. 68 
Table 4 
Fasting Hyperglycemia Management Guidelines ........................ 69 
Table 5 
Nausea and Vomiting Management Guidelines .......................... 71 
Table 6 
Rash Management Guidelines .................................................... 71 
Table 7 
Pneumonitis Management Guidelines ........................................ 72 
Table 8 
Hepatotoxicity Management Guidelines ...................................... 73 
Table 9 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 77 
Table 10 
Causal Attribution Guidance ....................................................... 78 
Table 11 
Timing of Overall Survival Analyses ............................................ 99 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 29 
Figure 2 
Type I Error Control .................................................................... 89 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ............................................................... 114 
Appendix 2 
 Schedule of Pharmacokinetic Samples and Exploratory 
Biomarker Samples ................................................................... 123 
Appendix 3 
 Eastern Cooperative Oncology Group Performance Status 
Scale ......................................................................................... 125 
Appendix 4 
 PSA Progression Eligibility Criteria .......................................... 126 
Appendix 5 
 Response Evaluation Criteria in Solid Tumors:  Excerpt from 
Original Publication ................................................................... 127 
Appendix 6 
 Criteria for Radiographic Progression per Prostate Cancer 
Working Group 3 ....................................................................... 138 
Appendix 7 
 Bone Scan Tumor Assessment Tool ........................................ 139 
Appendix 8 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire Core 30:  EORTC 
QLQ-C30................................................................................... 140 
Appendix 9 
 European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire:  Urinary Scale from 
EORTC QLQ-PR25 ................................................................... 142 
Appendix 10 
 Pain Severity Assessments ...................................................... 143 
Appendix 11 
 Analgesic Quantification Algorithm Score Categories and 
Equianalgesic Potency Conversions ......................................... 144 


 
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Appendix 12 
 Treatment-Related Symptoms ................................................. 146 
Appendix 13 
 EuroQol 5-Dimension, 5 Levels Questionnaire:  EQ-5D-5L ..... 148 
Appendix 14 
Investigational Medicinal Product and Non-Investigational 
Medicinal Product Designations (for Use in European 
Economic Area and United Kingdom) ....................................... 152 
 
 
 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER TRIAL 
TESTING IPATASERTIB PLUS ABIRATERONE PLUS 
PREDNISONE/PREDNISOLONE, RELATIVE TO 
PLACEBO PLUS ABIRATERONE PLUS 
PREDNISONE/PREDNISOLONE IN ADULT MALE 
PATIENTS WITH ASYMPTOMATIC OR MILDLY 
SYMPTOMATIC, PREVIOUSLY UNTREATED, 
METASTATIC CASTRATE-RESISTANT 
PROSTATE CANCER 
PROTOCOL NUMBER: CO39303 
VERSION NUMBER: 
8 
TEST COMPOUND: 
Ipatasertib (RO5532961) 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 






 
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Several key aspects of the study design and study population are summarized below.  
Phase: 
Phase III 
Population Type: 
Adult Patients 
Control Method: 
Placebo-controlled 
Population Diagnosis  
or Condition: 
Asymptomatic or 
mildly symptomatic 
patients previously 
untreated for mCRPC 
Interventional 
Model: 
Double-blind 
Population Age: 
 18 years 
Test Compound(s): 
Ipatasertib 
(RO5532961); 
Abiraterone acetate 
Site Distribution: 
Multi-site and 
Multi‑region 
Active Comparator: Not Applicable 
Study Intervention 
Assignment Method: 
Randomization 
Number of Arms: 
2 
Number of 
Participants to Be 
Enrolled: 
1100  
 
All eligible patients will receive abiraterone 1000 mg administered orally once daily (QD), 
prednisone/prednisolone 5 mg orally BID, and either ipatasertib at a dose of 400 mg 
(experimental arm) or placebo administered orally QD (control arm).  Study treatment will 
continue until disease progression, intolerable toxicity, elective withdrawal from the study, or 
study completion or termination.  The dose of ipatasertib/placebo can be reduced up to 
two times for management of drug-related toxicities. There will be no dose reductions for 
abiraterone for conditions other than hepatotoxicity. 
Recommended dose modifications for hepatotoxicity are outlined in Section 5.1.1.6. 
Duration of Participation 
The total duration of study participation for each individual, from randomization of the 
first patient to the end of the study, is expected to be approximately 7 years 
Committees 
List any committees that will be reviewing data during the study. 
Independent Committees: 
Independent Data Monitoring Committee 
Other Committees: 
Not applicable 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADT 
androgen deprivation therapy 
anti-HBc 
hepatitis B core antibody 
AQA 
Analgesic Quantification Algorithm 
AR 
androgen receptor 
BID 
twice daily 
CN 
copy number 
CRPC 
castration-resistant prostate cancer 
CSR 
Clinical Study Report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
EORTC QLQ-C30 
EORTC Quality of Life Questionnaire Core 30 
EORTC QLQ-PR25 
EORTC Quality of Life Questionnaire Prostrate Cancer 
Module 
EQ-5D-5L 
EuroQol 5 Dimensions, 5 Levels 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FISH 
fluorescence in situ hybridization 
FMI 
Foundation Medicine, Inc. 
GHS 
global health status 
GnRH 
gonadotropin-releasing hormone 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B virus surface antigen 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
hazard ratio 
ICH 
International Council for Harmonisation 
iDCC 
independent Data Coordinating Center 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 


 
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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRF 
independent review facility 
ISH 
in situ hybridization 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice-or Web-based response technology 
LOH1 
loss of heterozygosity with copy number  1 
LPLV 
last patient, last visit 
LVEF 
left ventricle ejection fraction 
mCRPC 
metastatic castrate-resistant prostate cancer 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria 
for Adverse Events 
NGS 
next-generation sequencing 
NRS 
Numeric Rating Scale 
OS 
overall survival 
PCWG3 
Prostate Cancer Working Group 3 
PF 
physical function 
PFS 
progression-free survival 
PFS2 
secondary progression-free survival 
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetic 
PopPK 
population pharmacokinetics 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events 
PSA 
prostate-specific antigen 
PTEN 
phosphatase and tensin homolog 
QD 
once daily 
QLQ-C30 
Quality of Life Questionnaire Core 30 
QLQ-PR25 
Quality of Life Questionnaire Prostate Cancer Module 
QoL 
quality of life 
RBR 
Research Biosample Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RF 
role functioning 
rPFS 
radiographic progression-free survival 


 
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Abbreviation 
Definition 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
SNV 
single nucleotide variant 
SSE 
symptomatic skeletal event 
ULN 
upper limit of normal 
VAS 
visual analog scale 
VHP 
Voluntary Harmonization Procedure 
WGS 
whole genome sequencing 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON METASTATIC CASTRATE-RESISTANT 
PROSTATE CANCER 
Prostate cancer is the most commonly diagnosed cancer in men and the second leading 
cause of death in men in the Western world (Ferlay et al. 2015).  Although most men are 
diagnosed with localized disease, progression to metastatic disease to the bones and 
visceral organs leads to significant morbidity and mortality (Logothetis et al. 2012; 
Basch et al. 2014).  In the United States, prostate cancer is the most common non-skin 
cancer diagnosed, with over 180,890 new cases and 26,120 deaths 
(American Cancer Society 2016).  Likewise, in Europe, prostate cancer leads male 
cancer diagnoses with approximately 417,000 new cases and 92,000 deaths 
(Ferlay et al. 2013). 
Treatment of localized prostate cancer often incorporates multimodality therapy and can 
be associated with significant functional sequelae.  Multimodality treatment includes 
surgery and/or radiation with or without androgen deprivation therapy (ADT).  For men 
with metastatic disease, primary treatment for prostate cancer is ADT; however, 
most patients will progress despite reduction in testosterone levels to castrate levels 
( 50 ng/dL) either through surgical or medical castration.  Despite the current availability 
of life-extending therapies for metastatic castration-resistant prostate cancer (mCRPC), 
the majority of men will die of their disease as the median life expectancy in this 
population is less than 3 years (Ryan et al. 2013; Beer et al. 2014). 
The phosphoinositide 3-kinase (PI3K)-AKT pathway is one of the most frequently 
activated pathways in prostate cancer, with genomic alterations occurring in 
approximately 50% of cases with genetic loss of phosphatase and tensin homolog 
(PTEN) as the most common cause (Robinson et al. 2015).  Deregulation of this 
pathway results in activation of downstream targets (e.g., PRAS40, mammalian target of 
rapamycin [mTOR], GSK3b, FOXO, etc.) involved in survival, proliferation, cell‑cycle 
progression, growth, migration, and angiogenesis (Yuan and Cantley 2008).  
Prostate‑specific deletion of PTEN in mouse models mimics features of human prostate 
cancer, and AKT1 deletion in a conditional PTEN knockout model significantly reduces 
prostate cancers (Chen et al. 2006; Guertin et al. 2009; Nardella et al. 2009).  
Additionally, PTEN deletion promotes androgen independence in cell lines and mouse 
models of prostate cancer (Gao et al. 2006; Jiao et al. 2007).  Activation of the 
PI3K‑AKT pathway is physiologically relevant as it compensates for androgen receptor 
(AR) downregulation and provides a means for receptor blockade escape; in a similarly 
reciprocal manner, blockade of the PI3K-AKT pathway leads to increased stability and 
activity of the androgen receptor, demonstrating the cooperative action of both pathways 
to enable prostate cancer progression (Carver et al. 2011; Mulholland et al. 2011). 
Clinical studies have consistently demonstrated that low PTEN expression and PTEN 
loss (further described as PTEN loss) is associated with worse prognosis 


 
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(Yoshimoto et al. 2007; Reid et al. 2010; Antonarakis et al. 2012; Chaux et al. 2012; 
Zafarana et al. 2012; Cuzick et al. 2013; Barnett et al. 2014; Ferraldeschi et al. 2015; 
Kim et al. 2015), regardless of whether patients are newly diagnosed, receiving 
treatment for localized disease, or have late-line advanced 
metastatic castrationresistant disease.  Collectively, these results suggest that 
activation of the PI3K-AKT pathway is an important driver for prostate cancer and that 
the pathway is a relevant target for treatment. 
1.2 
BACKGROUND ON IPATASERTIB  
Ipatasertib is a potent, highly selective, small-molecule inhibitor of all three isoforms of 
the serine/threonine kinase AKT and showed potent activity in nonclinical models, 
including prostate cancer, and in models both in vitro and in vivo with PTEN loss.  
In nonclinical prostate cancer models unselected for PTEN loss, the combination of 
ipatasertib with hormonal therapy (abiraterone acetate [hereafter referred to as 
abiraterone] or enzalutamide) resulted in more substantial tumor growth inhibition versus 
either agent alone.  In the Phase Ib/II study GO27983 in the post-docetaxel setting, 
ipatasertib (400-mg dose) when added to abiraterone and prednisone/prednisolone 
showed improved radiographic progression-free survival (rPFS) benefit compared with 
abiraterone and prednisone/prednisolone in the all-comer population and, in particular, 
in patients with PTEN-loss tumors (see Section 1.3). 
Refer to the Ipatasertib Investigator’s Brochure for details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT−RISK ASSESSMENT 
The activity of anti-hormonal therapies in the metastatic castration-resistant setting has 
resulted in improved survival for patients with prostate cancer.  Abiraterone acetate 
(Zytiga®), a pro-drug for abiraterone, is an androgen biosynthesis inhibitor that blocks the 
enzyme CYP17, which is expressed in testicular, adrenal, and prostatic tumor tissues.  
The efficacy and safety of abiraterone were initially demonstrated in patients with 
mCRPC who had received prior docetaxel and were assessed in a Phase III, 
randomized, placebo-controlled, multicenter, clinical trial (de Bono et al. 2011).  A total of 
1195 patients were randomized 2:1 to receive either abiraterone orally at a dose of 
1000 mg once daily (QD) in combination with prednisone/prednisolone orally at a dose 
of 5 mg twice daily (BID; n  797) or placebo QD plus prednisone/prednisolone at the 
same dose of 5 mg BID (n  398).  This Phase III study demonstrated that abiraterone is 
well tolerated and prolongs overall survival (OS) relative to placebo in patients with 
mCRPC previously treated with taxanes.  These results indicate that AR signaling 
continues to play a critical role in the setting of castration‑resistant disease.  Additional 
clinical benefit for abiraterone was demonstrated in the pre-docetaxel setting 
(Ryan et al. 2013).  Although treatment with abiraterone can significantly delay 
progression of disease and improve OS, there is nearly universal development of 


 
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therapeutic resistance and disease progression.  Refer to the Zytiga® prescribing 
information (Zytiga PI) for additional details. 
Recent nonclinical data suggest that reciprocal crosstalk between the AR and 
PI3K/AKT pathways occurs in PTEN-loss mCRPC.  Specifically, activation of the 
PI3K/AKT pathway is associated with repressed androgen signaling, and inhibition of the 
PI3K/AKT pathway restores AR signaling in PTEN-deficient prostate cells.  Proposed 
mechanisms to account for these observations include PI3K/AKT inhibition resulting in 
feedback activation of AR via upregulation of human epidermal growth factor receptor 
kinases and inhibition of AR, relieving feedback inhibition of AKT by the phosphatase 
PH domain and leucine-rich repeat-protein phosphatase (Carver et al. 2011).  
This reciprocal cooperativity between PI3K/AKT and AR pathways suggests inhibition of 
only one pathway would lead to suboptimal clinical efficacy.  Therefore, combined 
inhibition of the AR and PI3K/AKT pathways may result in measurable decline of 
tumor cell viability and more durable clinical benefit.  Given the strong implication of 
PI3K/AKT activity in prostate cancer cell survival and therapeutic resistance, ipatasertib 
could be particularly effective given in combination with abiraterone in 
PTEN‑loss mCRPC dependent on the PI3K/AKT pathway for growth and survival. 
A Phase Ib/II clinical trial (Study GO27983; NCT01485861) was conducted to evaluate 
ipatasertib in combination with abiraterone and prednisone/prednisolone in patients with 
mCRPC (de Bono et al. 2016a, 2018).  The Phase Ib portion of the study was 
open label, using dose escalation to determine the recommended Phase II dose of 
ipatasertib.  In the Phase II portion of the trial, patients with mCRPC previously treated 
with docetaxel-based therapy were randomized to three arms (in a 1:1:1 ratio) in a 
double‑blind fashion:  ipatasertib 400 mg, ipatasertib 200 mg, or placebo.  Each arm was 
in combination with abiraterone (1000 mg) and prednisone/prednisolone (5 mg 
twice daily [BID]).  Patients were stratified according to previous enzalutamide treatment 
(yes or no), number of chemotherapeutic regimens (1 or  1), and progression 
(prostate‑specific antigen [PSA] only or other).  The co-primary efficacy endpoints were 
rPFS in the intent-to-treat (ITT) population (i.e., with unselected tumors), as well as in 
patients with PTEN-loss tumors.  Secondary endpoints included safety, OS, time to PSA 
progression, and PSA response rate. 
The primary efficacy endpoint, as measured by rPFS at both dose levels over 
abiraterone and prednisone/prednisolone, indicated a larger improvement at 400 mg 
versus placebo (stratified hazard ratio [HR]  0.75; 90% CI: 0.56 to 1.04; p  0.17) relative 
to ipatasertib 200 mg versus placebo (stratified HR  0.94; 90% CI: 0.69 to 1.28; 
p  0.75).  A trend for improved OS was observed in the ipatasertib 400‑mg arm versus 
the placebo arm (median, 18.9 vs. 15.6 months, respectively; stratified HR  0.72; 
p  0.22), which was overall improved as assessed by HRs compared with the ipatasertib 
200‑mg vs. placebo arm (median, 21.5 vs. 15.6 months, respectively; 
stratified HR  0.96; p = 0.87).  Additionally, time to PSA progression was prolonged in 
the ipatasertib 400‑mg plus abiraterone and prednisone arm compared with the placebo 


 
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plus abiraterone and prednisone arm (median, 5.6 vs. 3.7 months, respectively; 
stratified HR  0.70; p  0.07) and relative to the ipatasertib 200‑mg plus abiraterone and 
prednisone arm (median, 3.8 vs. 3.7 months, respectively; stratified HR  0.95; p  0.79).  
Overall, both ipatasertib treatment arms had numerically favorable results over the 
placebo, with the ipatasertib 400-mg arm trending for improved OS. 
Ipatasertib dose levels of 400 mg and 200 mg QD in combination with abiraterone and 
prednisone were generally well tolerated; the adverse events were manageable and 
reversible in patients with mCRPC.  Major adverse events attributable to ipatasertib 
include diarrhea, nausea, asthenia, vomiting, rash, and hyperglycemia.  The most 
common adverse events ( 10%) associated with abiraterone are fatigue, joint swelling 
or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, 
urinary tract infection, and confusion.  Although data for the combination of ipatasertib 
and abiraterone indicate reasonable patient tolerability, there is some overlap in adverse 
event types.  Adverse events of special interest, in addition to overall safety, will be 
monitored as outlined in this protocol. 
In addition, as a component of the co-primary analysis, rPFS in patients with PTEN loss 
was assessed.  PTEN expression was analyzed by immunohistochemistry (IHC) via the 
Institute of Cancer Research assay (de Bono et al. 2016b).  PTEN status was 
IHC evaluable in 165 cases, with PTEN loss reported in 71 cases (43%).  PTEN loss 
was associated with a worse rPFS outcome in the placebo arm, but ipatasertib improved 
rPFS compared with placebo at both the 200-mg and 400-mg doses, with a greater 
treatment effect at 400 mg and in PTEN-loss cancers (de Bono et al. 2016b).  
Exploratory PTEN-loss assays included a Ventana IHC assay, and genomic loss of 
PTEN was further explored by fluorescence in situ hybridization (FISH) and 
next-generation sequencing (NGS).  There was high concordance for PTEN loss 
between FISH, NGS, and IHC.  This clinical data strongly support PTEN loss as being a 
predictive response biomarker for mCRPC for agents targeting the PI3K-AKT pathway. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of ipatasertib plus 
abiraterone plus prednisone or prednisolone (hereafter referred to as “abiraterone”), 
compared with placebo plus abiraterone in asymptomatic or mildly symptomatic patients 
previously untreated for mCRPC.  Specific objectives and corresponding endpoints for 
the study are outlined below (see Table 1). 






 
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pharmacokinetics of ipatasertib plus abiraterone compared with placebo plus 
abiraterone.  The target patient population is asymptomatic or mildly symptomatic 
patients previously untreated for mCRPC.  Patients must have documented metastatic 
disease by presence of bone lesions on bone scan and/or soft tissue lesions on 
computed tomography (CT)/magnetic resonance imaging (MRI).  Analysis will be based 
on the ITT and PTEN-loss populations, the latter defined using the Ventana 
PTEN IHC assay.  Patients must also have a valid PTEN IHC result from tumor to be 
enrolled. 
All eligible patients will receive abiraterone 1000 mg administered orally QD, 
prednisone/prednisolone 5 mg orally BID, and either ipatasertib at a dose of 400 mg 
(experimental arm) or placebo administered orally QD (control arm).  Study treatment 
will continue until disease progression, intolerable toxicity, elective withdrawal from the 
study, or study completion or termination. 
Tumor measurement for disease evaluation will be performed with bone scans and 
CT/MRI per schedule in Appendix 1, and response will be evaluated per Prostate 
Cancer Working Group 3 (PCWG3) guidelines.  For patients who have evidence of 
progression by bone scan alone, a confirmatory scan must be performed.  For patients 
with soft tissue progression, a confirmatory scan is not needed.  Patients with 
progression by PSA alone without evidence of radiographically assessed disease 
progression should continue on study treatment until evidence of radiographically 
assessed disease progression.  Images for tumor assessments will be collected for 
independent data review to enable blinded, independent central review as needed.  
Cross over will not be allowed. 
The study will enroll approximately 1100 patients at approximately 200 centers 
worldwide in about 20 months.  The study schema is shown in Figure 1.  




 
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and the China extension cohort.  The Chinese patients enrolled in the 
China extension cohort will undergo the same schedule of assessments and will receive 
study treatment as in the global (main study) cohort. 
The China subgroup may include all Chinese patients enrolled in the global (main study) 
cohort and the China extension cohort.  The China subgroup analysis will be performed 
as described in the Statistical Analysis Plan (SAP) and summarized in a separate clinical 
study report.  The Chinese patients enrolled in the global (main study) will be analyzed 
together with all other patients enrolled in the main study and reported in the main study 
clinical study report. 
Patients who meet the eligibility criteria will be randomized in a 1:1 ratio to one of the 
two following treatment arms (each consisting of 28-day cycles of oral administration): 
 
Arm 1:  abiraterone (1000 mg QD) plus prednisone/prednisolone (5 mg BID) plus 
ipatasertib (400 mg QD) 
 
Arm 2:  abiraterone (1000 mg QD) plus prednisone/prednisolone (5 mg BID) plus 
placebo (matched to ipatasertib appearance) 
 
A randomization scheme will be used across all study sites through a centralized 
interactive voice- or web-based response system (IxRS).  In this study, randomization of 
patients will be stratified on the basis of the following factors: 
 
Prior taxane-based therapy in the hormone-sensitive setting (yes vs. no) 
 
Progression factor (PSA only vs. other)  
 
Presence of visceral metastasis (liver or lung) (yes vs. no) 
 
Tumor PTEN-loss status by IHC assay (yes vs. no) 
 
Geographic region (not a factor for stratified analysis) 
 
Prior to enrollment, but after signing the Informed Consent Form, patients will have the 
PTEN-loss status of their tumor assessed by the central laboratory using a validated 
IHC assay with defined criteria for PTEN loss.  Patients whose tumor samples have 
invalid PTEN IHC test result will not be permitted to enroll in the study. 
Study assessments (efficacy, safety, patient-reported outcomes, and pharmacokinetic 
[PK] measurements) and timing of those assessments during each 28-day cycle are 
presented in Appendix 1. 
Radiographic tumor assessments, including CT or MRI, and bone scans will be 
evaluated locally by the investigators.  Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) will be used to assess CT or MRI scans of lesions in soft 
tissues.  Bone lesions will be assessed by bone scan only, using the PCWG3 criteria to 
assess disease progression.  All scans will be prospectively collected and centrally 
archived. 


 
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Timely and complete disease assessments by imaging methods in this study are 
imperative.  Each tumor assessment will be performed as scheduled according to the 
calendar, regardless of any study treatment doses omitted, to prevent the introduction of 
bias into the assessment of efficacy.  Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for that timepoint. 
In addition, an independent review facility (IRF) may provide an assessment of 
radiographically assessed disease progression as an exploratory endpoint to support the 
findings of the investigator assessed outcomes.  Details are included in the SAP.  
The data will be collected from all patients. 
Patients will receive study treatment until radiographically assessed disease progression 
(as assessed by the investigator per RECIST v1.1 and/or PCWG3 criteria as applicable), 
intolerable toxicity, elective discontinuation of the study treatment, elective withdrawal 
from the study, initiation of new anti-cancer therapy, study completion or termination by 
F. Hoffmann-La Roche Ltd (the Sponsor), or physician decision, whichever occurs first.  
For patients where disease progression is assessed only on the basis of bone scan 
findings, a confirmatory scan MUST be performed per PCWG3 criteria to establish 
disease progression.  Patients who discontinue one of the study treatments 
(i.e., ipatasertib/placebo or abiraterone) in the absence of radiographically assessed 
disease progression may continue the study and receive the remaining single‑agent 
treatment (i.e., abiraterone if ipatasertib/placebo is discontinued or ipatasertib/placebo 
if abiraterone is discontinued) at the discretion of the investigator. 
Patients who discontinue from study treatment will return for a study treatment 
completion visit within 30 days after the last dose of study treatment. 
Crossover between treatment arms is not allowed. 
Following radiographically assessed disease progression (as assessed by the 
investigator per RECIST v1.1 and/or PCWG3 criteria as applicable) and study treatment 
discontinuation, patients will continue post-treatment follow-up for selected assessments 
supporting secondary and exploratory efficacy endpoints, until death, loss to follow-up, 
withdrawal of consent from study, or study termination by Sponsor. 
Sites should record for all patients who are in follow-up, survival information including 
symptomatic skeletal events (SSEs), initiation of subsequent anti-cancer therapy 
(including the date of the first dose of agent, the date of the last dose of agent, patient’s 
best response, and date of disease progression), date of second radiographically 
assessed disease progression and any post-progression therapy for prostate cancer, as 
well as any serious adverse events considered by the investigator to be related to 
study treatment (abiraterone and/or ipatasertib/placebo). 


 
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Patients who discontinue from study treatment for reasons other than radiographically 
assessed disease progression will be asked to return to the clinic for disease follow-up 
visits approximately every 3 months to complete tumor assessments until 
radiographically assessed disease progression (per RECIST v1.1 and/or PCWG3 criteria 
as applicable) or withdrawal from study. 
All patients who discontinue from study treatment because of radiographically assessed 
disease progression or any other reasons will be asked to report at home or at the clinic, 
pain medications (including dose and type of opioids used), pain severity (7-day recall), 
and other patient-reported outcome (PRO) measures approximately every 28 days until 
initiation of any post-progression therapy for prostate cancer or up to 1 year, whichever 
occurs first. 
After initiation of post-progression therapy or after 1 year, patients will be asked to report 
pain severity, analgesic use (yes vs. no), EuroQol 5 Dimensions, 5 Levels (EQ‑5D‑5L); 
and three scales from the European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) every 3 months completed at 
home or at the clinic or via telephone calls. 
After the final OS analysis, only patients who are still receiving ipatasertib will be 
required to attend study visits.  Adverse events and drug accountability will be 
collected at 3 monthly study visits until the patient’s discontinuation from study 
treatment.  Tumor assessments will no longer be required at the study visits but will be 
conducted as per local practice and at the Investigator discretion.  Tumor assessment 
data will no longer be collected after the final OS analysis (please see Appendix 1).  
For all patients who have discontinued study treatment, only reportable serious adverse 
events will be collected after the final OS analysis. 
An independent Data Coordinating Center (iDCC) will prepare all summaries and 
analyses for the independent Data Monitoring Committee’s (iDMC’s) review.  The safety 
summaries will include but will not be limited to demographic data, adverse events, 
serious adverse events, and relevant laboratory data (see iDMC charter for details). 
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  Following the data review, the iDMC will provide 
a recommendation to the Sponsor whether to continue the study, amend the protocol, or 
stop the study.  The final decision will rest with the Sponsor. 
Any outcomes of the iDMC’s reviews on the safety and benefitrisk balance that affect 
study conduct will be communicated in a timely manner to the investigators for 
notification of Institutional Review Boards and Ethics Committees (IRBs/ECs). 


 
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3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit occurs 
(i.e., the date at which the last data point required for statistical analysis or safety 
follow-up is received; see Section 4.6). 
In addition, the Sponsor may decide to terminate the study at any time.  The Sponsor 
may evaluate whether to continue providing ipatasertib in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
3.2.1 
Duration of Participation 
The total duration of study participation for each individual, from randomization of the 
first patient to the end of the study, is expected to be approximately 7 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Dose Rationale for the Combination 
In the aforementioned Phase Ib/II study, ipatasertib was administered at doses of 
200 mg and 400 mg QD, continuously in 28-day treatment cycles.  Abiraterone was 
administered at a dose of 1000 mg QD alongside prednisone at a dose of 5 mg BID, 
continuously in 28-day treatment cycles.  The combination was well tolerated.  
Based upon the spectrum and frequency of adverse events attributable to the ipatasertib 
and abiraterone/prednisone combination, in addition to the trend of favorable efficacy, 
the recommended dose was determined to be 400 mg ipatasertib given continuously in 
28‑day treatment cycles, in combination with the standard dose for abiraterone. 
Complete information for ipatasertib is found in the Investigator’s Brochure, as the 
single reference safety document.  The single reference safety document for abiraterone 
is the most recent version of the Summary of Product Characteristics (SmPC). 
3.3.2 
Rationale for Patient Population 
The Phase II study (GO27983) evaluated ipatasertib in combination with abiraterone and 
prednisone in the post-docetaxel mCRPC setting.  This study will give the same 
combination in an mCRPC patient population that has not received docetaxel treatment 
in this setting (i.e., patients may have received docetaxel or other therapies in the 
hormone-sensitive setting).  Specifically, this study will investigate the efficacy and 
safety of ipatasertib as an add-on therapy to abiraterone and prednisone (standard of 
care) in previously untreated asymptomatic or mildly symptomatic patients with mCRPC.  
Although there are currently no data with this combination in previously untreated 
patients with mCRPC, the expectation is that the mechanism of action for ipatasertib is 
relevant in the pre- and post-docetaxel settings because PI3K-AKT pathway alterations 
are frequent in prostate cancer and are not limited to specific disease stage(s) as 


 
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discussed above.  For patients with untreated mCRPC, options for therapy include either 
hormonal‑based therapies or cytotoxic chemotherapy.  Current recommendations 
support the use of cytotoxic therapy for symptomatic disease, and therefore the defined 
study population will include only those patients with asymptomatic or mildly 
symptomatic disease at enrollment.  As described in Section 1.3, there was a greater 
rPFS improvement with the addition of ipatasertib to abiraterone in patients with 
PTEN‑loss cancers versus those without evidence of PTEN loss using both 
protein‑based and DNA-based assays.  As such, Study CO39303 was designed to test 
for a significant improvement of rPFS in patients with PTEN-loss tumors as a co‑primary 
endpoint alongside testing rPFS in the all-comer population (see Section 6.4.1). 
3.3.3 
Rationale for Control Group  
Abiraterone is indicated in combination with prednisone for the treatment of patients with 
mCRPC.  Abiraterone has demonstrated activity in both pre- and post‑docetaxel 
mCRPC settings.  Thus, the treatment benefit seen with ipatasertib in combination with 
abiraterone and prednisone in the post-docetaxel setting is likely to be observed in the 
pre‑docetaxel setting (Section 1.3). 
During this study, abiraterone administration will be as described in the most recent 
version of the local prescribing information. 
3.3.4 
Rationale for Double-Blind Design 
This is a double-blind study.  The use of abiraterone plus placebo control is to allow for 
discrimination between patient outcomes (changes in symptoms, signs, and other 
morbidity) caused by ipatasertib plus abiraterone and outcomes caused by 
natural progression of disease and patient expectations (via PROs). 
3.3.5 
Rationale for China Extension Cohort 
In order to characterize the efficacy and safety profile of ipatasertib in addition to 
abiraterone to potentially support a regulatory submission in China, a 
China extension cohort will be included in the study.  This study will initially enroll 
approximately 1100 patients across all sites in a global enrollment phase.  If at least 
1 patient is enrolled in China during the global enrollment phase, additional patients in 
China will be enrolled into a subsequent China extension phase, as needed, to enroll a 
total of approximately 200 patients in the China subpopulation.  Thus, 
the China subpopulation will include patients enrolled at sites in China during both the 
global enrollment phase and the China extension phase, if it is necessary. 
3.3.6 
Rationale for Pharmacokinetic Sampling and Schedule 
A sparse sampling strategy will be applied in this study (see Appendix 2 for schedule).  
The sampling schedule is designed to enable characterization of ipatasertib PK following 
first dose and at steady-state using population PK (popPK) methodology.  Individual 


 
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PK parameters estimated from the sparse sampling scheme will be used for exploratory 
exposureresponse analyses. 
3.3.7 
Rationale for Patient-Reported Outcomes Assessments 
In this study, examining and measuring the patient’s experience of symptoms and their 
interference with daily life will be accomplished using patient-completed rating scales.  
Symptomatic bone metastases are associated with high pain severity, which interferes 
with patients’ ability to function. 
Because these concepts cannot be observed, they are therefore best documented 
through standardized PROs.  PRO assessments provide the means to validly and 
reliably quantify subjective information, which can only by ascertained by the 
study patients in response to specific questions from validated instruments. 
Instruments implemented in the study—namely, a pain severity Numeric Rating Scale 
(NRS), the EORTC QLQ‑C30, and the urinary scale from the Prostate Cancer Module 
(EORTC QLQ-PR-25), the EQ-5D-5L in its entirety (including the visual analog scale 
[VAS]) and selected items from the National Cancer Institute (NCI)-developed 
Patient‑Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO‑CTCAE) item bank—have been selected on the basis of their content 
validity and performance and to minimize patients’ completion burden. 
A patient-completed log will be used to document the consumption of analgesic 
medications (including opioid) to treat pain related to prostate cancer.  The term “opioid” 
in the context of this study encompasses both natural and synthetic substances that act 
on the main opioid receptors. 
Changes in symptom severity and interference with daily life will be documented at 
specified time points throughout the study.  Data will be collected via a patient 
provisioned electronic device, including reminding alerts in order to maximize 
compliance.  Back-up paper forms will be available if needed in order to capture 
patient data.  It is critical to rigorously collect the PRO data as they support secondary 
endpoints. 
PRO data collected after initiation of post-progression therapy until death will be used as 
a unique opportunity to quantify patients’ post-treatment experience in terms of 
humanistic outcomes. 
In addition, the EQ-5D-5L will be completed to inform pharmacoeconomic models. 
3.3.8 
Tissue and Blood-Based Biomarker Assessments 
A key objective of the study biomarker analysis is to investigate candidate biomarkers 
assessed in tumor tissue and blood, obtained prior to treatment, for their potential 


 
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predictive value in identifying patients who may benefit from treatment with abiraterone 
and prednisone in combination with ipatasertib. 
3.3.8.1 
PTEN Expression Analysis by IHC 
Analysis of the co-primary endpoint of rPFS in patients with tumor PTEN loss in 
Study GO27983 demonstrated that these patients derived greater rPFS benefit relative 
to those without PTEN loss using multiple protein- and DNA-based methods.  
The Ventana PTEN IHC assay is a validated assay that will be performed at a central 
laboratory and will be used to prospectively describe the PTEN status of baseline tumor 
sample, as described in the laboratory manual. 
3.3.8.2 
RNA and DNA Sequencing Analysis 
NGS techniques such as targeted exome sequencing and whole genome sequencing 
(WGS) may offer a unique opportunity to identify biomarkers of response and/or de novo 
mechanisms of resistance to the study treatments.  In addition to the mutational 
activation of proteins detected by IHC techniques, NGS methodologies can detect 
changes in RNA and DNA that can also activate the PI3K and AR pathways.  Therefore, 
the NGS analysis of DNA and RNA from the patient specimens (e.g., tumor tissue and/or 
plasma-derived nucleic acids) allows further in-depth molecular characterization of the 
patient samples to help develop an integrative genomic landscape of patients with 
castrate‑resistant prostate cancer (CRPC). 
3.3.8.3 
Plasma Sample for Somatic Tumor Mutation Analysis 
There is increasing evidence that circulating-tumor DNA obtained from blood specimens 
of cancer patients is representative of the DNA and mutational status of tumor cells 
(Diehl et al. 2008; Maheswaran et al. 2008).  Assays are available that can detect the 
major AR mutations and copy number (CN; and other cancer‑related genes) in plasma, 
and results from these analyses may be correlated with the mutation result in tumor 
specimens (Romanel et al. 2015).  The use of circulating tumor DNA to monitor 
response to treatment is an area of great interest.  It could allow for an early, 
non-invasive, and quantifiable method for use in the clinical setting to identify candidates 
for specific therapies and monitoring of disease mutation status over time 
(Higgins et al. 2012).  In addition, sensitive methods for the purification and quantitation 
of RNA expression levels and specific RNA variants (e.g., AR‑V7) have enabled the 
analysis of RNA extracted from cancer cell vesicles released in blood 
(Del Re et al. 2016) and enables the opportunity to explore RNA‑based methodologies 
to identify possible predictive or prognostic biomarkers in CRPC. 
3.3.8.4 
Blood Sample for the Detection of Plasma Protein Biomarkers 
Emerging evidence indicates that increases in levels of systemic cytokines and 
chemokines, such as receptor tyrosine kinase growth factors, can attenuate responses 
to drugs, particularly, targeted agents (Wilson et al. 2012).  Assays that assess the 
expression of soluble, systemic cytokines and chemokines from the plasma of patients 
may be performed using ELISA-based mass spectrometry or appropriate methodologies. 


 
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3.3.8.5 
Blood Sample for Next-Generation Sequencing 
NGS technologies generate a large quantity of sequencing data.  Tumor DNA can 
contain both reported and unreported chromosomal alterations because of the 
tumorigenesis process.  To help control for sequencing calls in previously unreported 
genomic alterations, a blood sample for NGS control will be taken during predose to 
determine whether an observed alteration identified in the tumor tissue is somatic 
throughout the evaluation of the DNA isolated in peripheral blood. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 1100 patients with mCRPC are expected to be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
4.1.1.1 
General Inclusion Criteria 
 
Signed Informed Consent Form(s) 
 
Ages  18 years 
 
Eastern Collaborative Oncology Group (ECOG) performance status of 0 or 1 at 
screening (see Appendix 3 
) 
 
Adequate hematologic and organ function within 28 days before the 
first study treatment, defined using the following (hematologic parameters must be 
assessed  14 days after a prior transfusion, if any): 
– 
Neutrophils:  ANC  1500 cells/L (1.5  109/L) 
– 
Hemoglobin  10 g/dL 
– 
Platelet count  100,000 cells/L 
– 
Total bilirubin  1.5  the upper limit of normal (ULN) with the following 
exception: 
Patients with known Gilbert disease who have serum bilirubin  3  ULN 
may be enrolled. 
– 
AST and ALT  1.5  ULN, with the exception that patients with liver metastasis 
may have AST and/or ALT  2.5  ULN, and total bilirubin  1.5  ULN 
– 
Serum creatinine  1.5  ULN and creatinine clearance  50 mL/min based on 
CockroftGault glomerular filtration rate estimation: 
(140  age in years)  (weight in kg) 
72  (serum creatinine in mg/dL) 
– 
Serum albumin  3.5 g/dL 
– 
Serum potassium  3.5 mmol/L 
– 
Fasting glucose  150 mg/dL (8.3 mmol/L) and hemoglobin A1c  7.5% 
(58 mmol/mol) 


 
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 
Ability to comply with the study protocol, in the investigator’s judgment 
 
Willingness and ability of patients to use the electronic device to report selected 
study outcomes (e.g., symptom severity).  Caregivers and site staff can assist with 
patient diary input, but patient must be able to independently comprehend and 
answer the questionnaires. 
 
Life expectancy of at least 6 months 
 
Agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined 
below: 
– 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom along with another effective 
contraceptive method during the treatment period and for at least 28 days after 
the last dose of study treatment to avoid exposing the embryo.  Men must 
refrain from donating sperm during this same period. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post‑ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
For enrollment into the China extension cohort, residence in the People’s Republic 
of China 
 
4.1.1.2 
Disease-Specific Inclusion Criteria 
 
Histologically confirmed prostate adenocarcinoma without neuroendocrine 
differentiation or small-cell features 
 
Consent to provide a formalin-fixed paraffin-embedded (FFPE) tissue block 
(preferred) or a minimum of 15 (20 preferred) freshly cut unstained tumor slides 
from the most recently collected, available tumor tissue accompanied by an 
associated pathology report (with tumor content information, Gleason score, and 
disease staging) for PTEN IHC and NGS testing and for other protocol‑mandated 
secondary and exploratory assessments.  If only 1214 slides are available, the 
patient may still be eligible for the study, after discussion with and approval by the 
Medical Monitor.  Cytologic or fine-needle aspiration samples are not acceptable.  
Tumor tissue from bone metastases is not acceptable. 
 
A valid PTEN IHC result (central laboratory tested with results directly sent to IxRS) 
– 
Patients with an “invalid” or “failed” PTEN IHC result are not permitted to enroll. 
 
Metastatic disease documented prior to randomization by clear evidence of 
bone lesions on bone scan and/or measurable soft tissue disease by CT and/or MRI 
(at least one target lesion) according to RECIST v1.1 
– 
Patients whose spread of disease is limited only to regional pelvic lymph nodes 
are not eligible. 
 
Asymptomatic or mildly symptomatic form of prostate cancer: 


 
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– 
A score of 0 or 1 on the pain at its worst (24-hour recall) 10-point NRS will be 
considered asymptomatic, and a score of 2 or 3 will be considered 
mildly symptomatic. 
 
Progressive disease before initiating study treatment, defined using at least one of 
the following criteria: 
– 
Two rising PSA levels measured  1 week apart, with second result  1 ng/mL 
according to PCWG3 criteria (see Appendix 4): 
Patients who have received an anti-androgen therapy must have 
PSA progression after withdrawal ( 4 weeks since last flutamide or 
 6 weeks since last treatment of bicalutamide or nilutamide). 
– 
Radiographic evidence of disease progression in soft tissue according to 
RECIST v1.1 and/or bone scan according to PCWG3 criteria. 
 
Ongoing androgen deprivation with gonadotropin-releasing hormone (GnRH) analog 
or bilateral orchiectomy, with serum testosterone  50 ng/dL ( 1.7 nmol/L) within 
28 days before randomization 
– 
Patients on GnRH analog must have therapy initiated at least 4 weeks before 
Cycle 1, Day 1, and treatment must be continued throughout the study. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
4.1.2.1 
General Exclusion Criteria 
 
Inability or unwillingness to swallow whole pills 
 
History of malabsorption syndrome or other condition that would interfere with 
enteral absorption 
 
Clinically significant history of liver disease consistent with Child‑Pugh Class B or C, 
including cirrhosis, current alcohol abuse, or current known active infection with 
hepatitis B virus (HBV) or hepatitis C virus (HCV) 
– 
Active infection is defined as requiring treatment with antiviral therapy or 
presence of positive test results for hepatitis B (hepatitis B surface antigen 
[HBsAg] and/or total hepatitis B core antibody [anti-HBc]) or HCV antibody.  
Unless required by local regulations, patients are not required to have HIV, 
HBV, or HCV assessments at screening if these assessments have not been 
previously performed. 
– 
Patients who are positive for anti-HBc are eligible only if test results are also 
negative for HBsAg and polymerase chain reaction is negative for HBV DNA. 
– 
Patients who are positive for HCV serology are eligible only if testing for HCV 
RNA is negative. 
 
Need of more than 10 mg/day of prednisone or an equivalent dose of other 
anti-inflammatory corticosteroids as a current systemic corticosteroid therapy to 
treat a chronic disease (e.g., rheumatic disorder) 
– 
Concurrent use of inhaled corticosteroids is allowed. 


 
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 
Active infection requiring IV antibiotics within 14 days before Cycle 1, Day 1 
 
Immunocompromised status because of current known active infection with HIV or 
because of the use of immunosuppressive therapies for other conditions 
 
Major surgical procedure or significant traumatic injury within 28 days prior to 
Cycle 1, Day 1, or anticipation of the need for major surgery during study treatment 
 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such 
as structural heart disease (e.g., severe left ventricular systolic dysfunction, 
left ventricular hypertrophy), untreated coronary heart disease (symptomatic or 
with ischemia demonstrated by diagnostic testing), myocardial infarction or atrial 
thrombotic events within the past 6 months, severe or unstable angina, New York 
Heart Association Class III and IV heart disease or depressed left ventricular 
ejection fraction (LVEF; previously documented LVEF  50% without documentation 
of recovery), clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or 
long QT syndrome 
 
History of another malignancy within 5 years prior to randomization, except for either 
adequately treated non-melanomatous carcinoma of the skin, adequately treated 
melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of 
the bladder (Tis, Ta, and low grade T1 tumors), or other malignancies where the 
patient has undergone potentially curative therapy with no evidence of disease and 
are deemed by the treating physician to have a recurrence rate of  5% at 5 years 
 
Any other diseases, cardiovascular, pulmonary, or metabolic dysfunction, physical 
examination finding, or clinical laboratory finding giving reasonable suspicion of a 
disease or condition that contraindicates the use of an investigational drug or that 
may affect the interpretation of the results or renders the patients at high risk from 
treatment complications 
 
4.1.2.2 
Disease-Specific Exclusion Criteria 
 
Pathologic findings consistent with small-cell or neuroendocrine carcinoma of 
the prostate 
 
Use of opioid medication for cancer-related pain, including codeine and 
dextropropoxyphene, currently or any time within 4 weeks of Cycle 1, Day 1 
 
Any therapy including chemotherapy (e.g., docetaxel) or biological therapy 
(e.g., vaccine, immunotherapy) for the treatment of castration-resistant prostate 
cancer.  Previous treatment with flutamide, steroidal anti-androgens, androgens, 
estrogens, bicalutamide, nilutamide, or 5- reductase inhibitor is permitted. 
– 
In the setting of hormone-sensitive prostate cancer, chemotherapy 
(e.g., docetaxel) is permitted provided that it is initiated within 6 months from 
the time of first castration (i.e., concurrent initiation of chemotherapy and ADT 
for HSPC).  Patient should not have progressed during or within 3 months after 
the completion of chemotherapy-based treatment (i.e., rapid progression on 
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 
Prior treatment with abiraterone or other known potent CYP17 inhibitors 
(e.g., ketoconazole, orteronel) or investigational agents that block 
androgen synthesis.  Previous treatment with itraconazole and fluconazole is 
permitted. 
 
Prior treatment with enzalutamide or other potent androgen‑receptor blockers, 
approved or experimental (e.g., ARN-509, ODM-201, or galeterone) 
 
Prior treatment with flutamide (Eulexin®), steroidal anti-androgens 
(e.g., cyproterone acetate, chlormadinone acetate), androgens, or estrogens 
treatment within 4 weeks of Cycle 1, Day 1 
 
Prior treatment with bicalutamide (Casodex®) or nilutamide (Nilandron®) within 
6 weeks of Cycle 1, Day 1 
 
Prior treatment with 5- reductase inhibitors within 4 weeks of Cycle 1, Day 1 
 
Prior treatment with systemic radiopharmaceuticals (e.g., radium‑223 and 
strontium‑89).  Radiopharmaceuticals for the purpose of imaging are permitted.  
Focal palliative radiation to treat cancer-related pain is permitted provided that the 
last treatment with radiation is at least 14 days prior to Cycle 1, Day 1. 
 
Prior treatment with approved or experimental therapeutic agents with known 
inhibition of the PI3K pathway, including PI3K inhibitors, AKT inhibitors, and 
mTOR inhibitors 
 
Administration of an investigational therapeutic agent within 28 days of 
Cycle 1, Day 1 
 
Known untreated or active CNS metastases (progressing or requiring anticonvulsant 
medications or corticosteroids for symptomatic control); a CT or MRI scan of the 
brain will be performed at screening if required by the local health authority:  
– 
Patients with a history of treated CNS metastases are eligible, provided they 
meet all of the following criteria:  
Evaluable or measurable disease according to the inclusion criteria outside 
the CNS is present.  
Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic study. 
No history of intracranial hemorrhage or spinal cord hemorrhage. 
Minimum of 2 weeks between completion of radiotherapy and 
Cycle 1, Day 1, and recovery from significant (Grade  3) acute toxicity, 
with no ongoing requirement for  10 mg/day of prednisone or an 
equivalent dose of another corticosteroid. 
 
Any chronic therapy or use of food supplements that are strong CYP3A4/5 inducers 
or inhibitors or sensitive substrates of CYP3A or CYP2D6 with a narrow therapeutic 
window 
 


 
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4.1.2.3 
Abiraterone-Specific Exclusion Criteria 
 
Uncontrolled hypertension (systolic blood pressure  160 mmHg or diastolic blood 
pressure  95 mmHg) 
– 
Patients with a history of hypertension are eligible provided blood pressure is 
controlled by anti‑hypertensive treatment prior to or within the 28 days of 
screening period. 
 
History of pituitary or adrenal dysfunction 
 
Any ongoing cardiac arrhythmias (including atrial fibrillation) that require medical 
therapy 
 
4.1.2.4 
Ipatasertib-Specific Exclusion Criteria 
 
Type 1 or Type 2 diabetes mellitus requiring insulin at study entry: 
– 
Patients who are on a stable dose of oral diabetes medication  4 weeks prior to 
initiation of study treatment may be eligible for enrollment.  Patients must meet 
the laboratory eligibility criteria for fasting blood glucose and hemoglobin A1c as 
outlined in Section 4.1.1. 
 
History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), 
active bowel inflammation (e.g., diverticulitis) 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Patients will be allocated to one of two treatment arms through use of a permuted block 
randomization algorithm with predefined stratification variables:  prior taxane‑based 
therapy in the hormone-sensitive prostate cancer setting (yes vs. no), progression 
disease factor (PSA vs. other), presence of visceral metastasis (liver or lung, yes vs. no), 
and tumor PTEN‑loss status by IHC assay (yes vs. no).  The stratification factor of 
geographic region will not be a factor used for the stratified analysis.  A placebo for 
ipatasertib will be used in the control arm.  Patients, investigators, and the Sponsor will 
be blinded to treatment arm assignment until the final OS analysis, at which time 
unblinding will be done by the Sponsor, and patients and investigators will be informed 
about the treatment the patient has been receiving. 
If unblinding is necessary before the final OS analysis for patient management related to 
adverse events during study treatment (e.g., in the case of a serious adverse event for 
which patient management might be affected by knowledge of treatment arm 
assignment), the investigator will be able to break the treatment arm code by contacting 
the IxRS; approval from the Sponsor is not required in such circumstances.  Treatment 
arm codes should not be broken except in emergency situations.  If the investigator 
wishes to know the identity of the study drug for any other reason, he or she should 
contact the Medical Monitor directly.  In the event of unblinding prior to study completion, 
the investigator should document and provide an explanation for any premature 
unblinding (e.g., accidental unblinding, unblinding on account of a serious adverse 
event). 


 
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For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment arm code for all serious, unexpected suspected 
adverse reactions (see Section 5.7) that are considered by the investigator or Sponsor to 
be related to study drug. 
4.3 
STUDY TREATMENT  
The investigational medicinal products (IMPs) for this study, ipatasertib, placebo, and 
abiraterone acetate, will be given to patients orally daily.  Prednisone/prednisolone is a 
non‑investigational medicinal product (non-IMP) in the study.  Appendix 14 identifies all 
investigational medicinal products, auxiliary medicinal products, and 
non‑investigational medicinal products for this study. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Ipatasertib and Placebo 
Ipatasertib drug product will be supplied by the Sponsor as 100-mg and 200‑mg tablets 
packaged in bottles.  For information on the formulation and handling of ipatasertib, 
see the Ipatasertib Investigator’s Brochure. 
The placebo drug product will be supplied by the Sponsor as a tablet formulation and will 
be matched in size, color, and shape to ipatasertib tablets to maintain the study blind.  
For information on the formulation and handling of placebo, see the Ipatasertib 
Investigator’s Brochure.  After the final OS analysis and the patients’ unblinding, 
the patients who are on placebo will no longer be provided with placebo. 
A sufficient amount of ipatasertib/placebo should be provided to the patient to last until 
the next visit or, at the investigator’s discretion, to last for up to one treatment cycle.  
Patients will be instructed to bring their study drug and medication diary with them to 
each study visit. 
4.3.1.2 
Abiraterone Acetate 
For information on the formulation, packaging, and handling of abiraterone acetate, 
see the local prescribing information. 
Note:  Abiraterone must be taken on an empty stomach.  Abiraterone should be taken at 
least two hours after eating, and no food should be eaten for at least one hour after 
taking the tablets.  These should be swallowed whole with water. 
Note:  Women who are or may be pregnant should not handle abiraterone without 
protection (e.g., gloves). 
4.3.1.3 
Prednisone/Prednisolone 
For information on the formulation, packaging, and handling of prednisone/prednisolone, 
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4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Ipatasertib, Placebo, and Abiraterone Acetate 
Treatment should be initiated no later than 7 days after randomization.  
Ipatasertib/placebo tablets are given once daily beginning on Cycle 1, Day 1 until the 
patient experiences disease progression, intolerable toxicity, elective withdrawal from 
the study treatment, elective withdrawal from the study, initiation of new anti‑cancer 
therapy, study completion or termination by F. Hoffmann-La Roche Ltd (the Sponsor), or 
physician decision, whichever occurs first.  Ipatasertib/placebo may be dosed with or 
without food.  If a dose is missed or omitted (not taken within 8 hours after the scheduled 
dosing time), the patient should resume dosing with the next scheduled dose the 
following day.  Missed, omitted, or vomited doses will not be made up. 
For all clinic visits, the glucose level of the patient must be reviewed prior to further 
ipatasertib/placebo administration and prior to discharge from the clinic. 
On Days 1 and 15 of Cycle 1 and on all other clinic visit days that require a predose 
blood draw for PK sampling (see Appendix 2) and/or laboratory assessments, patients 
will be instructed to take their morning oral dose of study drug in the clinic after 
completion of the pretreatment assessments outlined in Appendix 1.  For all other days 
of Cycle 1 and other cycles, the daily dose of study drug should be taken approximately 
the same time each day at home. 
Patients may temporarily suspend study treatment for up to 28 consecutive days if they 
experience a toxicity that is considered related to study treatment and requires a 
dose hold.  Patients who miss  28 consecutive days of scheduled treatment with 
ipatasertib/placebo or  28 consecutive days of abiraterone because of 
study treatmentrelated adverse events will discontinue the respective study treatment, 
except for patients with a favorable benefitrisk assessment who may be allowed to re-
initiate treatment at the investigator’s discretion following consultation with the 
Medical Monitor.  Treatment interruptions for reasons other than toxicity (e.g., surgical 
procedures) may be allowed at the investigator’s discretion following consultation with 
the Medical Monitor.  Patients who discontinue one of the study treatments 
(i.e., ipatasertib/placebo or abiraterone) in the absence of radiographically assessed 
disease progression may continue the remaining single‑agent treatment 
(i.e., abiraterone if ipatasertib/placebo is discontinued or ipatasertib/placebo if 
abiraterone is discontinued) until radiographically assessed disease progression.  
Patients whose treatment with ipatasertib/placebo is transiently held or discontinued for 
adverse effects should continue abiraterone, and vice versa.  The 
prednisone/prednisolone dose may be reduced or discontinued for safety in either 
treatment arm.  Equivalent doses of dexamethasone (e.g., 0.5 mg BID) may be 
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An increase in PSA, without evidence of radiographically assessed disease progression, 
should not be used as a criterion to discontinue study treatment and to start a new 
systemic anti‑neoplastic therapy during the study. 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.  Complete information for ipatasertib is found in the 
Investigator’s Brochure as the single reference safety document.  The single reference 
safety document for abiraterone is the most recent version of the SmPC. 
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.3.5.12. 
4.3.3 
Dosage Modifications 
Every effort should be made to administer study treatment on the planned dose and 
schedule.  However, in the event of significant treatment-related toxicity, administration 
of study drugs (ipatasertib/placebo or abiraterone or prednisone/prednisolone) may need 
to be adjusted as described below and in further detail in Section 5.1.  Depending on the 
nature of the toxicity observed, dosing adjustment(s) may be required for just one or 
both study drugs in the combination. In the event of multiple toxicities, dose modification 
should be based on the worst toxicity observed.  Patients are to be instructed to notify 
investigators at the first occurrence of any adverse sign or symptom. 
Dose modifications may occur in three ways: 
 
Dosing interruption 
 
Dosing reduction(s) 
 
Permanent discontinuation 
 
Patients discontinuing ipatasertib/placebo treatment because of 
treatment‑related toxicity may continue on the active treatment phase of the study 
receiving abiraterone monotherapy as per the investigator’s discretion.  Patients 
discontinuing abiraterone treatment because of treatment-related toxicity may continue 
in the active treatment phase of the study receiving ipatasertib/placebo monotherapy as 
per the investigator’s discretion. 
4.3.3.1 
Ipatasertib/Placebo 
The ipatasertib/placebo dose reduction instructions provided in Table 2 are intended to 
serve as recommended guidelines to allow ongoing treatment for patients without signs 
or symptoms of disease progression while monitoring patient safety.  Guidelines for 
implementing dosage modifications and treatment interruption or discontinuation for 
patients who experience specific adverse events are provided in Section 5.1.1. 


 
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Table 2 
Dose Reductions for Ipatasertib/Placebo 
Dose Level 
Ipatasertib 400 mg/Placebo 
Starting Dose Level 
400 mg 
First Dose Reduction 
300 mg 
Second Dose Reduction 
200 mg 
Indication for further dose reduction 
Discontinue treatment 
 
No more than two dose reductions are allowed, and dose re-escalation is not permitted. 
4.3.3.2 
Abiraterone 
There will be no dose reductions for abiraterone for conditions other than hepatotoxicity.  
Recommended dose modifications for hepatotoxicity are outlined in Section 5.1.  
Refer to the local prescribing information for other guidance. 
4.3.3.3 
Prednisone/Prednisolone 
The dose of prednisone/prednisolone may be decreased to 5 mg daily for adverse 
effects or taken as 10 mg once daily, at the discretion of the investigator.  In the event 
discontinuation of prednisone/prednisolone is necessary for the management of 
study treatmentrelated adverse events, it may be replaced by equivalent doses of 
dexamethasone.  Patients may continue other study treatments despite discontinuation 
of prednisone/prednisolone.  For patients who were taking chronic prednisone 
 10 mg/day (or equivalent) prior to start of study treatment, the total daily dose of 
prednisone with study treatment will be 10 mg/day (or less, if decreased by investigator). 
Any overdose or incorrect administration of prednisone/prednisolone will not be collected 
as an adverse event unless accompanied with concurrent symptoms. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study, ipatasertib/placebo and abiraterone, will 
be provided by the Sponsor where required by local health authority regulations.  
The study site (i.e., investigator or other authorized personnel [e.g., pharmacist or mobile 
nurse]) is responsible for maintaining records of IMP delivery to the site, IMP inventory at 
the site, IMP use by each patient, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received, and for ensuring that patients are provided with doses 
specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced. 
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit, either by time monitoring (shipment arrival date and 
time) or temperature monitoring, for all IMPs received and that any discrepancies have 


 
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been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any IMP is destroyed, and IMP destruction must be documented on the appropriate 
form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Accountability Log. 
Refer to the Ipatasertib Investigator’s Brochure for information on IMP handling, 
including preparation and storage, and accountability. 
4.3.5 
Post-Trial Access to Ipatasertib 
The Sponsor will offer post-trial access to the study drug ipatasertib free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being. 
 
There are no appropriate alternative treatments available to the patient. 
 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
 
The study drug is commercially marketed in the patient’s country and is reasonably 
accessible to the patient (e.g., is covered by the patient’s insurance or wouldn’t 
otherwise create a financial hardship for the patient). 
 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for mCRPC. 
 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for mCRPC. 


 
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 
Provision of study drug is not permitted under the laws and regulations of the 
patient’s country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
Participants who are still receiving ipatasertib after the final OS analysis may be 
eligible to receive ipatasertib via a post-trial access program or as part of an extension 
study. 
4.4 
CONCOMITANT THERAPY, PROHIBITED THERAPY, AND 
EXCLUDED DRUGS 
Concomitant therapy includes any medication (e.g., prescription drugs, over‑the‑counter 
drugs, vaccines, homeopathic remedies, nutritional supplements) used by a patient from 
7 days before the screening visit (or 28 days prior to initiation of study treatment on 
Cycle 1, Day 1, whichever occurs first) until 28 days after the last dose of study 
treatment.  In addition, anti-diabetic medications for hyperglycemia related to 
study treatment and opioid consumption for cancer-related pain should be recorded in 
the eCRF from Cycle 1, Day 1 to initiation of the next line of prostate cancer therapy.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy  
Patients who are taking GnRH agonists or antagonists should continue their use during 
the study treatment.  For patients who did not undergo orchiectomy, concurrent 
treatment with GnRH analog is mandatory during the study treatment and must be 
recorded on the concomitant medication eCRF. 
Concurrent use or initiation of bisphosphonates, or other approved 
bone‑targeting agents, and standard-of-care steroid and pain management are allowed 
and should not result in discontinuation of study treatment.  All such medications should 
be recorded on the Concomitant Medications eCRF until initiation of a subsequent line of 
therapy and identified for their use as pain relief. 
Because the hyperglycemia observed with ipatasertib treatment is consistently 
associated with endogenous elevations in insulin, insulin-based therapy to manage any 
hyperglycemia should be used with caution because severe hypoglycemic episodes 
could potentially occur.  Therefore, initial treatment should be considered with metformin 
(preferred), sulfonylureas, and other hypoglycemic treatments. 
Focal palliative radiotherapy (e.g., external-beam radiotherapy to address single sites of 
disease) for preexisting bone metastasis or other oncology‑related issues may be 
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assessed progression, clinically apparent SSE, and unequivocal clinical progression 
prior to initiation of palliative radiation. 
Patients who require radiation or surgery as part of medical treatment in the absence of 
radiographically assessed disease progression must exercise caution, and all study 
treatment should be temporarily held for at least 7 days before and after the procedure 
(at least 14 days after radiation is recommended).  After the temporary treatment hold is 
complete, study treatment may be re-initiated when the patient has sufficiently 
recovered. 
Diarrhea is observed with ipatasertib and abiraterone, and patients will be asked to be 
cognizant of the onset, duration, severity, and frequency of symptoms.  Treatments such 
as loperamide (racecadotril as used in Europe), a loperamide/simethicone combination, 
or bismuth subsalicylate are options for treatment.  Additional details are provided 
in Section 5.1.1.1. 
4.4.2 
Prohibited Therapy 
Use of the following therapies and food supplements is prohibited during 
study treatment: 
 
Cytotoxic chemotherapy, systemic radiopharmaceuticals (e.g., radium‑223, 
strontium‑89, excluding imaging agents), alternate anti-hormone therapies 
(e.g., enzalutamide), or other investigational agents for the treatment of prostate 
cancer are not allowed. 
– 
Initiation of any of these treatments requires discontinuation of study treatment. 
 
Quinidine or other anti-arrhythmic agents with a narrow therapy window. 
 
Systemic corticosteroid use ( 20 mg of prednisone or prednisolone or an equivalent 
dose of other anti-inflammatory corticosteroids) for  7 days or use of other 
immunosuppressant agents 
 
Chronic use of a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A and 
CYP2D6 substrates with a narrow therapeutic window that are deemed not 
permissible by the investigator in consultation with the Medical Monitor after 
enrollment (refer to the guidance below).  Patients are permitted to take moderate 
inhibitors of CYP3A4 with caution. 
 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer may 
be used during the study at the discretion of the investigator. 
– 
Formulations containing St. John’s Wort are prohibited due to 
CYP3A4 induction. 
 
4.4.2.1 
Protocol-Specific Guidance on CYP450Drug Interactions 
 
Strong CYP3A4/5 inhibitors, such as but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 


 
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telithromycin, troleandomycin, voriconazole, and/or grapefruit juice or grapefruit 
supplements 
– 
Itraconazole, a strong CYP3A4 inhibitor, increases ipatasertib AUC and Cmax by 
approximately 5-fold and 2-fold, respectively (DDI Study GP30057).  Given that 
ipatasertib is a substrate of CYP3A4/5, other strong inhibitors of CYP3A4/5 may 
also result in an increase in ipatasertib exposure. 
 
Strong CYP3A4/5 inducers, such a, but not limited to rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin 
– 
In vitro data suggest that abiraterone and ipatasertib are partially metabolized 
by CYP3A4, and the presence of strong CYP3A4 inducers in vivo have shown 
to reduce their exposure by approximately 50%. 
 
CYP3A4/5 substrates with a narrow therapeutic index 
– 
In vitro data suggest that ipatasertib is a time-dependent inhibitor of CYP3A4/5, 
and in vivo data of ipatasertib have been shown to moderately increase 
CYP3A4 substrate midazolam exposure by approximately 2.2-fold. 
 
CYP2D6 substrates with a narrow therapeutic index 
– 
In vitro data suggest that abiraterone is a strong inhibitor of CYP2D6, and 
in vivo data of abiraterone have been shown to moderately increase CYP2D6 
substrates exposure by approximately 2.8 to 2.9-fold. 
 
Patients who require short-term use of a strong CYP3A4/5 inhibitor or use of sensitive 
CYP3A substrates with a narrow therapeutic window for medical treatment (i.e., an 
alternative treatment cannot be used) must exercise caution and ipatasertib/placebo 
should be temporarily held until at least 7 days after the last dose of these drugs.  
Patients should be closely monitored.  Patients who require short-term use of moderate 
CYP3A4 inhibitors may continue study treatment with caution. 
Use of CYP3A4 inhibitors or inducers concomitantly with abiraterone should be 
according to the local prescribing information.  Avoid co-administration of abiraterone 
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 (refer to abiraterone prescribing information). 
Refer to the following information for further guidance on CYP450drug interactions and 
a list of common substrates, inhibitors, and inducers:  
 
Drug Development and Drug Interactions:  Table of Substrates, Inhibitors and 
Inducers (U.S. Food and Drug Administration [FDA]):  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ 
DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm 
 
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of activities to be performed during the study. 


 
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All activities must be performed and documented for each patient.  Patients will be 
closely monitored for safety and tolerability throughout the study.  Patients should be 
assessed for toxicity prior to each dose when administered in the clinic; dosing will occur 
only if the clinical assessment is acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Voluntary, written, dated, and signed informed consent for participation in the study must 
be obtained before performing any study-related procedures.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
If eligibility assessments for PTEN tumor testing and/or CT/MRI are not completed within 
28 days prior to planned date of Cycle 1, Day 1, bone scans are not completed within 
42 days prior to planned date of Cycle 1, Day 1, or if appropriate wash-out for 
medications/procedures per exclusion criteria have not been fulfilled during screening 
window prior to the planned date of Cycle 1, Day 1, the patient will need to be 
rescreened for eligibility.  Rescreening refers to repeating the entire screening process 
except for assessments that are still within the 28-day window.  In the case of 
rescreening, and if required by local regulation, HBV, HCV, HIV testing from the initial 
screening may be acceptable for screening assessment if performed  60 days from 
Cycle 1, Day 1.  Patients will be allowed to be rescreened only once.  Blood samples 
may be redrawn because of sample handling problems, breakage, or sample integrity, 
without the patient being considered a rescreen. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases within the previous 5 years, 
surgeries, complete cancer history (including prior cancer therapies and procedures), 
complete cardiovascular history, reproductive status, smoking history, use of alcohol, 
and drugs of abuse.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, homeopathic remedies, nutritional supplements) used 
by the patient from 7 days before screening (or 28 days before initiation of study 
treatment on Day 1 of Cycle 1, whichever occurs first) will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination should be performed at screening and at study 
treatment discontinuation visit and should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 


 
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gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse (heart) rate systolic and 
diastolic blood pressures while the patient is in a seated position, and oral, axilla, or 
tympanic temperature.  Oxygen saturation will be assessed by pulse oximetry at rest 
(optional).  Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits (or as clinically indicated), record 
new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
4.5.5 
ECOG Performance Status 
Performance status will be measured using the ECOG Performance Status scale 
(see Appendix 3) and recorded on the eCRF. 
4.5.6 
Tumor and Response Evaluations 
On the basis of the recommendations of the PCWG3 guidelines (Scher et al. 2016), 
tumor assessments will be performed at screening, every 8 weeks (approximately every 
two cycles) following randomization for 24 weeks (i.e., Cycles 2, 4, and 6), and every 
12 weeks thereafter (i.e., Cycles 9 and every three cycles after) regardless of dose 
delays.  Any measurable and non-measurable disease should be documented at 
screening and re-assessed at each subsequent tumor evaluation.  Baseline tumor 
assessments should be performed by CT/MRI within  28 days and by bone scan within 
42 days of Cycle 1, Day 1.  Subsequent tumor assessments during the study should be 
performed  7 days of the scheduled tumor assessment date.  A tumor assessment must 
be done at the treatment completion visit as well, unless the most recent assessment 
was completed  28 days before the treatment completion visit or radiographically 
assessed disease progression has already been confirmed. 
Patients who discontinue study treatment for reasons other than confirmed 
radiographically assessed disease progression (e.g., toxicity) should continue to 
undergo scheduled tumor assessments per the protocol schedule until death, the 
patients experiences confirmed radiographically assessed disease progression per 
PCWG3 guidelines, the patient withdraws consent, or the study is closed, whichever 
occurs first.  Tumor assessments should continue regardless of whether the patient 
starts a new anti-cancer therapy in the absence of confirmed radiographically assessed 
disease progression unless the patient withdraws consent. 


 
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After the final OS analysis, tumor assessments will no longer be required at 
study visits for patients who are still on ipatasertib treatment, but they should be 
performed as per local practice and at the investigator’s discretion in order to monitor 
for possible tumor progression and whether the patient is in need for a new cancer 
therapy.  These tumor assessment data will not be collected.  Patients who are in the 
placebo arm and are receiving abiraterone only will no longer be required to attend 
study visits after the final OS analysis.  These patients will be followed up by 
investigators as per local practice. 
Response assessments will be performed by the investigator, on the basis of CT or MRI 
scans, according to RECIST v1.1 (see Appendix 5) for soft tissue disease and on the 
basis of bone scan according PCWG3 criteria (see Appendix 6) for the bone lesions. 
The same imaging method and serum marker tests used at screening must be used 
throughout the study.  A documented standard-of-care tumor assessment performed 
within 28 days before Cycle 1, Day 1 may be used for the screening assessment, 
provided it meets the following requirements: 
 
CT scans are the preferred imaging modality for soft tissue tumor assessments.  
Tumor assessments should include a diagnostic quality, contrast-enhanced CT scan 
of the chest, abdomen, and pelvis at baseline.  CT scans of other body region(s) 
should be included if clinically indicated.  To be suitable for RECIST v1.1 
assessments, CT scans should have a maximum thickness of 5 mm and no gaps. 
Subsequent tumor assessments should include CT scans of the chest, abdomen, 
and pelvis (and other known body region[s] if applicable).  In addition to the 
scheduled on-protocol CT scans, CT scans may be performed at the investigator’s 
discretion at any time if progressive disease is suspected. 
 
In patients for whom a CT scan is contraindicated because of an allergy to 
CT IV contrast, a CT of the chest without contrast and MRI of the abdomen and 
pelvis with contrast are recommended. 
 
MRI scans may be performed in lieu of CT scans. 
 
In case MRI measurements are performed, the following conditions should be met: 
– 
At screening, tumor assessments should include a diagnostic quality, 
contrast-enhanced MRI scan of the chest, abdomen, and pelvis. 
– 
MRI scans of other body region(s) should be included if clinically indicated. 
– 
To be suitable for RECIST v1.1 assessments, MRI scans should ideally have a 
maximum thickness of 5 mm and minimal gaps.  Subsequent tumor 
assessments should include MRI scans of the chest, abdomen, and pelvis (and 
other known body region[s] if applicable). 
– 
In addition to the scheduled on-protocol MRI scans, MRI scans may be 
repeated at the investigator’s discretion at any time if progressive disease is 
suspected. 


 
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 
Bone lesions should be assessed by bone scans and evaluated by PCWG3 criteria.  
During study treatment, the bone scan may be performed with  1 week for flexibility 
in the event of isotope shortage; the Medical Monitor should be contacted if the scan 
cannot be performed within allowed time window.  For adequate assessment of 
bone lesions, it is expected that the radiologist will adjust window leveling 
accordingly.  If progressive disease is suspected only on the basis of new lesions 
detected by bone scan, a confirmatory bone scan MUST be performed at least 
6 weeks after the initial scan which showed disease progression.  Bone scans done 
prior to Week 12 of study treatment may show a false positive due to “flare” 
phenomenon and should not be considered a confirmatory scan for disease 
progression (see Appendix 7 for guidance). 
 
PSA samples collected will be tested at a central laboratory obtained on Day 1 of 
each cycle starting with Cycle 1.  If medically indicated, additional PSA samples 
maybe collected and tested locally.  Patients with rising PSA levels only (i.e., in the 
absence of radiographic or clinical disease progression) should remain on study 
treatment per PCWG3 criteria and recommendations. 
 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples  
Laboratory samples should be drawn according to the schedule of activities 
(see Appendix 1 and Appendix 2).  Screening local laboratory assessments obtained 
 96 hours before Cycle 1, Day 1 do not have to be repeated for Cycle 1, Day 1. 
 
Hematology:  complete blood count, including RBC count, hemoglobin, hematocrit, 
WBC count with differential (neutrophils [bands, segmentedoptional], eosinophils, 
basophils, lymphocytes, monocytes, and other cells), and platelet count 
 
Coagulation (aPTT, PT, and INR) 
 
Fasting blood glucose (may be obtained by a glucometer [fingerstick]) 
 
Chemistry panel:  BUN or urea, creatinine, sodium, potassium, chloride, 
magnesium, phosphorus, bicarbonate, uric acid, calcium, total protein, albumin, total 
and direct bilirubin, alkaline phosphatase, AST, ALT, and LDH 
 
For investigational sites in countries where bicarbonate may not be collected as part 
of the standard chemistry panel, bicarbonate will not be measured. 
 
Fasting lipid profile (total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, amylase, and lipase) performed following  8-hour fast 
 
Glycosylated hemoglobin (HbA1c) 
 
Urinalysis:  specific gravity, pH, glucose, protein, ketones, and blood 
 
PSA (local laboratory assessment at screening, a central laboratory sample should 
also be submitted at screening and at every cycle visit).  After the final OS 
analysis, PSA central laboratory samples should no longer be collected. 
 
Serum testosterone (local and central laboratory sample should also be assessed at 
screening and study treatment discontinuation visit).  After the final OS analysis, 
serum testosterone central laboratory samples should no longer be collected. 


 
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 
In countries where home self-monitoring of glucose is mandatory1, self‑monitoring 
of glucose levels will be performed at least once daily by all patients after a "bigger 
meal" throughout the study treatment period (i.e., until discontinuation of 
ipatasertib/placebo).  After the final OS analysis and patients’ unblinding, home 
glucose monitoring will be performed only for patents who are receiving 
ipatasertib. 
 
Instruction manuals and supply kits will be provided for central laboratory assessments.  
The following assessments will be performed at Genentech, at a central laboratory, or at 
a specialty laboratory: 
 
Blood samples for PK analyses (see Appendix 2):  plasma samples to measure 
ipatasertib and abiraterone 
 
Blood sample for DNA extraction to enable analysis via WGS and NGS 
 
Pharmacogenomic sample (if approved by local regulatory authorities) 
 
PSA samples collected at screening and subsequently on Day 1 of every cycle to be 
tested at a central laboratory 
 
In the event that multiple tissue blocks are available for a given patient (i.e., primary 
tumor and metastatic site), the most recently collected tumor sample that fulfills the 
criteria listed below should be submitted. 
 
Evaluation of the patient’s archival tumor sample for PTEN status must occur prior 
to enrollment. 
– 
Archival or newly collected (fresh) tumor samples for central laboratory 
assessment of PTEN loss:  All patients must consent to protocol-mandated 
exploratory assessments at baseline.  Tumor tissue should be of good quality 
on the basis of total and evaluable tumor content.  Evaluation of the patient’s 
tumor sample for adequate tumor tissue content and determination of PTEN 
status by a central laboratory must occur before the initiation of study treatment.  
A tumor block or a minimum of 15 (20 preferred) unstained slides from a FFPE 
tissue sample will be required for enrollment eligibility purposes.  If only 
1214 slides are available, the Medical Monitor should be consulted. 
– 
An associated pathology report should also be sent with the sample.  If slides 
are provided, the 1520 slides should originate from the same tumor block.  If 
only 1214 slides are available, the Medical Monitor should be consulted.  
Alternatively, the patient may agree to the collection of a fresh tumor sample if 
feasible.  A detailed description of tissue quality requirements and procedures 
for collection, handling, and shipping of the samples will be provided in a 
separate laboratory manual.  Tumor tissue from bone metastases is not 
acceptable. 
 
                                            
1 Countries with mandatory self-monitoring of glucose are Austria, Belgium, Denmark, 
Hungary, Ireland, Italy, Norway, Poland, Portugal, Spain, and the United Kingdom. 


 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biologic samples will be destroyed 
when the final Clinical Study Report (CSR) has been completed, with the following 
exceptions: 
 
Plasma samples collected for PK analysis will be destroyed no later than 5 years 
after the final CSR has been completed. 
 
Blood samples collected for WGS will be stored until they are no longer needed or 
until they are exhausted. 
 
When a patient withdraws from the study, samples collected before the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, 
if samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.8 
Assay Methods for Biomarker Samples 
If multiple tumor samples that were surgically obtained at different times are submitted to 
satisfy this enrollment criterion, the assay result (i.e., tumor PTEN IHC status) will be on 
the basis of a valid result from the most recently collected tumor sample that meets the 
protocol tumor tissue eligibility criteria.  
4.5.8.1 
Ventana PTEN IHC  
The PTEN IHC assay will be performed by a central investigational testing site. 
PTEN loss is defined as a minimum of 50% of the specimen’s tumor area with no 
detectable PTEN staining in a patient’s FFPE prostate cancer sample.  A designation of 
PTEN IHC status (e.g., PTEN loss, PTEN intact, or invalid/failed) will be assigned to a 
sample.  Patients with an “invalid” or “failed” PTEN IHC result will not be eligible for 
enrollment. 
4.5.8.2 
Foundation Medicine Next-Generation Sequencing 
On samples with sufficient tumor tissue, NGS will be performed using the Foundation 
Medicine, Inc. solid tumor platform (FMI NGS). 
The FMI NGS platform detects somatic genomic alterations within hundreds of 
cancer‑related genes in tumor tissue samples.  These somatic alterations include base 
substitutions, insertions, deletions, CN alterations, and rearrangements 
(Frampton et al. 2013; Sun et al. 2014). 


 
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If research reports of the FMI NGS assay are available, the investigator may obtain the 
report on request upon documented radiographic progression (per PCWG3 criteria) with 
discontinuation from the study treatment phase, or following end of the study, whichever 
occurs earlier, unless required by law.  If allowed by local laws, the investigator may 
share and discuss the results with the patient, unless the patient chooses otherwise.  
The FMI NGS assay has not been cleared or approved by health authorities.  The NGS 
reports are generated for research purposes and are not provided for the purpose of 
guiding future treatment decisions.  Results may not be available for samples that do not 
meet testing criteria. 
The proposed definition of the PTEN loss NGS classifier by the FMI NGS assay is a 
composite group consisting of genetic abnormalities predicted to lead to a loss of 
PTEN function as described below. 
 
Homozygous deletion (CN of 0) 
 
Single nucleotide variants (SNVs) that are predicted to contain a deleterious 
mutation, described below, with a concomitant loss of the non-mutant PTEN allele 
defined by loss of heterozygosity with CN  1 (LOH1) or loss of heterozygosity with 
CN  1 (LOHx) 
 
LOH1 without concomitant SNVs that is predicted to be a deleterious mutation 
 
Known dominant negative SNV (e.g., C124S, G129E, R130X; Papa et al. 2014); 
details to be provided in the SAP 
 
It is anticipated that approximately 40% of patients with mCRPC would be classified as 
part of a PTEN-loss sample using this definition. 
Additional exploratory analyses may be performed to assess for associations between 
somatic alterations identified by NGS and clinical study measures and may provide 
information on response or resistance to therapy. 
4.5.8.3 
Circulating-Tumor DNA and RNA Analysis 
Circulating-tumor DNA and RNA may be extracted from plasma samples collected from 
patients and used for the detection of oncogenic mutations, copy number changes, 
DNA methylation, and/or RNA expression using appropriate technologies.  
The prevalence of the mutations measured at baseline and after treatment may provide 
information on response or resistance to therapy. 
4.5.8.4 
Messenger RNA Expression Profiling 
In cases where there is sufficient archival tissue to isolate RNA, gene expression may be 
performed using gene expression assays conducted using appropriate technologies.  
Analysis may include the entire transcriptome or a limited panel of genes that are 
important for prostate cancer biology, immune oncology, and signaling related to the AR 
and PI3K pathways. 


 
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4.5.8.5 
Copy Number Analysis  
The level of CN alterations in cancer-related genes may be determined using 
DNA-based technologies, either cytogenetically, using chromosomal in situ hybridization 
(ISH), NGS platforms, reverse transcription PCR, or equivalent technologies.  
For cytogenetic assays, detection may be either fluorescence-based (FISH assay) or 
chromogenic-based (chromogenic ISH).  Data on increased CN of 
PI3K pathwaysactivating genes may provide information on response or resistance to 
therapy. 
4.5.8.6 
Plasma Biomarker Analyses 
Assays that assess the expression of soluble, systemic cytokines, and chemokines from 
the plasma of patients will be completed using appropriate methodologies, such as 
ELISA-based, mass spectrometrybased, or equivalent technologies. 
4.5.8.7 
Plasma Pharmacokinetic Assay 
Plasma samples will be evaluated for ipatasertib, its metabolite (G‑037720) and for 
abiraterone through use of a validated liquid chromatography tandem mass 
spectrometry assay.  Samples may be used for exploratory evaluation of ipatasertib 
related metabolites and additional PK and pharmacodynamic assessments or assay 
development. 
4.5.8.8 
Pharmacogenetic Polymorphism Assay 
For the pharmacogenetic analysis, gene mutations will be assayed using multiplex PCR, 
allele‑specific PCR, direct sequencing, or other acceptable methods. 
4.5.9 
Electrocardiograms and Multigated Acquisition 
Scan/Echocardiogram 
An ECG will be obtained at screening and as clinically indicated during study treatment 
and at the end of treatment visit.  ECGs for each patient should be obtained from the 
same machine wherever possible.  Lead placement should be as consistent as possible.  
ECG recordings must be performed after the patient has been resting in a supine 
position for at least 10 minutes. 
ECGs will be reviewed by the investigator to determine patient eligibility at screening.  
Baseline evaluation of LVEF by MUGA or ECHO should be considered for patients with 
cardiac risk factors and/or history of clinically significant cardiac disease (including 
anatomic abnormality, coronary artery disease, congestive heart failure, or previously 
documented LVEF  50%.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient’s permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 


 
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4.5.10 
PROs 
To more fully characterize the clinical profile of ipatasertib, patients will rate their 
symptoms and their functioning impacts through use of the following instruments:  the 
EORTC QLQ-C30 and selected items from the Quality of Life Questionnaire Prostate 
Cancer Module (QLQ-PR25), pain severity NRS, selected items from the PRO-CTCAE, 
and the EQ-5D-5L.  In addition, patients will record their analgesic medication 
consumption in a log from Cycle 1, Day 1 to initiation of the next line of prostate cancer 
therapy. 
Patients will complete these assessments as follows: 
 
Pain severity at its worst (24-hour recall) NRS will be captured at screening to be 
used for inclusion. 
 
A medication analgesic log will be completed, starting on Cycle 1, Day 1 until 
initiation of subsequent line of therapy or 1-year post-treatment discontinuation, 
whichever occurs first. 
 
Selected items from the PRO-CTCAE will be completed by at Cycle 1 on Days 1, 8, 
and 15; from Cycle 2 to Cycle 6 on Days 1 and 15; and on Day 1 of each 
subsequent cycle and as clinically indicated while on study treatment. 
 
The pain severity at its worst (7-day recall) NRS, the EORTC QLQ-C30, the 8‑item 
urinary scale from the QLQ-PR25, and the EQ-5D-5L (including VAS) will be 
completed on Cycle 1, Day 1 and every cycle thereafter until the end of treatment 
visit (included) and as clinically indicated.  In addition, these questionnaires will be 
completed approximately every 28 days from treatment discontinuation (for any 
reason) to initiation of subsequent line of therapy. 
 
Selected scales from the EORTC QLQ-C30 (physical functioning [PF], role 
functioning [RF], global health status [GHS]), the pain severity at its worst 
(7‑day recall) NRS, and the EQ-5D-5L in its entirety will be completed by patients 
every 3 months after initiation of subsequent line of therapy or 1 year after treatment 
discontinuation, whichever occurs first, until death.  Patients will be asked (i.e., not 
part of the electronic device) to report any recent (7-day) analgesic uses (response: 
yes or no). 
 
The pain severity at its worst (24-hour recall) NRS completed at screening at the site will 
be administered on paper and documented on the appropriate eCRF. 
It is imperative that each PRO questionnaire and NRS be completed on Cycle 1, Day 1 
until initiation of subsequent line of therapy, disregarding treatment discontinuation.  
All PRO questionnaires and NRS that are completed at the clinic are required to be 
completed prior to any study assessment(s) that could bias patient responses. 
The questionnaires and NRS will be translated in the country language(s) and as 
feasible in the local language. 


 
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Patients will use an electronic device to capture all PRO data.  Instructions to use the 
device and to complete the PRO questionnaires and medication log will be provided by 
site staff once the patient is randomized and before initiation of study treatment.  
If needed, back-up paper forms will be available to ensure collection of PRO data from 
each patient.  The data will be transmitted to a centralized database maintained by the 
vendor and will be available for access by appropriate study personnel at the site. 
After the final OS analysis, PROs data and analgesics medication consumption 
information will no longer be collected (see Appendix 1).  
4.5.10.1 
EORTC QLQ-C30 and Urinary Scale from QLQ-P25 
The EORTC QLQ-C30 (see Appendix 8) consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social), 
three symptom scales (fatigue, nausea and vomiting, pain), GHS/quality of life (QoL), 
and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) with a recall period of the previous week (van Andel et al. 2008).  
In addition, an 8-item urinary scale from the EORTC prostate module 
(EORTC QLQ-PR25; see Appendix 9) will be added to capture symptom-specific to 
prostate cancer (Dąbrowska-Bender et al. 2015). 
All items other than those forming the GHS scale are rated on a 4-point categorical 
scale.  A high score (4) for a functional scale represents a high or healthy level of 
functioning, a high score (7) for the GHS/QoL represents a high QoL, but a high score 
for a symptom scale or item represents a high level of symptomatology or problems. 
To understand patients’ symptom experience post-treatment and the course of their 
health-related QoL, the PF, RF, and GHS scales will be completed as part of the 
follow-up visits.  These scales were selected for their content validity in documenting 
patients’ functioning in daily activities and QoL. 
4.5.10.2 
Pain Assessments 
Cancer-related pain will be assessed using a patient report of pain severity at its worst 
and rated on a 10-point NRS, with 10 indicating a worst outcome.  This assessment is a 
commonly used assessment across diseases and treatments.  Patients will complete the 
pain severity assessment (24-hour recall) at screening; this recall period was selected to 
account for the fact that patients will have had no training to appropriately recall their 
pain experience over a longer time period.  Following randomization, patients will 
complete the pain severity assessment (7-day recall) at each visit.  Recognizing that a 
monthly assessment using a short assessment window (past 24 hours) would provide 
only limited information of patients’ experience with signs of clinical deterioration, the 
assessment window was broadened to 7 days. 


 
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Thresholds to inform a clinical deterioration on the pain severity NRS were documented 
in patients with breast cancer and bone metastases and will be applied to this study 
(Mathias et al. 2011; Cleeland et al. 2013; see Appendix 10). 
4.5.10.3 
Medication Log  
A country-specific patient-reported medication log will be used to document analgesic 
use for cancer-related pain, particularly opioid intake (e.g., name of molecule, form, 
number of pills/patch) from Cycle 1, Day 1 to initiation of the next line of prostate cancer 
therapy.  The patient medication log should be used when completing the concomitant 
medications eCRF pages for the consumption of analgesics for cancer-related pain. 
4.5.10.4 
PRO-CTCAE 
The PRO-CTCAE is an item bank reflecting 78 symptomatic adverse events rated 
according to their severity, interference with daily function, frequency, and/or occurrence.  
The item bank was designed and validated as a repository of stand-alone items. 
Symptoms selected for this study include those symptoms occurring in  15% of patients 
for any treatment (ipatasertib and/or abiraterone) and/or those with a Grade  3 event, 
with incidence of  5% in the treatments of any treatment (ipatasertib and/or 
abiraterone), and/or those with a Grade  3 with incidence of  5% in the treatments of 
any study arm. 
Only adverse events relevant for patient reporting, as being subjective, with or without 
observable components (e.g., vomiting and nausea, respectively) or primarily observable 
with subjective components (e.g., rash), were selected (Basch et al. 2014).  
Adverse events of which assessments relied on laboratory testing (e.g., anemia) that 
were presented as being primarily asymptomatic or with non-specific signs and 
symptoms (e.g., hyperglycemia) were disregarded.  Adverse events that did not have an 
identifiable symptom equivalent in the PRO-CTCAE were also excluded.  Lastly, 
considering patients’ completion burden, symptoms with substantial coverage across 
PRO measures (e.g., pain) were also excluded from the pool.  Based on the above 
criteria, eight symptomatic adverse events were selected from the PRO‑CTCAE 
item bank, namely decreased appetite, nausea, vomiting, constipation, diarrhea, rash, 
and fatigue, representing a total of 11 items.  The free-text item from the PRO‑CTCAE 
item bank was not included. 
An additional item providing an overall assessment of symptom tolerability was added to 
the 11 select PRO-CTAE items (see Appendix 12). 
Based on the data available to date regarding the tolerability of ipatasertib in 
combination with abiraterone, the targeted symptomatic adverse events should have 
occurred by Cycle 6.  Therefore, patients will be asked to complete the 11-item 
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each cycle until Cycle 6, and then on Day 1 of each cycle and as clinically indicated 
while on study treatment. 
4.5.10.5 
EQ-5D-5L 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses 
(EuroQoL Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013).  There 
are two components to the EQ-5D-5L:  a five-item health state profile that assesses 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a 
VAS that measures health state.  Published weighting systems allow for the creation of a 
single composite score of the patient’s health status.  The EQ-5D-5L will be used in this 
study to inform pharmacoeconomic evaluations (see Appendix 13). 
4.5.11 
Survival Follow-Up 
Survival follow-up information will be collected via telephone calls, patient’s medical 
records, and/or clinic visits approximately every 3 months until death, loss to follow-up, 
or study termination by Sponsor.  All patients will be followed for survival information 
unless the patient requests to be withdrawn from study; this request must be 
documented in the source file and signed by the investigator.  If the patient withdraws 
from the study, the study staff may use a public information source (e.g., county records) 
to obtain information about survival status only.  After the final OS analysis, survival 
follow-up information will no longer be collected. 
4.5.12 
Optional Samples for Research Biosample Repository 
4.5.12.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives: 
 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
 
To increase knowledge and understanding of disease biology 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 


 
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4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biologic samples to the RBR is contingent upon the review 
and approval of the exploratory research and the RBR portion of the Informed Consent 
Form by each site’s IRB/EC and, if applicable, an appropriate regulatory body.  If a site 
has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.12) will not be applicable at that site. 
4.5.12.3 
Sample Collection 
Leftover patient samples (e.g., blood and/or residual tumor tissue samples) collected for 
this study will be stored in the RBR and used for research purposes, including but not 
limited to research on biomarkers related to ipatasertib or prostate cancer. 
The above samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations via WGS, NGS, or other 
genomic analysis methods. 
Genomics is increasingly informing researchers’ understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR specimens are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.12.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number.  Patient medical information associated with RBR specimens is confidential and 
may be disclosed to third parties only as permitted by the Informed Consent Form 
(or separate authorization for use and disclosure of personal health information) signed 
by the patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses, data derived from 
RBR specimens will generally not be provided to study investigators or patients unless 
required by law.  The aggregate results of any conducted research will be available in 
accordance with the effective Sponsor policy on study data publication. 


 
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Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RBR research. 
4.5.12.6 
Withdrawal from the Research Biosample Respository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 
his or her RBR samples during the study, the investigator must inform the 
Medical Monitor in writing of the patient’s wishes through use of the appropriate RBR 
Subject Withdrawal Form and must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  If a patient wishes to withdraw consent 
to the testing of his or her RBR samples after closure of the trial site, the investigator 
must inform the Sponsor by emailing the study number and patient number to the 
following email address: 
global.rcr-withdrawal@roche.com 
A patient’s withdrawal from Study CO39303 does not, by itself, constitute withdrawal 
of consent for testing of RBR samples.  Likewise, a patient’s withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from Study CO39303. 


 
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4.5.12.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality‑controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include but are not limited to the following: 
 
Patient withdrawal of consent at any time 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he continues in the study 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients discontinuing study treatment for any reason other than radiographically 
assessed disease progression should continue to undergo tumor response evaluations 
until confirmed radiographic evidence of progressive disease regardless of initiation of 
another anti‑cancer therapy.  Additionally, because the secondary endpoint of pain 
progression may occur after radiographic progression, collection of pain endpoints will 
continue to be collected on a periodic basis, until initiation of another anti‑cancer therapy 
or up to 1 year, whichever occurs first.  See Section 5.1 for adverse events and 
discontinuation details. 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 


 
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4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Ipatasertib is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with ipatasertib in completed and 
ongoing studies. 
The anticipated important safety risks for ipatasertib and abiraterone are outlined below.  
Refer to the Ipatasertib Investigator’s Brochure for a complete summary of safety 
information.  Refer to the abiraterone and prednisone/prednisolone local prescribing 
information for a summary of safety information. 
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events, as well as 
expedited reporting of protocol-defined adverse events of special interest regardless of 
seriousness.  In addition, guidelines for managing adverse events, including criteria for 
dosage modification and treatment interruption or discontinuation, are provided below to 
investigators.  Educational materials will be provided to patients outlining these safety 
guidelines. 
This study will use an iDMC.  The iDMC will be responsible for ongoing monitoring of the 
safety of patients in the study according to the iDMC Charter.  During the study, the 


 
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iDMC will evaluate safety data on a periodic basis, approximately every 3 months for the 
first year and approximately every 6 months thereafter, until the time of the primary 
analysis.  The iDMC will make recommendation as to whether or not the trial should 
continue based on ongoing reviews of safety data.  The Sponsor will designate an iDCC 
to prepare data for iDMC review.  Only if action or consultation with health authorities is 
required will other than designated Sponsor staff be involved.  Clinical sites will be 
restricted from access to study results until the conclusion of the study. 
5.1.1 
Management of Selected Identified and Potential Risks of 
Ipatasertib and Abiraterone 
Guidelines for managing selected adverse events are provided in this section to improve 
safety and tolerability; however, patients may be treated per institutional practices as 
appropriate.  If any observed toxicity is attributable to only one drug as assessed by the 
investigator, the dose of the other drug may not require modification.  Reasons for dose 
modifications (interruptions or reduction) or delays, the supportive measure taken, and 
the outcome will be recorded in the eCRF. 
5.1.1.1 
Diarrhea 
For diarrhea occurring after Cycle 2 that persists for more than 5 days, despite treatment 
with an anti-diarrheal agent, a stool culture for infectious workup (i.e., Clostridium 
difficile, enteric bacteria, CMV) will be obtained, and diarrhea should be treated with the 
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Table 3 
Diarrhea Management Guidelines 
Severity of Diarrhea 
Management Guideline 
Grade 1 
Continue study drugs at the current dose level. 
Manage with loperamide 4 mg initially, and then 2 mg every 4 hours or 
after every unformed stool until after 12-hour diarrhea free interval. 
Dietary modifications such as avoiding any lactose-containing foods. 
Hydration with 810 glasses of clear liquid such as broth and low-calorie 
electrolyte-enhanced drinks per day. 
Grade 2 
Manage with loperamide as early as possible 4 mg initially, and then 2 mg 
every 4 hours or after every unformed stool until after 12-hour diarrhea 
free interval. 
Dietary modifications such as avoiding any lactose-containing foods.  
Hydration with 810 glasses of clear liquid, such as broth and low-calorie 
electrolyte-enhanced drinks, per day. 
For non-infectious diarrhea lasting more than 48 hours despite optimal 
loperamide treatment, manage with second-line anti-diarrheal agents, 
including, but not limited to Lomotil®, codeine, or octreotide, or as per 
institutional guidelines. 
Interrupt ipatasertib/placebo until diarrhea improves to Grade  1.  
Ipatasertib can be resumed at the same dose or one dose lower per 
investigator evaluation upon improvement to Grade  1. 
Reduce ipatasertib/placebo by one additional dose level (see Table 2) for 
recurrent Grade 2 diarrhea. 
Grade  3 
Rule out infectious etiology. 
Treatment per Grade 2 management guidelines and supportive care. 
Interrupt ipatasertib/placebo until diarrhea improves to Grade  1. 
Ipatasertib/placebo should be reduced by one dose level (see Table 2) 
when treatment is restarted. 
For recurrent Grade 3 diarrhea, reduce ipatasertib/placebo dose by one 
additional dose level (see Table 2), or permanently discontinue 
ipatasertib/placebo per investigator discretion. 
Grade 4 
Management as per Grade 3 guidelines.  Permanently discontinue 
ipatasertib/placebo. 
 
5.1.1.2 
Fasting Hyperglycemia 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours. 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment 
are outlined below (see Table 4) and are intended to provide guidance for fasting 
glucose measurements assessed in the clinic.  Decisions regarding study treatment 
should be made on fasting levels drawn in the clinic whenever possible. 
Home glucose measurements may be used to trigger contact between patient and the 
investigative site team and may lead to an unscheduled clinic visit to assess fasting 


 
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glucose.  Guidance for when to call the investigator/site staff (or designated 
endocrinologist, if applicable) should be provided to patients for hypoglycemia 
(e.g., glucose value under 70 mg/dL [3.9 mmol/L]) and hyperglycemia (e.g., glucose 
value over 300 mg/dL [16.7 mmol/L]).  Alternative thresholds may be selected as 
clinically indicated per investigator discretion or institutional guidance and noted in the 
source documents.  For any patients performing home glucose monitoring, a blood 
glucose log should be reviewed at each clinic visit (and source data retained); entry of 
results into the patient’s eCRF will be limited to values, which result in intervention. 
In the event of ipatasertib/placebo interruption, anti-diabetic medications may need to be 
held or reduced (per investigator judgement) and glucose should be monitored closely to 
minimize the risk of hypoglycemia. 
Ipatasertib/placebo should be discontinued for recurrent Grade 4 fasting hyperglycemia 
or a single event of hyperglycemia Grade  3 associated with metabolic acidosis 
Grade  3. 
Table 4 
Fasting Hyperglycemia Management Guidelines 
Severity of Fasting 
Hyperglycemia 
Management Guideline 
Grade 1:  fasting glucose value 
 ULN to 160 mg/dL (8.9 mmol/L) 
Monitor fasting glucose per protocol.  Continue home glucose 
monitoring daily for patients from countries with mandatory 
self-monitoring of glucose. a For all other patients, consider 
home glucose monitoring.  
Grade 2:  fasting glucose 
value > 160 to 250 mg/dL (>8.9 
to 13.9 mmol/L) 
Interruption of ipatasertib/placebo until fasting hyperglycemia 
resolves to Grade  1. 
Continue home glucose monitoring for patients from countries 
with mandatory self-monitoring of glucose. a  For all other 
patients, initiate home glucose monitoring.  
Start oral anti-diabetic medications (e.g., metformin). 
If patient is already on an oral anti-diabetic medication, the 
dose of ipatasertib/placebo should be reduced by one dose 
level (refer to Table 2 
). 
If the patient previously has not been receiving any oral 
anti-diabetic medication, ipatasertib/placebo may be resumed 
at the previous dose level with initiation of oral anti-diabetic 
medication. 
 
 
 


 
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Table 4 
Fasting Hyperglycemia Management Guidelines (cont.) 
 
Grade 3:  fasting glucose value 
 250 to 500 mg/dL (13.9 to 
27.8 mmol/L) 
Interrupt ipatasertib/placebo until resolution to Grade  1. 
Continue home glucose monitoring for patients from countries 
with mandatory self-monitoring of glucose a.  For all other 
patients, initiate home glucose monitoring or continue with 
it if already started.  Treat hyperglycemia as medically 
appropriate. 
Start (or increase dose of) oral anti-diabetic medications 
(e.g., metformin). 
If the patient is already on an oral anti-diabetic mediation, 
ipatasertib/placebo should be reduced by one dose level when 
treatment is restarted. 
If previously, the patient has not been receiving any oral 
anti‑diabetic medication, ipatasertib/placebo may be resumed 
at the previous dose level with initiation of oral anti-diabetic 
medication. 
If Grade  3 fasting hyperglycemia recurs, the dose of 
ipatasertib/placebo should be reduced by one dose level when 
treatment is restarted. 
Grade 4:  fasting glucose value 
 500 mg/dL (27.8 mmol/L) 
Interrupt ipatasertib/placebo until resolution to Grade  1. 
Treat hyperglycemia as medically appropriate. 
Continue home glucose monitoring for patients from countries 
with mandatory self-monitoring of glucose a.  For all other 
patients, initiate home glucose monitoring or continue with it 
if already started.  Start (or increase dose of) oral anti-diabetic 
medications (e.g., metformin). 
Assess for volume depletion and appropriate intravenous or 
oral hydration. 
Reduced ipatasertib/placebo by one dose level when treatment 
is restarted. 
If Grade 4 hyperglycemia recurs, permanently discontinue 
ipatasertib/placebo. 
ULN  upper limit of normal; VHP  Voluntary Harmonization Procedure. 
Note:  For all grades, the patient should receive education on a diabetic diet. 
a The countries with mandatory self-monitoring of glucose are Austria, Belgium, Denmark, 
Hungary, Ireland, Italy, Norway, Poland, Portugal, Spain, and the United Kingdom.  
Mandatory self‑monitoring of glucose was implemented with Protocol Version 5 (VHP) dated 
14 August 2018 in response to a health authority requirement issued via VHP to implement 
minimum once daily post-prandial home glucose monitoring for the entire duration of study 
treatment to monitor the risk of hyperglycemia. 
 
 
5.1.1.3 
Nausea and/or Vomiting  
Dose reductions for nausea and/or vomiting should occur only if the symptoms persist 
despite a minimum of two treatments with adequate (combination) anti‑emetic 
treatment(s), including ondansetron (or equivalent anti-emetic; see Table 5 ). 


 
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For persistent nausea and/or vomiting attributable to ipatasertib/placebo, 
dosage-modification guidelines are outlined in Table 5 
. 
Table 5 
Nausea and Vomiting Management Guidelines 
Severity of Nausea and 
Vomiting 
Management Guideline 
Grade 1 
Provide maximum supportive care as needed. 
Grade 2 
Provide maximum supportive care as needed. 
Provide ondansetron (or equivalent anti-emetic medication) as 
needed. 
Grade  3 
Interrupt ipatasertib/placebo until nausea or vomiting resolves 
to Grade  2. 
Provide maximum supportive care as needed. 
Provide ondansetron (or equivalent anti-emetic) as needed. 
If Grade  3 nausea or vomiting recurs, ipatasertib/placebo 
should be reduced by one dose level (refer to Table 2) when 
treatment is restarted. 
 
5.1.1.4 
Rash 
Ipatasertib/placebo should be permanently discontinued for rash associated with 
Stevens-Johnson syndrome, toxic epidermal necrolysis, or other suspected severe 
hypersensitivity or allergic reaction.  Dosage modification and symptom management 
guidelines for skin toxicity, including erythema multiforme, attributable to 
ipatasertib/placebo are shown below (see Table 6). 
Table 6 
Rash Management Guidelines 
Severity of Rash 
Management Guideline 
Grade 1 
Continue study drugs. 
Consider topical corticosteroids. 
Grade 2 
Interrupt ipatasertib/placebo treatment until resolution to Grade 1 or the 
toxicity is no longer clinically significant. 
Treat rash with topical corticosteroids. 
Consider treatment of rash with oral corticosteroids. 
Follow above guidance and reduce ipatasertib/placebo by one dose level 
for recurrent Grade 2 rash. 
 
 
 


 
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Table 6 
Rash Management Guidelines (cont.) 
Severity of Rash 
Management Guideline 
Grade 3 
Interrupt ipatasertib/placebo treatment until resolution to Grade 1 or the 
toxicity is no longer clinically significant. 
Treat rash with topical and systemic corticosteroids. 
Consider dermatological consultation. 
If the skin toxicity resolves to Grade 1 or is no longer clinically significant 
within 28 days, following completion of the steroid taper, 
ipatasertib/placebo may be resumed at one dose level below the previous 
dose (refer to Table 2). 
If recovery of the skin toxicity to Grade 1 does not occur or skin toxicity 
remains clinically significant continuously for 4 weeks, or Grade 3 rash 
recurs, permanently discontinue ipatasertib/placebo. 
Grade 4 
Administration of systemic steroids (oral or intravenous) is recommended.  
Consider dermatological consultation and skin biopsy.  Ipatasertib should 
be permanently discontinued. 
 
5.1.1.5 
Pneumonitis 
Pneumonitis is not known to be causally related to any of the study drugs; however, it 
has been observed with other drugs treating pathways similar to ipatasertib.  Every effort 
should be made to determine the etiology of dyspnea and changes in pulmonary 
function (see Table 7). 
Table 7 
Pneumonitis Management Guidelines 
Severity of 
Pneumonitis 
Management Guideline 
Grade 1 
Continue study drugs. 
Perform CT scan and pulmonary function tests.  Repeat CT scan every 8 weeks 
until a return to baseline. 
Grade 2 
Prescribe corticosteroids if there are clinical symptoms and infectious etiology is 
ruled out.  Interrupt ipatasertib/placebo treatment as long as corticosteroids are 
being given.  
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return to 
baseline. 
If pneumonitis resolves to Grade  1 after completion of the steroid taper, 
ipatasertib/placebo may be resumed at either the previous dose or one dose 
level below the previous dose (see Table 2) per investigator assessment. 
For recurrent Grade 2 pneumonitis, ipatasertib/placebo must be resumed at one 
dose level below the previous dose. 
Discontinue ipatasertib/placebo if recovery to Grade  1 is not evident within 
28 days. 
 
 
 


 
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Table 7 
Pneumonitis Management Guidelines (cont.) 
Severity of 
Pneumonitis 
Management Guideline 
Grade 3 
If infectious etiology is ruled out, prescribe corticosteroids as clinically indicated. 
Interrupt ipatasertib/placebo treatment as long as corticosteroids are being given. 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return to 
baseline.  Bronchoscopy is recommended. 
If pneumonitis resolves to Grade  1, following completion of the steroid taper, 
continue ipatasertib/placebo at one dose level below the previous dose 
(see Table 2).  Discontinue ipatasertib/placebo if recovery to Grade  1 is not 
evident within 28 days. 
For recurrent non-infectious Grade 3 pneumonitis events, ipatasertib/placebo 
should be permanently discontinued. 
Grade 4 
If infectious etiology is ruled out, prescribe corticosteroids as clinically indicated. 
Permanently discontinue ipatasertib/placebo. 
Perform CT scan and PFTs.  Repeat CT scan every 4 weeks until a return to 
baseline.  Bronchoscopy is recommended. 
CT  computed tomography; PFT  pulmonary function test. 
 
5.1.1.6 
Hepatotoxicity 
Permanently discontinue abiraterone and ipatasertib/placebo for any patients who 
develop a concurrent elevation of ALT and/or AST greater than 3  ULN and total 
bilirubin greater than 2  ULN and/or clinical jaundice in the absence of biliary obstruction 
or other causes responsible for the concurrent elevation, including patients having 
abnormal liver function tests that meet Hy’s law criteria (see Section 5.3.5.6).  Dosage 
modification and symptom management guidelines for hepatotoxicity, attributable to 
study treatment are shown below (see Table 8 
). 
Table 8 
Hepatotoxicity Management Guidelines 
Severity of LFT Elevation 
Management Guideline 
Grade 1  
AST or ALT  baseline 3  ULN 
or  
T bilirubin  baseline  1.5  ULN 
Continue study drugs. 
Grade 2  
AST or ALT  3–5  ULN or 
T bilirubin  1.5–3.0  ULN 
Continue study drugs.  
The frequency of liver function test monitoring should be 
increased as clinically indicated if the investigator judges that 
the laboratory abnormalities are potentially related to study 
medication. 
LFT  liver function test; ULN  upper limit of normal. 
 
 
 


 
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Table 8 
Hepatotoxicity Management Guidelines (cont.) 
Severity of LFT Elevation 
Management Guideline 
Grade 3  
AST or ALT  5–20  ULN or 
T bilirubin  3–10  ULN 
Immediately interrupt abiraterone and ipatasertib/placebo. 
On return of LFTs to baseline or to AST and ALT  2.5  ULN 
and total bilirubin  1.5  ULN levels, restart 
ipatasertib/placebo at previous dose level (see Table 2) and 
restart abiraterone at reduced dose of 750 mg QD. 
Following treatment resumption, monitor serum 
transaminases and bilirubin at a minimum every 2 weeks for 
3 months and monthly thereafter. 
If another Grade 3 event occurs, interrupt abiraterone and 
ipatasertib/placebo.  On return of LFTs to baseline or AST 
and ALT  2.5  ULN and total bilirubin  1.5  ULN levels, 
restart ipatasertib/placebo, reducing the dose by one level 
and abiraterone at a reduced dose of 500 mg QD. 
Further Grade 3 occurrences must result in permanent 
discontinuation of abiraterone and ipatasertib/placebo. 
Grade 4 
AST or ALT  20  ULN or 
T bilirubin  10  ULN 
Permanently discontinue abiraterone and ipatasertib/placebo. 
LFT  liver function test; QD  once daily; ULN  upper limit of normal. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined 
in Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described 
in Section 5.3.5.9 


 
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 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
– 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator’s judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to 
NCI CTCAE v4.0; see Section 5.3.3); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 


 
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see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study include the following: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s law (see Section 5.3.5.6). 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
– 
Any organism, virus, or infectious particle (e.g., prion protein 
transmittingtransmissible spongiform encephalopathy), pathogenic or 
non-pathogenic, is considered an infectious agent.  A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a patient exposed to a medicinal product.  
This term applies only when a contamination of the study drug is suspected. 
 
Grade  3 diarrhea 
 
Grade  3 hyperglycemia 
 
Grade  3 rash 
 
Grade  2 pneumonitis 
 
Grade  2 colitis/enterocolitis 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4−5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but before initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study drug or initiation of subsequent lines of anti-cancer therapy, whichever 
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Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 9 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 9 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE  
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see 
also Table 10 
): 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 10 Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
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5.3.5.1 
Diagnosis versus Signs and Symptoms 
For adverse events, a diagnosis (if known) should be recorded on the Adverse Event 
eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 
reported adverse events based on signs and symptoms should be nullified and replaced 
by one adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from "non-serious" to "serious," providing the date that 
the event became serious, and completing all data fields related to serious adverse 
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A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated LDH" as opposed to "abnormal LDH").  If the laboratory abnormality can 
be characterized by a precise clinical term per standard definitions, the clinical term 
should be recorded as the adverse event.  For example, an elevated serum potassium 
level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment 
 


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either 
an elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  baseline value in combination with total 
bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  baseline value in combination with 
clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see  Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.7 
Deaths 
Deaths that are attributed by the investigator solely to progression of mCRPC should be 
recorded on the Death Attributed to Progressive Disease eCRF.  During the study 
adverse event reporting period (as defined in Section 5.3.1) all other deaths, regardless 
of relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  Instructions for reporting 
deaths that occur after the adverse event reporting period are provided in Section 5.6.  
An independent monitoring committee will monitor the frequency of deaths from all 
causes. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 


 
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cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.9 
Lack of Efficacy or Worsening of mCRPC 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1 and PCWG3 criteria.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Hospitalization is an outcome, and should not be reported as an adverse event.  
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
– 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
– 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
 


 
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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours. 
 
5.3.5.11 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  No attempt will be made to reconcile 
the findings from reports of treatment-related symptoms by the clinicians (NCI CTCAE) 
and from the patients (NCI PRO-CTCAE) given the different ways in which these 
two data sources are collected. 
Although sites are not expected to review the PRO data, it is possible that an 
investigator could become aware of PRO data that may be indicative of an 
adverse event.  Under these circumstances, the investigator will determine whether the 
criteria for an adverse event have been met, and, if so, will report the event on the 
Adverse Event eCRF. 
5.3.5.12 
Cases of Accidental Overdose, Medication Error, Drug Abuse, 
or Drug Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
– 
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
– 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 


 
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event; see Section 5.4.2).  For ipatasertib, placebo, and abiraterone, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with ipatasertib, placebo, and abiraterone, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 


 
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 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require 
two entries on the Adverse Event eCRF, one entry to report the accidental overdose and 
one entry to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information for these events to the Sponsor immediately 
(i.e., no more than 24 hours after becoming aware of the information).  New significant 
information includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event’s outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 


 
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Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours per day, 7 days per week. Details will be provided separately. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur before Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Clinical Trial Adverse Event/Special Situations Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur  28 days after the last dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
28 days after the last dose of study drug.  The investigator should report the pregnancy 
on the Clinical Trial Pregnancy Reporting Form in paper format and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
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or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form with additional 
information on the pregnant partner and the course and outcome of the pregnancy as it 
becomes available.  An investigator who is contacted by the male patient or his pregnant 
partner may provide information on the risks of the pregnancy and the possible effects 
on the fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
5.4.3.2 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female partner of a male patient 
exposed to study drug should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial‑related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 28 days 
[see Section 5.3.1] after the last dose of study drug), all deaths, regardless of cause, 
should be reported through use of the Long-Term Survival Follow-Up eCRF. 


 
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After the end of the adverse event-reporting period, if the investigator becomes aware of 
any serious adverse event that is believed to be related to prior study drug treatment, the 
event should be reported through use of the Adverse Event eCRF. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
 
Ipatasertib Investigator’s Brochure 
 
SmPC for abiraterone 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
All analyses discussed in this section will be restricted to the patients enrolled in the 
global enrollment phase only (i.e., excluding the China extension cohort), unless 
otherwise noted. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Approximately 1100 patients in total will be randomized into this study in about 
20 months.  Assuming 50% prevalence of IHC PTEN-loss tumors in all patients, it’s 
estimated that approximately 550 patients will have PTEN loss tumors. 
6.1.1 
Type I Error Control 
The overall type I error () for this study is 0.05 (two-sided).  Type I error will be 
controlled for the following efficacy endpoints: 
 
Co-primary efficacy endpoints:  Investigator-assessed rPFS (per PCWG3 criteria, 
see Section 6.4.1) in the ITT population and in patients with PTEN‑loss tumors 
by IHC 
 
Key secondary endpoints:  OS in the ITT population and in patients with 
PTEN-loss tumors by IHC 
 


 
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Type I error will be controlled by comparing these endpoints between treatment arms 
according to the following testing procedure Figure 2). 
Figure 2 Type I Error Control 
 
Dx  diagnosis; ITT  intent to treat; OS  overall survival; rPFS  radiographic 
progression‑free survival. 
 
Testing of rPFS 
Both rPFS in the ITT population and in patients with PTEN-loss tumors by IHC will be 
tested at the time of the primary analysis of rPFS in order as follows: 
 
Firstly, test the null hypothesis of no difference in rPFS between the two arms in 
patients with PTEN-loss tumors by IHC using the stratified log-rank test with 
significance level  of 0.05. 
 
If the null hypothesis of test 1 described above is rejected,  of 0.05 will then be 
passed along and allocated between rPFS in the ITT population (0.01) and OS in 
patients with PTEN-loss tumors by IHC (0.04).  That is, rPFS in the ITT population 
will be tested using the stratified log-rank test with significance level  of 0.01. 
Testing of OS in patients with PTEN-loss tumors by IHC 
 
OS in patients with PTEN-loss tumors by IHC will be tested only if the test of rPFS in 
patients with PTEN-loss tumors by IHC (i.e., test 1 described above) is positive with 
 of 0.05.  If the test of rPFS in the ITT population (i.e., test 2 described above) is 
also positive with  of 0.01, then the OS in patients with PTEN-loss tumors by IHC 
will be tested with  of 0.05; otherwise the OS in patients with PTEN-loss tumors by 
IHC will be tested with  of 0.04.  When the test of rPFS in patients with 
PTEN‑loss tumors by IHC (i.e., test 1 described above) is passed, at the time of the 
primary analysis of rPFS, an interim analysis of OS in patients with 
PTEN‑loss tumors by IHC will be performed.  The interim analysis boundary for 
statistical significance will be determined based on the Lan-DeMets implementation 
of the O’Brien-Fleming alpha spending function according to the type I error  
allocated to this endpoint (see Figure 2 ). 


 
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Testing of OS in the ITT population 
OS in the ITT population will be tested only if the test of OS in patients with 
PTEN-loss tumors by IHC (i.e., test 3 described above) is positive, and it will be tested 
with the same type I error  that is used for the test of OS in patients with 
PTEN‑loss tumors by IHC.  At the time of the primary analysis of rPFS, if the interim 
analysis of OS in patients with PTEN-loss tumors by IHC test is positive, an interim 
analysis of OS in the ITT population will be performed.  At the time of final OS analysis in 
patients with PTEN-loss tumors by IHC, if the test of OS in patients with 
PTEN‑loss tumors by IHC is positive, an interim analysis of OS in the ITT population will 
be performed.  The interim analysis boundary for statistical significance will be 
determined based on the Lan-DeMets implementation of the O’Brien-Fleming 
alpha spending function according to the type I error  allocated to this endpoint, which 
should be the same type I error  that is used for the test of OS in patients with 
PTEN‑loss tumors by IHC. 
 
6.1.2 
Co-Primary Endpoint:  Progression-Free Survival 
This study has two co-primary endpoints:  rPFS in the ITT population and rPFS in 
patients with PTEN-loss tumors by IHC.  At the time of primary analysis of rPFS, rPFS in 
patients with PTEN-loss tumors by IHC will be firstly tested with  of 5%.  If the test is 
positive, then rPFS in the ITT population will be tested with  of 1%. 
The primary analysis of rPFS will occur when approximately 275 rPFS events in patients 
with PTEN-loss tumors and approximately 550 rPFS events in the ITT population have 
been observed, whichever occurs later.  The primary analysis is expected to occur 
approximately 34 months after the first patient is randomized. 
In the PTEN-loss population, 275 events will allow for 98.4% power to detect an 
improvement in median rPFS from 14 months in the placebo arm to approximately 
23 months in the ipatasertib arm (HR  0.61) at the 5% level of significance (two‑sided).  
The largest hazard ratio deemed to be statistically significant will be approximately 0.79 
(with median rPFS improvement from 14 months in the placebo arm to approximately 
17.7 months in the ipatasertib arm). 
In the ITT population, 550 events will allow for 94.5% power to detect an improvement in 
median rPFS from 16.5 months in the placebo arm to approximately 23.6 months in the 
ipatasertib arm (HR  0.70) at the 1% level of significance (two-sided).  The largest 
hazard ratio deemed to be statistically significant will be approximately 0.80 (with 
median rPFS improvement from 16.5 months in the placebo arm to approximately 
20.6 months in the ipatasertib arm. 
6.1.3 
Key Secondary Endpoint:  Overall Survival 
The “final” analysis of OS in patients with PTEN-loss tumors by IHC is scheduled to be 
around 24 months after the rPFS primary analysis when there are approximately 


 
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327 OS events in patients with PTEN-loss tumors by IHC (with an assumption of 5% 
loss to follow-up for OS per two years).  It’s estimated that, for the interim analysis of OS 
in patients with PTEN-loss tumors at the time of the rPFS primary analysis, there are 
approximately 196 OS events in patients with PTEN-loss tumors (i.e., with information 
fraction of approximately 60%). 
 
If the test of rPFS in the ITT population is positive with  of 0.01, then the OS in 
patients with PTEN-loss tumors by IHC will be tested with  of 0.05.  With alpha 
spending to the IA (at the rPFS primary analysis), at the final analysis of OS in 
patients with PTEN-loss tumors, the largest hazard ratio deemed to be statistically 
significant will be approximately 0.803 (with median OS improvement from 
29 months in the placebo arm to approximately 36.1 months in the ipatasertib arm). 
 
If the test of rPFS in the ITT population is negative with  of 0.01, then the OS in 
patients with PTEN-loss tumors by IHC will be tested with  of 0.04.  With alpha 
spending to the IA (at the rPFS primary analysis), at the final analysis of OS in 
patients with PTEN-loss tumors, the largest hazard ratio deemed to be statistically 
significant will be approximately 0.795 (with median OS improvement from 
29 months in the placebo arm to approximately 36.5 months in the ipatasertib arm). 
 
The “final” analysis of OS in the ITT population is scheduled to be around 9 months after 
the “final” analysis of OS in patients with PTEN-loss tumors by IHC and when there are 
approximately 660 OS events in the ITT population (with an assumption of 5% loss to 
follow-up for OS per two years).  It’s estimated that, for the interim analysis of OS in the 
ITT population, the information fractions are approximately 50% and 90%at the time of 
the rPFS primary analysis and the “final” analysis of OS in patients with PTEN-loss 
tumors by IHC respectively. 
 
If the OS in patients with PTEN-loss tumors by IHC is tested with  of 0.05, then the 
OS in the ITT population will be tested with  of 0.05 as well.  With alpha spending 
to the IAs, at the final analysis of OS in the ITT population, the largest hazard ratio 
deemed to be statistically significant will be approximately 0.852 (with median OS 
improvement from 35 months in the placebo arm to approximately 41.1 months in 
the ipatasertib arm). 
 
If the OS in patients with PTEN-loss tumors by IHC is tested with  of 0.04, then the 
OS in the ITT population will be tested with  of 0.04 as well.  With alpha spending 
to the IAs, at the final analysis of OS in the ITT population, the largest hazard ratio 
deemed to be statistically significant will be approximately 0.846 (with median OS 
improvement from 35 months in the placebo arm to approximately 41.4 months in 
the ipatasertib arm). 
 
6.1.4 
China Extension Cohort 
After approximately 1100 patients have been randomized into the global main study and 
if China has not reached approximately 200 patients, ex-China enrollment (i.e., global 
enrollment) will be closed and additional Chinese patients may be recruited into the 
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(i.e., the China subgroup) in the combination of the global (main study) cohort and the 
China extension cohort. 
Among the approximately 200 Chinese patients in the ITT population, 100 rPFS events 
will allow to demonstrate approximately 83% probability of maintaining  50% of rPFS 
risk reduction from the global cohort.  It is estimated that there will be approximately 
53 rPFS events among the Chinese patients with PTEN-loss tumors that can 
demonstrate approximately 84% probability of maintaining  50% of rPFS risk reduction 
from the global cohort. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration, and discontinuations from the study will be 
summarized by treatment arm.  The incidence of treatment discontinuation for reasons 
other than disease progression will be tabulated by treatment arm.  Major protocol 
violations, including violations of inclusion/exclusion criteria, will be summarized by 
treatment arm. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, and race), and baseline 
disease characteristics such as presence of visceral metastasis (liver or lung; yes vs. 
no), progression factor (PSA only vs. other), prior taxane-based therapy in the 
hormone-sensitive setting (yes vs. no) and tumor PTEN-loss status by IHC assay (yes 
vs. no) will be summarized by treatment arm.  Continuous variables will be summarized 
with use of means, SDs, medians, and ranges.  Categorical variables will be 
summarized by counts and proportions. 
6.4 
EFFICACY ANALYSES 
The primary objective for this study is to evaluate the efficacy of ipatasertib plus 
abiraterone compared with placebo plus abiraterone on the basis of rPFS in patients in 
the ITT population and in patients with PTEN-loss tumors determined by IHC assay. 
Efficacy analyses will include all patients who were included in the randomization, except 
for the objective response rate (ORR) analysis.  ORR analysis will include all patients 
with measurable disease at baseline only.  For efficacy, patients will be analyzed 
according to the treatment arm to which they were randomized. 
6.4.1 
Primary Efficacy Endpoint 
The primary endpoint of rPFS is defined as the time from date of randomization to the 
first occurrence of documented disease progression, as assessed by the investigator 
with use of the PCWG3 criteria (soft tissue by CT or MRI scans according to 
RECIST v1.1 and bone metastasis by bone scan according to the PCWG3 criteria) or 
death from any cause, whichever occurs first. 


 
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Data for patients without the occurrence of disease progression or death as of the 
clinical data cutoff date will be censored at the time of the last tumor assessment (or 
at the time of randomization plus 1 day if no tumor assessment was performed after the 
baseline visit). 
Firstly, the primary efficacy analysis of rPFS in patients with PTEN-loss tumors by IHC 
assay will be performed by the two-sided log-rank test (  0.05) using the following 
factors in stratified analyses to compare rPFS between the two treatment arms: 
 
Presence of visceral metastasis (liver or lung; yes vs. no) 
 
Progression factor (PSA only vs. other) 
 
Prior taxane-based therapy in the hormone-sensitive setting (yes vs. no) 
 
A Cox proportional-hazards model stratified using the four factors above will be used to 
estimate the HR and 95% CI.  The results from the unstratified log-rank test will also be 
provided. 
The Kaplan-Meier approach will be used to estimate median rPFS for each 
treatment arm, and the Kaplan-Meier curve will be constructed to provide a visual 
description of the difference between the treatment arms. 
When the primary efficacy analysis of rPFS in patients with PTEN-loss tumors by IHC 
assay is positive, (i.e., a p-value  0.05), similar methods will then be used for the 
primary efficacy analysis of rPFS in the ITT population.  The two-sided log‑rank test 
(  0.01) stratified by the following factors will be used to compare rPFS between the 
two treatment arms: 
 
Presence of visceral metastasis (liver or lung; yes vs. no) 
 
Progression factor (PSA only vs. other) 
 
Prior taxane-based therapy in the hormone-sensitive setting (yes vs. no) 
 
Tumor PTEN status by IHC assay (loss vs. non-loss) 
 
6.4.2 
Key Secondary Efficacy Endpoints 
6.4.2.1 
Overall Survival 
OS will be measured from randomization to the time of death due to any cause.  Data for 
patients who are not reported as having died at the time of analysis will be censored at 
the date when they were last known to be alive.  Data for patients who do not have 
post-baseline information will be censored at the randomization date plus 1 day. 
The analysis populations for OS are: patients in the ITT population and patients with 
PTEN-loss tumors as determined by IHC.  The key OS analyses will be performed by 
stratified two-sided log-rank tests with the significance levels as described in Section 6.1.  
Additional similar analyses as those specified for the primary endpoint 


 
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(see Section 6.4.1) will also be performed for OS analyses, including unstratified 
log-rank test, Cox proportional-hazards model, Kaplan-Meier approach, etc. 
OS will be analyzed at the time of rPFS primary analysis and the event-driven 
time points as described in Section 6.1. 
6.4.2.2 
Time to Pain Progression 
Pain severity progression refers to pain onset for those patients asymptomatic at 
baseline (i.e., patients with a score of 0 or 1 on pain severity at its worst on the 
10‑point NRS) or pain worsening for those patients who are mildly symptomatic at 
baseline (score of 2 or 3).  Pain severity progression is defined as a  2‑point 
absolute increase from baseline. 
Pain severity progression at a given timepoint will be considered clinically meaningful if 
followed by any of the following: 
 
A subsequent pain severity assessment within approximately 28 days showing that 
the score on pain severity at its worst is stable or increased 
 
Initiation of opioid analgesic medication as measured by the Analgesic 
Quantification Algorithm (AQA) score within approximately 28 days following the 
initial pain event.  AQA scores range from 0 to 7, in which a score of 0 is no 
analgesic use and a score of 7 is strong opioid use (Chung et al. 2014).  The QA 
score will be calculated based on the consumption of opioids documented in the 
eCRF.  Equianalgesic potency conversions and AQA are displayed in Appendix 11. 
 
Initiation of palliative radiotherapy within approximately 28 days following the initial 
pain event 
 
Any increase in glucocorticosteroids usage for the intent of treating cancer pain 
within approximately 28 days following the initial pain event 
 
In the absence of further pain assessments and initiation of analgesic or palliative 
therapy, documentation of death attributable to cancer progression (not death of 
other causes, including adverse events) within a 3-month interval following the initial 
pain event for these patients who might be lost at follow-up 
 
Note that an initiation of opioid analgesic use for cancer-related pain be defined as an 
increase from a score 0 or 1 at the time of the initial pain event to a score of  2 on the 
AQA reported on at least 7 consecutive days in the 28-day period until the pain 
assessment. 
Time to pain progression will be defined as the time from randomization to the 
first occurrence of a confirmed clinically meaningful cancer-related pain progression 
event. 
All patients who underwent randomization will be included in the time to pain progression 
analysis. 


 
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The analysis for this secondary endpoint will include any pain progression event 
collected until initiation of the next line of therapy or up to one year following treatment 
discontinuation, whichever occurs first. Note that data collected post initiation of next line 
of therapy will not be used for the analysis of the secondary endpoint but will be used to 
inform understanding of the disease burden post-progression in exploratory analyses. 
Patients without occurrence of pain progression at the time of analysis will be censored 
at the last available pain severity assessment. 
Patients whose death is not preceded by an increase in pain of  2 points will be 
censored at the latest date of the last pain severity assessment. 
In addition, patients who do not report baseline data will be censored at the 
randomization date plus 1 day. 
The same analysis methods as described in Section 6.4.1 for the primary endpoint rPFS 
will be used for this time to pain progression endpoint. 
6.4.2.3 
Time to Initiation of Cytotoxic Chemotherapy 
Time to initiation of cytotoxic chemotherapy is defined as the time interval from the date 
of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer.  
Cytotoxic chemotherapy was defined as the use of any of the following antineoplastic 
agents for prostate cancer:  docetaxel, cabazitaxel, mitoxantrone, estramustine, 
cisplatin, carboplatin, cyclophosphamide, doxorubicin, mitomycin, irinotecan, 
5‑fluorouracil, gemcitabine, or etoposide.  Data for patients who do not receive cytotoxic 
chemotherapy will be censored at the last known date of no cytotoxic chemotherapy 
administered. 
The same analysis methods as described in Section 6.4.1 for the primary endpoint rPFS 
will be used for this time to initiation of cytotoxic chemotherapy endpoint. 
6.4.2.4 
Time to Function Deterioration 
Time to function deterioration is defined as the time interval from the date of 
randomization to the date of a decrease of 10-point or more on either the 0100 PF or 
the RF scores from the EORTC QLQ-C30. 
The analysis methods will be the same as for the primary endpoint (see Section 6.4.1). 
6.4.2.5 
Time to Prostate-Specific Antigen Progression 
PSA progression is defined as a PSA increase that is  25% and  2 ng/mL above the 
baseline or nadir, which is confirmed by a second value  3 weeks later (per the 
PCWG3 criteria). 


 
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Time to PSA progression is defined as the time from the date of randomization to the 
first occurrence of PSA progression.  The analysis methods will be the same as for the 
primary efficacy endpoint (see Section 6.4.1). 
6.4.2.6 
Time to First Opioid Use 
Time to first opioid use is defined as the time interval from the date of randomization to 
the date of an initiation of opioid analgesic use for cancer-related pain, and consumption 
reported on at least 7 consecutive days. 
The analysis methods will be the same as for the primary efficacy endpoint 
(see Section 6.4.1). 
6.4.2.7 
Time to Symptomatic Skeletal Events 
Time to first SSE is defined as the time interval from the date of randomization to the 
date of an SSE.  The analysis methods will be the same as for the primary efficacy 
endpoint (see Section 6.4.1). 
6.4.2.8 
Objective Response Rate 
An objective response is defined as a CR or PR on two consecutive occasions  4 weeks 
apart, according to RECIST v1.1 and PCWG3 criteria, in patients with measurable 
disease at baseline.  Patients without a postbaseline tumor assessment will be 
considered non-responders. 
ORR is defined as the proportion of patients who have an objective response in patients 
with measurable disease at baseline.  An estimate of ORR will be calculated for each 
treatment arm, and its 95% CI will be calculated using the Blyth-Still-Casella method.  
ORR will be compared between treatment arms using the stratified 
Cochran‑Mantel‑Haenszel test.  The stratification factors will be the same as those 
described for the analysis of the primary endpoint (see Section 6.4.1).  The difference in 
ORR between treatment arms will be calculated, and its 95% CI will be calculated using 
the normal approximation to the binomial distribution. 
6.4.2.9 
Prostate-Specific Antigen Response Rate 
PSA response rate is defined as the proportion of patients achieving a PSA decline 
 50% from baseline.  Patients without a postbaseline PSA assessment will be 
considered non-responders.  The analysis population for PSA response rate will be all 
randomized patients.  The analysis methods will be the same as for the ORR endpoint 
(see Section 6.4.2.1). 
6.4.2.10 
Investigator-Assessed rPFS in Patients with PTEN-Loss 
Tumors by NGS 
Investigator-assessed rPFS per PCWG3 criteria will be analyzed in patients with 
PTEN-loss tumors by NGS.  The analysis methods will be the same as for the primary 
efficacy endpoint (see Section 6.4.1). 


 
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6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will be evaluated in patients in the ITT population and 
in patients with PTEN-loss tumors by IHC.  P-values will be reported for descriptive 
purposes.  The exploratory efficacy endpoints include IRF-assessed radiographic 
progression, PFS after next line of treatment (secondary PFS; PFS2), time to 
deterioration in health-related QoL, time to deterioration in urinary symptoms (per 
EORTC QLQ-PR25 urinary scale), time to deterioration in fatigue (per EORTC QLQ-C30 
fatigue scale, clinical PFS, and PRO-CTCAE.  Analyses will be performed as data allows 
as described in the SAP. 
6.5 
SAFETY ANALYSES 
Safety analyses will be conducted in all patients who were randomized and received any 
amount of ipatasertib, placebo, or abiraterone (the safety-evaluable population). 
Patients will be analyzed accordingly to the treatment arm associated with the actual 
regimen received.  Specifically, a patient will be included in the ipatasertib plus 
abiraterone arm in the safety analyses if this patient receives any amount of ipatasertib, 
regardless of the initial treatment assignment at randomization. 
Safety endpoints will include incidence, severity, and seriousness of adverse events, 
deaths, and clinically significant laboratory measurement. 
Adverse events will be summarized by mapped Medical Dictionary for Regulatory 
Activities preferred terms.  All adverse events occurring during or after the first dose of 
study treatment until the end of the adverse event reporting window will be summarized 
by treatment arm.  In addition, serious adverse events, adverse events of special 
interest, and adverse events leading to study drug discontinuation will be summarized 
accordingly.  Multiple occurrences of the same event will be counted once at the 
maximum severity. 
Deaths will be summarized by treatment arm. 
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized by treatment arm and grade. 
Drug exposure will be summarized to include duration of treatment, cumulative dose, 
and dose intensity by treatment arm. 
6.6 
PHARMACOKINETIC ANALYSES 
Ipatasertib and its metabolite (G-037720) levels will be measured on Days 1 and 15 of 
Cycle 1, Day 1 of Cycle 3, and Day 1 of Cycle 6.  Ipatasertib and its metabolite plasma 
concentration versus time data, together with information on dosing and patient 
characteristics, will be pooled and analyzed using a PopPK analysis approach, as 
appropriate.  Non-linear mixed-effect modeling will be used for the estimation of PopPK 


 
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parameters for ipatasertib.  Covariates such as patient demographics (e.g., age, sex, 
body size), may be tested for significance on PK parameters of interest. 
The PK data may be combined with the safety, efficacy, and biomarker data for 
exposure-response modeling as an exploratory objective.  PK and PK/pharmacodynamic 
analyses may be reported in separate stand-alone reports.  Additional analyses may be 
explored as warranted by the data. 
Abiraterone levels will be measured on Day 15 of Cycle 1 and Day 1 of Cycle 3.  
Abiraterone trough plasma concentrations will be compared between arms (ipatasertib 
vs. placebo). 
6.7 
BIOMARKER ANALYSES 
Exploratory biomarker analyses (in tumor tissues and plasma, whole blood, or serum) 
will be performed in an effort to understand the association of these markers with study 
drug response, including efficacy and/or adverse events.  Results will be presented in a 
separate report. 
WGS data will be analyzed in the context of this study and explored in aggregate with 
data from other studies to increase researchers’ understanding of disease pathobiology 
and guide the development of new therapeutic approaches. 
6.8 
INTERIM ANALYSES 
6.8.1 
Planned Interim Safety Analyses 
An iDMC will evaluate safety data (including but not limited to serious adverse events, 
death, and adverse events of special interest) during the study on a periodic basis, 
approximately every 3 months for the first year and approximately every 6 months 
thereafter, until the time of the rPFS primary analysis (see Section 6.4.1), according to 
the policies and procedures detailed in an iDMC charter.  The Sponsor will be blinded 
until the rPFS primary analysis. 
An iDCC will prepare all summaries and analyses for the iDMC’s review.  The safety 
summaries will include demographic data, adverse events, serious adverse events, and 
relevant laboratory data. 
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  Following the data review, the iDMC will provide 
a recommendation to the Sponsor whether to continue the study, amend the protocol, or 
stop the study.  The final decision will rest with the Sponsor. 
Any outcomes of the iDMC’s reviews on the safety and benefitrisk balance that affect 
study conduct will be communicated in a timely manner to the investigators for 
notification of IRB/ECs and competent authorities as required. 


 
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6.8.2 
Planned Interim Efficacy Analyses 
No interim efficacy analyses are planned for the primary endpoint of rPFS. 
A total of four analyses of OS are planned: 
 
The first interim analysis of OS was performed at the time of primary analysis 
of rPFS. 
 
The second interim analysis of OS will take place when approximately 
229 OS events in the patients with PTEN-loss tumors by IHC occur, or when the 
minimum follow-up time (from the last patient enrollment date of 17 January 2019) is 
approximately 32 months, whichever occurs later. 
 
The third analysis of OS is the final analysis of OS in the patients with 
PTEN‑loss tumors by IHC, and it is also the third interim analysis of OS in the 
ITT population. It is scheduled when approximately 327 OS events in patients with 
PTEN‑loss tumors by IHC occur.  This target number of OS events is unchanged 
per the original Protocol Version 6, Section 6.1.3. 
 
The fourth analysis of OS is the final analysis of OS in the ITT population. It is 
scheduled when approximately 660 OS events in the ITT population occur.  
This target number of OS events is unchanged per the original Protocol Version 6, 
Section 6.1.3. 
 
The projected analysis timing and the corresponding numbers of OS events for OS 
interim and final analyses in patients with PTEN‑loss tumors by IHC and in the 
ITT population are shown in Table 11.  When the timing of the third and fourth analyses 
are very close, these two analyses could be combined and the alpha-spending will be 
adjusted using O’Brien-Fleming alpha-spending method. 
Table 11 Timing of Overall Survival Analyses 
 
PTEN Loss 
ITT 
Analysis 
Time from FPI 
(months) 
Information 
Fraction (%) 
No. of Events 
(EPR %) 
Information 
Fraction (%) 
No. of Events 
(EPR %) 
OS 1st IA 
33 
43 
140 (27) 
40 
267 (24) 
OS 2nd IA 
50 
70 
229 (44) 
69 
450 (41) 
OS 3rd IA/ FA 
78 
100 
327 (63) 
98 
646 (59) 
OS FA 
81 
- 
- 
100 
660 (60) 
EPR  EventPatient-Ratio; FA  final analysis; FPI  first patient in; ITT  intent-to-treat; 
OS  overall survival; PTEN  phosphatase and tensin homolog. 
 


 
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6.8.3 
Optional Interim Analysis 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis for futility.  Below are the 
specifications in place to ensure the study continues to meet the highest standards of 
integrity when an optional interim analysis is executed. 
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the 
iDMC charter. 
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months before the conduct of the 
interim analysis.  The iDMC charter will be updated to document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis 
(e.g., stop the study for futility), and the iDMC charter will also be made available to 
relevant health authorities. 
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will be included in the SAP.  Additional criteria 
for recommending that the study be stopped for futility may be added to the 
iDMC charter.  An interim analysis that might lead to stopping the study for futility will not 
occur before at least 67% of the information in both the ITT population and patients with 
PTEN‑loss tumors has been accumulated. 
After the primary analysis for PFS, additional OS interim analyses may be conducted to 
provide additional OS data, per the recommendation from health authorities.  
If conducted, the Lan-DeMets-spending function with an O’Brien‑Fleming boundary will 
be used to control the overall type I error for OS accounting for the additional OS interim 
analyses. 
6.9 
CHINA SUBGROUP ANALYSES 
The primary efficacy objective of the China subgroup analysis is to evaluate whether the 
efficacy, as measured by rPFS, of ipatasertib plus abiraterone compared with placebo 
plus abiraterone in the Chinese patients with mCRPC is consistent with the efficacy 
observed in the global cohort.  Consistency is defined as maintaining  50% of risk 
reduction from the global cohort.  Therefore, the China subgroup is not powered to 
demonstrate the statistical significance of efficacy and no formal hypothesis testing will 
be performed.  The results of the China subgroup analyses will be summarized in a 
separate CSR.  The statistical details for such analyses in the China subgroup will be 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
PRO data will be collected through the use of an electronic device provided by a vendor.  
If back‑up paper forms are used by the patient, the data will be entered by the sites 
through an electronic portal.  The device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with U.S. FDA regulations for electronic 
records (21 CFR Part 11).  The electronic data are available for view access only via 
secure access to a vendor-hosted, password-protected Web portal. Only identified and 
trained users may view the data, and their actions become part of the audit trail.  
The Sponsor will have view access only.  System backups for data stored by the 
Sponsor and records retention for the study data will be consistent with the Sponsor’s 
standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 


 
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7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
At screening, patients will complete one pain severity item (24-hour recall) by paper in 
the clinic.  Upon randomization, patients will use an electronic device to capture 
PRO data.  Back-up paper forms will be available if needed in order to capture 
patient data.  The data from the electronic device will be transmitted to a centralized 
database maintained by the electronic device vendor. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human‑ and 
machine‑readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable 
audit trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMPs, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trials Directive (2001/20/EC) 
or Clinical Trials Regulation (536/2014) and applicable local, regional, and national 
laws. 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form) will be provided to each site.  
If applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 


 
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Sponsor’s sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient’s agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 


 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study‑related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare for treatment purposes. 
Given the complexity and exploratory nature of the analyses, data derived from 
exploratory biomarker specimens will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.6). 


 
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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV occurs or the 
date at which the last data point required for statistical analysis has been observed 
[see Section 6.4]). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 


 
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9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  
The Sponsor will identify potential risks associated with critical trial processes and data 
and will implement plans for evaluating and controlling these risks.  Risk evaluation and 
control will include the selection of risk-based parameters (e.g., adverse event rate, 
protocol deviation rate) and the establishment of quality tolerance limits for these 
parameters.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored and managed by F. Hoffmann-La Roche Ltd.  
Approximately 200 centers worldwide will participate in the study and approximately 
1100 patients will be enrolled.  After approximately 1100 patients have been randomized 
into the study, ex-China enrollment (i.e., global enrollment) will be closed and 
additional Chinese patients will be recruited into the China extension cohort to enroll a 
total of approximately 200 Chinese patients (i.e., the China subgroup) if that number of 
Chinese patient is not reached within the global enrollment. 
Randomization will occur through use of an IxRS.  Central facilities will be used for study 
assessments throughout the study (e.g., specified laboratory tests and PK analyses).  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
An iDMC will be convened to evaluate safety data during the study according to policies 
and procedures detailed in the iDMC charter. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and/or other summaries of clinical study results may be 
available in health authority databases for public access, as required by local regulation, 


 
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108/Protocol CO39303, Version 8 
and will be made available upon request, provided the requirements of Roche's global 
policy on data sharing have been met.  For more information, refer to the Roche Global 
Policy on Sharing of Clinical Study Information at the following Web site: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective CSR.  In addition, for all clinical trials in patients involving an IMP for 
which a marketing authorization application has been filed or approved in any country, 
the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Appendix 1  
Schedule of Activities 
Assessment/Procedure 
(Window) 
Screening 
a 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥ 4 
Study 
Treatment 
Discontinuation b 
Disease 
Follow-
Up c; jj 
Post-
Treatment 
Follow-Up d; jj 
Days –28  
to –1 
Day 
1 
Day  
4 
(± 1) 
Day 
8 
(± 2) 
Day 
15 e 
(±2) 
Day 
1 
Day 
15 e 
Day 
1 
Day  
15 e 
Day  
1 
Within 30 days 
of the Last 
Study Treatment 
Every 3 
(± 1) 
Months 
Every 3  
(± 1)  
Months 
Informed consent(s) 
x f 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data (age, 
sex,  
and self-reported 
race/ethnicity) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
baseline conditions g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Archival FFPE tumor tissue 
x h 
 
 
 
 
 
 
 
 
 
 
 
 
PTEN IHC results 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Patient randomization 
number assignment (IxRS) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications i 
x 
x 
 
x 
x 
x 
x 
x 
x  
x 
x 
x j 
 
Adverse events k 
x 
x  
x 
x 
x 
x 
x 
x 
x  
x 
x 
x 
x 
Complete physical 
examination l 
x a 
 
 
 
 
 
 
 
 
 
x 
 
 
Limited physical 
examination m 
 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
ECOG performance status 
x a 
x 
 
 
 
x 
 
x 
 
x jj 
x jj 
x 
x 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
115/Protocol CO39303, Version 8 
Assessment/Procedure 
(Window) 
Screening 
a 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥ 4 
Study 
Treatment 
Discontinuation b 
Disease 
Follow-
Up c; jj 
Post-
Treatment 
Follow-Up d; jj 
Days –28  
to –1 
Day 
1 
Day  
4 
(± 1) 
Day 
8 
(± 2) 
Day 
15 e 
(±2) 
Day 
1 
Day 
15 e 
Day 
1 
Day  
15 e 
Day  
1 
Within 30 days 
of the Last 
Study Treatment 
Every 3 
(± 1) 
Months 
Every 3  
(± 1)  
Months 
Vital signs n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Weight and height (height 
at screening only) 
x 
x 
 
 
 
x 
 
x 
 
x 
x 
 
 
Electrocardiogram o  
x o 
As clinically indicated 
x o 
 
 
Historic values for PSA 
velocity 
x p 
 
 
 
 
 
 
 
 
 
 
 
 
PSA p 
x p, q 
x r 
 
 
 
x r 
 
x r 
 
x r, jj 
x jj 
 
 
Serum testosterone s 
x  
 
x jj 
 
 
Hematology t 
x 
x r 
 
x r 
x r 
x r 
x r 
x r 
x r 
x r 
x 
 
 
Fasting blood glucose u  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 Home glucose monitoring v 
 
Post-meal blood glucose measurement and recording in daily 
glucose log  
(while receiving ipatasertib/placebo treatment) 
 
 
 
Chemistry panel w 
x 
x r 
 
x r 
x r 
x r 
x r 
x r 
x r 
x r 
x 
 
 
Urinalysis x 
x 
As clinically indicated 
x 
 
 
Coagulation:  aPTT, PT, 
and INR  
x 
As clinically indicated 
x 
 
 
Amylase and lipase 
x 
 
 
 
 
x 
 
 
 
x 
 
 
Fasting lipid profile 
x 
 
 
 
 
x 
 
 
 
x 
 
 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
116/Protocol CO39303, Version 8 
Assessment/Procedure 
(Window) 
Screening 
a 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥ 4 
Study 
Treatment 
Discontinuation b 
Disease 
Follow-
Up c; jj 
Post-
Treatment 
Follow-Up d; jj 
Days –28  
to –1 
Day 
1 
Day  
4 
(± 1) 
Day 
8 
(± 2) 
Day 
15 e 
(±2) 
Day 
1 
Day 
15 e 
Day 
1 
Day  
15 e 
Day  
1 
Within 30 days 
of the Last 
Study Treatment 
Every 3 
(± 1) 
Months 
Every 3  
(± 1)  
Months 
Hemoglobin A1c  
x 
 
 
 
 
x 
 
 
 
Day 1 of 
Cycles 4, 6, 
9, 12, and 
every 
3 cycles 
thereafter 
 
 
 
Tumor assessment of soft 
tissue per RECIST v1.1 y 
x a 
 
 
 
 
End of Cycles 2, 4, 6,  
and every 3 cycles 
thereafter aa, jj 
x jj 
x 
 
Tumor assessment:  bone 
scan z 
x a 
 
 
 
 
x jj 
x 
 
Pain severity at its worst 
NRS (24h recall) bb 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pain severity at its worst 
NRS (7 -day recall) bb 
 
x 
 
 
 
x 
 
x 
 
x jj 
x jj 
x  
x  
EORTC QLQ-C30, Urinary 
Scale from EORTC PR-25 
bb 
 
x 
 
 
 
x 
 
x 
 
x jj 
x jj 
x  
x  
EQ-5D-5L bb 
 
x 
 
 
 
x 
 
x 
 
x jj 
x jj 
x  
x  
PRO-CTCAE (selected 
items) bb 
 
x 
 
x 
x 
x 
x 
x  
x  
x jj 
 
 
 
Medication log cc 
 
Record per medication consumption jj 
x jj 
x 
 
Study treatment 
administration dd 
 
Daily administration of ipatasertib/placebo, abiraterone plus 
prednisone/prednisolone 
 
 
 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
117/Protocol CO39303, Version 8 
Assessment/Procedure 
(Window) 
Screening 
a 
Cycle 1 
Cycle 2 
Cycle 3 
Cycles ≥ 4 
Study 
Treatment 
Discontinuation b 
Disease 
Follow-
Up c; jj 
Post-
Treatment 
Follow-Up d; jj 
Days –28  
to –1 
Day 
1 
Day  
4 
(± 1) 
Day 
8 
(± 2) 
Day 
15 e 
(±2) 
Day 
1 
Day 
15 e 
Day 
1 
Day  
15 e 
Day  
1 
Within 30 days 
of the Last 
Study Treatment 
Every 3 
(± 1) 
Months 
Every 3  
(± 1)  
Months 
Symptomatic skeletal 
events ee 
 
Record any symptomatic jj 
skeletal events 
x jj 
x 
x 
Drug accountability 
 
 
 
 
 
x 
 
x 
 
x 
x 
 
 
Plasma PK sample ff 
 
See Appendix 2 
 
 
Blood sample for NGS 
control gg 
 
See Appendix 2 
 
 
Blood sample for 
pharmacogenomics gg 
 
See Appendix 2 
 
 
Plasma sample for somatic 
tumor mutations gg 
 
See Appendix 2 
 
 
Plasma sample for 
exploratory biomarkers gg 
 
See Appendix 2 
 
 
Blood sample for RBR (for 
DNA extraction; optional) hh 
 
See Appendix 2 
 
 
Subsequent line of prostate 
cancer therapy and 
outcome ii 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
x 
x 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
118/Protocol CO39303, Version 8 
CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; EORTC = European Organisation 
for Research and Treatment of Cancer; EORTC QLQ-C30 = EORTC Quality of Life Questionnaire Core 30; EORTC QLQ-PR25 = EORTC Quality of 
Life Questionnaire Prostrate Cancer Module; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels; FFPE = formalin-fixed, paraffin-embedded; 
IHC = immunohistochemistry; IxRS = interactive voice- or Web-based response system; LVEF = left ventricular ejection fraction; MRI = magnetic 
resonance imaging; NGS = next-generation sequencing; NRS = Numeric Rating Scale; PK = pharmacokinetic; PCWG3 = Prostate Cancer Working 
Group 3; PRO = patient-reported outcome; PRO-CTCAE = Patient-Reported Outcomes Version of the Common Terminology for Adverse Events; 
PSA = prostate-specific antigen; RBR = Research Biosample Repository; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Notes:  All visits should occur within ± 3 days of the scheduled visit, unless otherwise specified.  On treatment visit days, all assessments should be 
performed prior to dosing, unless otherwise specified.  Patients should receive their first dose of study treatment no later than 7 days after 
randomization.  Unplanned visits not specified by the protocol or unscheduled assessments (possibly including PK sample collection) may be 
performed as clinically indicated at discretion of the investigator; the associated data should be recorded on the relevant eCRF in support of an 
adverse event diagnosis or tumor assessments.  After the final OS analysis, for the patients who are still on ipatasertib, the study visits will 
occur every 3 months (± 7 days) instead of monthly.  The patients who are receiving abiraterone only will no longer be required to attend study 
visits. 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Cycle 1, Day 1 may 
be used; such tests do not need to be repeated for screening.  Bone scans within 42 days prior to Cycle 1, Day 1 may be used.  If eligibility 
assessments were not completed within 28 days from the original date of the screening visit, the patient will need to be rescreened for eligibility 
(see Section 4.5.1 for details).  
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit within 30 (± 3) days after the last dose of 
study treatment.  The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit, 
provided that all tests required at the treatment discontinuation visit are performed.  Tumor assessments at the treatment discontinuation visit 
may be omitted if the most recent prior assessment was performed less than 28 days ago or the patient has already had confirmation of 
radiographic disease progression. 
c After treatment discontinuation, patients who discontinue study treatment in the absence of radiographically assessed disease progression will 
return to the clinic for tumor assessment follow-up visits approximately every 3 months from the last tumor assessment (CT or MRI scan and 
bone scans) until radiographically assessed disease progression.  See Section 4.5.5 and PCWG3 guidelines.  Following initiation of a new 
anti‑cancer therapy for prostate cancer, information on disease progression from patient’s medical records may be used to complete disease 
follow‑up via telephone calls and/or clinic visits.  These data will not be collected after the final OS analysis. 
d After treatment discontinuation and radiographically assessed disease progression, unless the patient requests to be withdrawn from survival 
follow-up, the required information will be collected via telephone calls and/or clinic visits, or patients’ medical records, approximately every 
3 months until death, loss to follow-up, or study termination by the Sponsor.  These data will not be collected after the final OS analysis.  
e Day 15 clinical visit and assessments up to Cycle 3 only.  During subsequent cycles, site personnel may contact the patient by telephone to 
assess the occurrence of adverse events as described in footnote "k".  The rationale for the telephone call is to allow proactive medical 
management of adverse events and to minimize delayed reporting by patient, owing to the monthly clinic visit schedule. 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
119/Protocol CO39303, Version 8 
f Informed consent, including optional consent, must be documented before any study-specific screening procedure is performed and may be 
obtained more than 28 days before initiation of study treatment. 
g Medical history includes clinically significant diseases within the previous 5 years, surgeries, complete cancer history (including prior cancer 
therapies and procedures), complete cardiovascular history, reproductive status, smoking history, use of alcohol, and drugs of abuse 
(see Section 4.5.2). 
h A tumor tissue block or a minimum of 1015 (15 slides preferred) freshly cut, unstained slides from patients will be collected at screening.  If only 
1214 slides are available, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor. A valid PTEN 
IHC test result (from the central laboratory) must be available prior to initiation of study treatment on Cycle 1, Day 1.  If archival tissue is 
insufficient, a fresh tumor biopsy meeting the minimum requirement may be used. 
i Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from 7 days prior to screening (or 28 days prior to initiation of study treatment on Cycle 1, Day 1, whichever occurs first) until 
28 days after the last dose of study treatment. 
j Opioid consumption for cancer-related pain and anti-diabetic medications for hyperglycemia related to study treatment should be recorded in the 
eCRF from Cycle 1, Day 1 to initiation of the next line of prostate cancer therapy. 
k After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol‑mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the last dose of study 
treatment.  After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed by the investigator as stable and no further changes are expected, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered by the investigator to be related to study treatment or 
trial‑related procedures until a final outcome can be reported. 
l Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At study discontinuation visit, record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF. 
m Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF. 
n Vital signs include respiratory rate, pulse (heart) rate, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  Oxygen saturation per pulse oximetry (optional).  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
o ECG recordings will be obtained as part of the screening assessment as clinically indicated during study treatment, and at the end of treatment 
visit.  ECGs will be reviewed by the investigator to determine patient eligibility at screening.  Baseline evaluation of LVEF by MUGA or ECHO 
should be considered for patients with cardiac risk factors and/or history of coronary artery disease. 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
120/Protocol CO39303, Version 8 
p If the progression disease will be based on PSA at screening, at least two PSA samples (obtained at least 1 week apart) will be assessed locally 
at screening for confirmation of eligibility (if no data are available prior to screening). 
q Regardless of PSA used for confirmation of progression disease at screening, historic values of PSA will be collected as available for calculation 
of PSA velocity per PCWG3 criteria (at least three PSA values with each values  0.2 ng/dL, including the most recent value during 
androgen‑derivation therapy, and the interval between first and last PSA value to be  8 weeks but  12 months).  A central laboratory sample 
should also be submitted at screening and at all other timepoints.  PSA central laboratory samples will no longer be collected after the final OS 
analysis.  If medically indicated, additional PSA samples may be collected and tested locally.  An increase in PSA, without evidence of 
radiographic progression or unequivocal clinical progression, should not be used as a criterion to start a new systemic anti-cancer therapy during 
the study. 
r May be performed  96 hours prior to dosing for each clinic visit during study treatment; screening assessments performed  96 hours prior to 
dosing on Cycle 1, Day 1 do not have to be repeated on Cycle 1, Day 1.  PSA may be performed  96 hours prior to dosing at each Day 1 visit. 
s Serum testosterone samples will be assessed locally and centrally at screening for determination of eligibility and at study treatment 
discontinuation to confirm testosterone remains at castration level.  Serum testosterone central laboratory samples will no longer be collected 
after the final OS analysis. 
t Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, bands [optional] 
eosinophils, basophils, monocytes, lymphocytes, and other cells). 
u For all clinic visits during study treatment, the glucose level of the patient must be performed  96 hours prior to dosing, except for Cycle 1, 
Day 4, which must be done  24 hours prior to the visit, and must be reviewed prior to further ipatasertib/placebo administration and prior to 
discharge from the clinic.  Blood glucose may be obtained by a glucometer (fingerstick).  For fasting blood glucose, patients should fast  8 hours 
prior to testing. 
v Countries with mandatory self-monitoring of glucose are Austria, Belgium, Denmark, Hungary, Ireland, Italy, Norway, Poland, Portugal, 
Spain, and the United Kingdom.  Patients enrolled in these countries will be supplied with a blood glucose meter and a blood glucose log to 
record blood glucose at least once daily.  Self-monitoring should be performed at least once daily by the patient after "a bigger meal" throughout 
the study treatment period (i.e., until discontinuation of ipatasertib/placebo).   After the final OS analysis and patients’ unblinding, this test 
should only be performed for patients who are receiving ipatasertib. 
w Chemistry panel includes sodium, potassium, chloride, magnesium, bicarbonate, BUN (or urea), creatinine, total protein, albumin, phosphorus, 
calcium, uric acid, and liver function test panel (total and direct bilirubin, alkaline phosphatase, ALT, AST, and LDH).  The occurrence of 
Grade  3 abnormalities should be monitored at a minimum of every 2 weeks. 
x Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood). 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
121/Protocol CO39303, Version 8 
y Tumor assessments should include the chest, abdomen, and pelvis (and other body regions if clinically indicated) at screening and at 
subsequent tumor assessments, even if there are no detectable lesions at baseline.  CT scans are the preferred imaging modality for tumor 
assessments.  MRI scans may be substituted for CT scans and the same imaging method used at screening must be used throughout the study.  
Soft tissue responses will be assessed locally by the investigator (and/or radiologists) according to RECIST v1.1 for patient management.  
All films should be submitted for central archive to enable radiologic review if determined by the Sponsor to be necessary for the primary 
endpoint analysis. 
z A technetium bone scan will be performed at screening (within 42 days before Cycle 1, Day 1) to evaluate for the presence of bone metastases.  
In cases of ambiguous findings on bone scan, an X-ray or CT/MRI confirmatory scan should be performed at baseline, to ensure that ambiguous 
findings on bone scan are related to cancer and not healing bone.  For adequate assessment of bone lesions, it is expected that the radiologist 
will adjust the window leveling accordingly (refer to the Imaging Charter).  In case of isotope shortage, the Sponsor or Medical Monitor should be 
contacted if the scan cannot be performed within 1 week from the allowable window.  All films should be submitted for central archive, to enable 
radiologic review if determined necessary for primary endpoint analysis by the Sponsor. 
aa Tumor assessments should be performed  7 days of the scheduled cycles.  After the final OS analysis, tumor assessments will no longer be 
required at study visits, but they will be performed as per local practice and at the investigator’s discretion.  Data will not be collected from 
tumor assessments performed after the final OS analysis. 
bb The pain severity at its worst (24-hour recall) NRS at screening will be completed on paper.  The PRO questionnaires, namely, the 
EORTC QLQ‑C30 scales, urinary scale from QLQ-PR25, pain severity (7-day recall) NRS, and EQ-5D-5L, should be completed by patients 
using a provisioned electronic device or back-up paper forms as needed.  It is imperative that each questionnaire aforementioned is completed 
at Cycle 1, Day 1 to have a baseline, then on Day 1 of each cycle, at the end-of-treatment visit, and at unscheduled visits as clinically indicated.  
In addition, these questionnaires will be completed approximately every 28 days from treatment discontinuation (for any reason) to initiation of 
subsequent line of therapy.  Selected scales from the abbreviated EORTC QLQ-C30 (physical functioning [PF], role functioning [RF], global 
health status [GHS]), pain NRS, and EQ-5D-5L will also be completed after initiation of subsequent line of therapy or 1 year after treatment 
discontinuation, whichever occurs first, then every 3 months until death.  The PRO-CTCAE will be completed by patients at Cycle 1 Days 1, 8, 
and 15, then from Cycle 2 to Cycle 6 on Days 1 and 15, and then on Day 1 of each subsequent cycle and as clinically indicated while on study 
treatment.  All PRO questionnaires are required to be completed prior to any study assessment(s) that could bias patient’s responses.  
PRO data will not be collected after the final OS analysis. 
cc Consumption of analgesics (including opioids) will be documented by the patients or their caregivers, using the provisioned devices or back-up 
paper forms.  These data will not be collected after the final OS analysis. 
dd If dosing of study treatment is withheld for any reason, study day count should continue and the omitted dose will not be made up and will be 
reported on the eCRF as “not administered” for that day. 
ee Symptomatic skeletal events in this study are defined using one of the following:  (1) use of external-beam radiotherapy to relieve skeletal 
symptoms (including initiation of radium-223 to treat symptoms of bone metastases); (2) occurrence of a new symptomatic pathological bone 
fracture (vertebral or non-vertebral), (3) clinically apparent occurrence of spinal cord compression, or (4) a tumor-related orthopedic surgical 
intervention.  These data will not be collected after the final OS analysis. 


Appendix 1 
 
Schedule of Activities (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
122/Protocol CO39303, Version 8 
ff See Appendix 2 for PK sample collection.  All samples in Appendix 2 are no longer required after the final OS analysis. 
gg Samples will be collected only at sites with local regulatory authority approval.  See Appendix 2 for further details.  All samples in Appendix 2 
are no longer required after the final OS analysis. 
hh The optional RBR blood sample (for DNA extraction) requires an additional informed consent and can be collected at any time during the course 
of the study.  See Appendix 2 for further details.  All samples in Appendix 2 are no longer required after the final OS analysis. 
ii Subsequent line of prostate cancer therapy is defined as initiation of cytotoxic chemotherapy, radium-223 (Xofigo®), alternate potent 
anti‑androgen (e.g., enzalutamide), other approved or investigational agent used for the treatment of prostate cancer.  Required information 
includes date of first dose of agent, date of last dose of agent, patient’s best response, and date of disease progression.  These data will not be 
collected after the final OS analysis. 
jj Until the final OS analysis. 
 
 


 
 
Appendix 2  
Schedule of Pharmacokinetic Samples and Exploratory 
Biomarker Samples 
Study Visit 
Timepoint(s) 
Sample Type 
Cycle 1, Day 1 
Prior to ipatasertib/placebo and 
abiraterone 
Blood for NGS control 
Plasma (somatic tumor mutations) 
Plasma (exploratory biomarkers) 
Pharmacogenetic blood sample 
Optional blood for RBR  
(for DNA extraction) a 
13 hours postipatasertib/placebo 
and abiraterone administration 
PK plasma sample for 
ipatasertib/placebo 
Cycle 1, Day 15 
(  3 days) 
Prior to ipatasertib/placebo and 
abiraterone 
PK plasma sample for 
ipatasertib/placebo and abiraterone  
13 hours postipatasertib/placebo 
and abiraterone administration 
PK plasma sample for 
ipatasertib/placebo 
Cycle 3, Day 1 
Prior to ipatasertib/placebo and 
abiraterone 
Plasma (somatic tumor mutations) 
Plasma (exploratory biomarkers) 
PK plasma sample for 
ipatasertib/placebo and abiraterone  
13 hours postipatasertib/placebo 
and abiraterone administration 
PK plasma sample for 
ipatasertib/placebo 
NGS = next-generation sequencing; PK = pharmacokinetic; RBR = Research Biosample 
Repository; SDDV = study drug discontinuation visit. 
Notes:  After Cycle 1, Day 1, all study visits and assessments during the treatment period should 
be performed within  3 days of the scheduled date.  Study assessments may be delayed or 
moved ahead of the window to accommodate holidays, vacations, and unforeseen delays.  PK 
samples will be collected in both arms. 
If ipatasertib/placebo (either alone or with abiraterone) has been on temporary hold for  2 days 
prior to PK assessment timepoint, then PK sampling for both ipatasertib/placebo and abiraterone 
may be rescheduled to another day within that cycle after ipatasertib/placebo has been 
administered for at least 3 consecutive days prior to the visit day.  If only abiraterone is held for 
any number of days prior to PK sampling time point, continue sampling of ipatasertib/placebo as 
per schedule; do not collect abiraterone PK sample and resume abiraterone sampling at the next 
scheduled timepoint.  If ipatasertib/placebo is permanently discontinued, PK sampling for 
ipatasertib/placebo and abiraterone can be discontinued.  All samples in Appendix 2 are no 
longer required after the final OS analysis. 
a 
Requires additional informed consent and can be collected at any time during the course of 
the study. 
 


 
 
 
Appendix 2 
 
Schedule of Pharmacokinetic Samples and Exploratory Biomarker Samples 
(cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
124/Protocol CO39303, Version 8 
Study Visit 
Timepoint(s) 
Sample Type 
Cycle 6, Day 1 
Prior to ipatasertib/placebo and 
abiraterone administration 
PK plasma sample for 
ipatasertib/placebo 
Cycle 12, Day 1 
 At visit 
Plasma (somatic tumor mutations) 
Plasma (exploratory biomarkers) 
SDDV 
At visit 
Plasma (somatic tumor mutations) 
Plasma (exploratory biomarkers) 
NGS = next-generation sequencing; PK = pharmacokinetic; RBR = Research Biosample 
Repository; SDDV = study drug discontinuation visit. 
Notes:  After Cycle 1, Day 1, all study visits and assessments during the treatment period 
should be performed within  3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.  PK samples will be collected in both arms. 
If ipatasertib/placebo (either alone or with abiraterone) has been on temporary hold for 
 2 days prior to PK assessment timepoint, then PK sampling for both ipatasertib/placebo and 
abiraterone may be rescheduled to another day within that cycle after ipatasertib/placebo has 
been administered for at least 3 consecutive days prior to the visit day.  If only abiraterone is 
held for any number of days prior to PK sampling time point, continue sampling of 
ipatasertib/placebo as per schedule; do not collect abiraterone PK sample and resume 
abiraterone sampling at the next scheduled timepoint.  If ipatasertib/placebo is permanently 
discontinued, PK sampling for ipatasertib/placebo and abiraterone can be discontinued.   
All samples in Appendix 2 are no longer required after the final OS analysis. 
a Requires additional informed consent and can be collected at any time during the course of 
the study. 


 
 
Appendix 3  
Eastern Cooperative Oncology Group Performance Status Scale 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature; e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
126/Protocol CO39303, Version 8 
Appendix 4  
PSA Progression Eligibility Criteria  
 
PSA  prostate-specific antigen. 
Eligibility based on prostate-specific antigen (PSA) changes.  The reference value (#1) is the 
last PSA measured before increases are documented, with subsequent values obtained a 
minimum of 1 week apart.  If the PSA at time point 3 (value #3A) is greater than that at point 2, 
then eligibility has been met.  If the PSA is not greater than point 2 (value #3B), but value #4 is, 
the patient is eligible assuming that other criteria are met, if values 3A or #4 are 1 ng/mL or 
higher. 
 
REFERENCES 
Bubley GJ, Carducci M, Dahut W, et al: Eligibility and response guidelines for phase II 
clinical trials in androgen-independent prostate cancer: Recommendations from 
the PSA Working Group. J Clin Oncol 1999;17:34617. [Erratum: J Clin Oncol 
2000;18:2644, J Clin Oncol 2007;25:1154]. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. 
J Clin Oncol 2008;26:112859. 


 
 
Appendix 5  
Response Evaluation Criteria in Solid Tumors:  
Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.1 2 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.3 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
MEASURABLE TUMOR LESIONS 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a 
minimum size of:  
 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be  15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow‑up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement. 
NON-MEASURABLE TUMOR LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm 
or pathological lymph nodes with  10 to  15 mm short axis), as well as truly 
non‑measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
                                            
2 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228–47. 
3 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
128/Protocol CO39303, Version 8 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions: 
 
Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of bone 
lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
 
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS  
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
129/Protocol CO39303, Version 8 
Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option. 
Clinical Lesions.  Clinical lesions will only be considered measurable when they are 
superficial and  10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans 
with IV contrast due to allergy or renal insufficiency, the decision as to whether a 
non‑contrast CT or MRI (without IV contrast) will be used to evaluate the patient at 
baseline and during the study should be guided by the tumor type under investigation 
and the anatomic location of the disease.  For patients who develop contraindications to 
contrast after baseline contrast CT is done, the decision as to whether non-contrast CT 
or MRI (enhanced or non-enhanced) will be performed should also be based on the 
tumor type and the anatomic location of the disease and should be optimized to allow for 
comparison with the prior studies if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions on a different modality and interpretation of 
non-target disease or new lesions since the same lesion may appear to have a different 
size using a new modality. 
Ultrasound.  Ultrasound is not useful in the assessment of lesion size and should not be 
used as a method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization of 
these techniques for objective tumor evaluation cannot generally be advised. 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
130/Protocol CO39303, Version 8 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is  10 mm by 
CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement, 
in which circumstance the next largest lesion that can be measured reproducibly should 
be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 
but  15 mm) should be considered non-target lesions.  Nodes that have a short axis 
 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
131/Protocol CO39303, Version 8 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the Case Report Form (CRF) (e.g., “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
 
Complete response (CR):  disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to  10 mm. 
 
Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 
 
Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline 
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
 
Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study 
 
Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to  10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero  
even if CR criteria are met since a normal lymph node is defined as having a short axis 
 10 mm. 
Target Lesions That Become Too Small to Measure.  While in the study, all lesions 
(nodal and non-nodal) that are recorded at baseline should be recorded as actual 
measurements at each subsequent evaluation, even when very small (e.g., 2 mm).  


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
132/Protocol CO39303, Version 8 
However, sometimes lesions or lymph nodes that are recorded as target lesions at 
baseline become so faint on the CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being too small to measure.  
When this occurs, it is important that a value be recorded on the CRF as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well and BML should also be ticked.) 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may 
be maintained that would aid in obtaining maximal diameter measurements of 
each individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion. 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol. 
 
CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level) 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
133/Protocol CO39303, Version 8 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III studies when it is not a criterion of study entry to have measurable 
disease.  The same general concepts apply here as noted above; however, in this 
instance, there is no measurable disease assessment to factor into the interpretation of 
an increase in non-measurable disease burden.  Because worsening in non-target 
disease cannot be easily quantified (by definition:  if all lesions are truly 
non‑measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based 
on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare progressive disease (PD) for measurable disease, that 
is, an increase in tumor burden representing an additional 73% increase in volume 
(which is equivalent to a 20% increase in diameter in a measurable lesion).  Examples 
include an increase in a pleural effusion from “trace” to “large” or an increase in 
lymphangitic disease from localized to widespread or may be described in protocols as 
“sufficient to require a change in therapy.”  If unequivocal progression is seen, 
the patient should be considered to have had overall PD at that point.  While it would be 
ideal to have objective criteria to apply to non-measurable disease, the very nature of 
that disease makes it impossible to do so; therefore, the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a 
CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify whether it represents truly new disease.  If repeat scans 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
134/Protocol CO39303, Version 8 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial scan. 
EVALUATION OF RESPONSE 
Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.   
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 
 is 
to be used. 
Table 1 
Timepoint Response:  Patients with Target Lesions 
(With or Without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not 
all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; 
PR  partial response; SD  stable disease. 
 
Table 2 
Timepoint Response:  Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised. 
 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
135/Protocol CO39303, Version 8 
Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned timepoint response.  This would be most likely 
to happen in the case of PD.  For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and, during the study, only two lesions were assessed, but 
those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the 
contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint. 
 
 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
136/Protocol CO39303, Version 8 
Table 3 
Best Overall Response When Confirmation Is Required 
Overall Response at 
First Timepoint 
Overall Response at 
Subsequent Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR a 
CR 
SD 
SD, provided minimum duration for 
SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration for 
SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration for 
SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration for 
SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration for 
SD was met; otherwise, NE 
NE 
NE 
NE 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
a If a CR is truly met at the first timepoint, any disease seen at a subsequent timepoint, 
even disease meeting PR criteria relative to baseline, qualifies as PD at that point 
(since disease must have reappeared after CR).  Best response would depend on 
whether the minimum duration for SD was met.  However, sometimes CR may be 
claimed when subsequent scans suggest small lesions were likely still present and in 
fact the patient had PR, not CR, at the first timepoint.  Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size ( 10 mm), they may still have a measurement reported on scans.  
This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the CRF. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  
The objective response status of such patients is to be determined by evaluation of 
target and non-target disease as shown in Table 1, Table 2, and  
 


 
Appendix 5 
Response Evaluation Criteria in Solid Tumors:   
Excerpt from Original Publication (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
137/Protocol CO39303, Version 8 
Table 3.  
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non-target 
lesion, as appropriate.  This is to avoid an incorrect assessment of complete response if 
the primary tumor is still present but not evaluated as a target or non-target lesion. 
 


 
 
Appendix 6  
Criteria for Radiographic Progression per Prostate Cancer 
Working Group 3 
Date 
Progression 
Detected 
(Visit) a 
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(Requirement and 
Timing) 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 8 
Bone lesions: Two or 
more new lesions 
compared to baseline 
bone scan by PCWG3. 
Timing: at least 6 weeks 
after progression 
identified or at Week 16 
visit. c 
Two or more new bone 
lesions on bone scan 
(compared to Week 8 
scan). 
Soft tissue lesions: 
Progressive disease on 
CT or MRI scan by 
RECIST v1.1  b 
No confirmatory scan 
required for soft tissue 
disease progression. 
NA 
Week 16 or 
later 
Bone lesions: Two or 
more new lesions on 
bone scan compared to 
Week 8 bone scan. 
Timing: at least 6 weeks 
after progression 
identified; required for 
bone lesions observed 
on bone scan c 
Persistent d or increased 
number of bone lesions 
on bone scan compared 
to prior scan. 
Soft tissue lesions: 
Progressive disease on 
CT or MRI scan by 
RECIST v1.1. b 
No confirmatory scan 
required for soft tissue 
disease progression. 
NA 
CT  computed tomography; MRI  magnetic resonance imaging; NA  not applicable; 
PCWG3  Prostate Cancer Working Group 3, RECIST v1.1  Response Evaluation Criteria in 
Solid Tumors, Version 1.1. 
Note:  Adapted from Scher et al. 2016. 
a In a situation where the bone scan at Week 8 is missed, the first post-treatment bone scan 
should be treated as the “Week 8” bone scan.  Progression detected by bone scan at an 
unscheduled visit will require a confirmatory scan at least 6 weeks later and should follow 
confirmation criteria outlined in the table for the next scheduled scan. 
b For RECIST v1.1, see Appendix 5.  Up to five lesions (with a maximum of 2 lesions per 
organ) will be recorded as target lesions (e.g., lung, liver, adrenal, nodal). 
c Confirmation must occur at the next available scan regardless of whether the patient will 
continue study treatment. 
d For confirmation, at least two of the lesions first identified as new must be present at the next 
available scan. 
 


 
 
Appendix 7  
Bone Scan Tumor Assessment Tool 
 


 
 
Appendix 8  
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire Core 30:  EORTC QLQ-C30 
 
 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
141/Protocol CO39303, Version 8 
 
 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
142/Protocol CO39303, Version 8 
Appendix 9  
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire:  Urinary Scale from 
EORTC QLQ-PR25 
 
 
EORTC  QLQ-PR25 
 
 
Patients sometimes report that they have the following symptoms or problems. Please 
indicate the extent to which you have experienced these symptoms or problems during 
the past week. Please answer by circling the number that best applies to you. 
 
During the past week 
Not 
at all 
A 
little 
Quite 
a bit 
Very 
much 
1. 
Have you had to urinate frequently during the day? 
1 
2 
3 
4 
2. 
Have you had to urinate frequently at night? 
1 
2 
3 
4 
3. 
When you felt the urge to pass urine, 
did you have to hurry to get to the 
toilet? 
1 
2 
3 
4 
4. 
Was it difficult for you to get enough sleep, 
because you needed to get up frequently at 
night to urinate? 
1 
2 
3 
4 
5. 
Have you had difficulty going out of 
the house because you needed to be 
close to a toilet? 
1 
2 
3 
4 
6. 
Have you had any unintentional release (leakage) of 
urine? 
1 
2 
3 
4 
7. 
Did you have pain when you urinated? 
1 
2 
3 
4 
8. 
Have your daily activities been limited by your urinary 
problems? 
1 
2 
3 
4 
 
 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
143/Protocol CO39303, Version 8 
Appendix 10  
Pain Severity Assessments 
Pain Severity Assessment (Screening)* 
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 
 
Pain Severity Assessment (Cycle 1, Day 1 and following Assessments)* 
Please rate your pain by tapping the one number that best describes your pain at its worst in the 
last week. 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No 
Pain 
 
 
 
 
 
 
 
 
Pain as bad as 
you can imagine 
 
Note: Questions from Brief Pain Inventory and Brief Pain Inventory-Short Form per author 
permission. 


 
 
Appendix 11  
Analgesic Quantification Algorithm Score Categories and 
Equianalgesic Potency Conversions 
Analgesic Quantification Algorithm Score Categories 
Score 
Description 
0 
No analgesic 
1 
Non-opioid analgesics 
2 
Weak opioids (i.e., codeine and tramadol) 
3 
Strong opioids  75 mg OME/day 
4 
Strong opioids  75150 mg OME/day 
5 
Strong opioids  150300 mg OME/day 
6 
Strong opioids  300600 mg OME/day 
7 
Strong opioids  600 mg OME/day 
OME  oral morphine equivalent. 








 
Ipatasertib—F. Hoffmann-La Roche Ltd 
148/Protocol CO39303, Version 8 
 
Appendix 13  
EuroQol 5-Dimension, 5 Levels Questionnaire:  EQ-5D-5L 
 
 
Health Questionnaire 
 
 
English version for the USA 
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 
❑ 
 


 
 
 
Appendix 13 
EuroQol 5-Dimension, 5 Levels Questionnaire:  EQ-5D-5L (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
149/Protocol CO39303, Version 8 
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 
 
❑ 


 
 
 
Appendix 13 
EuroQol 5-Dimension, 5 Levels Questionnaire:  EQ-5D-5L (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
150/Protocol CO39303, Version 8 
 


 
 
 
Appendix 13 
EuroQol 5-Dimension, 5 Levels Questionnaire:  EQ-5D-5L (cont.) 
Ipatasertib—F. Hoffmann-La Roche Ltd 
151/Protocol CO39303, Version 8 
 
 


 
Ipatasertib—F. Hoffmann-La Roche Ltd 
152/Protocol CO39303, Version 8 
 
Appendix 14 Investigational Medicinal Product and Non-
Investigational Medicinal Product Designations (for Use in 
European Economic Area and United Kingdom) 
 
Table A1-1 Investigational, Authorized Auxiliary, and Unauthorized 
Auxiliary Medicinal Product Designations for European 
Economic Area 
Product Name 
IMP/AxMP Designation 
Marketing 
Authorization Status in 
EEA  
Used within 
Marketing 
Authorization 
Ipatasertib 
(RO5532961) 
IMP (test product)  
Unauthorized 
Not applicable  
Abiraterone 
IMP (test product) a 
Authorized 
Noa  
RO5532961 
placebo 
IMP (placebo) 
Unauthorized 
Not applicable 
Prednisone 
AxMP (background 
therapy) 
Authorized 
Yes 
Prednisolone 
AxMP (background 
therapy) 
Authorized  
Yes 
AxMP  auxiliary medicinal product; EEA   European Economic Area; IMP  investigational 
medicinal product; mCRPC  metastatic castrate-resistant prostate cancer.  
a Abiraterone is approved for the treatment of mCRPC but not in combination with ipatasertib. 
 
 
Table A1-2 Investigational and Non-Investigational Medicinal Product 
Designations for European Economic Area and United Kingdom 
Product Name 
IMP/NIMP Designation 
Marketing 
Authorization Status in 
EEA and UK  
Used within 
Marketing 
Authorization 
Ipatasertib 
(RO5532961) 
IMP (test product)  
Unauthorized 
Not applicable  
Abiraterone 
IMP (test product) a 
Authorized 
No a 
RO5532961 
placebo 
IMP (placebo) 
Unauthorized 
Not applicable 
Prednisone 
NIMP (background 
therapy) 
Authorized 
Yes 
Prednisolone 
NIMP (background 
therapy) 
Authorized  
Yes 
EEA  European Economic Area; IMP  investigational medicinal product; mCRPC   metastatic 
castrate-resistant prostate cancer; NIMP  non-investigational medicinal product.  
a Abiraterone is approved for the treatment of mCRPC but not in combination with ipatasertib. 
 


Signature Page for Prot CO39303 Ipatasertib v8 - Published
System identifier: RIM-CLIN-458114
Approval Task
Company Signatory
15-Nov-2022 14:32:13 GMT+0000

SAP_001.pdf: 
Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Trial Testing Ipatasertib Plus Abiraterone Plus 
Prednisone/Prednisolone, Relative to Placebo Plus Abiraterone 
Plus Prednisone/Prednisolone In Adult Male Patients With 
Asymptomatic or Mildly Symptomatic, Previously Untreated, 
Metastatic Castrate-Resistant Prostate Cancer 
NCT Number: NCT03072238 
Document Date: SAP Version 2: 23-Dec-2020 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Ipatasertib—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan CO39303, Version 2
STATISTICAL ANALYSIS PLAN
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, MULTICENTER TRIAL TESTING 
IPATASERTIB PLUS ABIRATERONE PLUS 
PREDNISONE/PREDNISOLONE, RELATIVE TO PLACEBO PLUS 
ABIRATERONE PLUS PREDNISONE/PREDNISOLONE IN ADULT MALE 
PATIENTS WITH ASYMPTOMATIC OR MILDLY SYMPTOMATIC, 
PREVIOUSLY UNTREATED, METASTATIC CASTRATE-RESISTANT 
PROSTATE CANCER
PROTOCOL NUMBER:
CO39303
STUDY DRUG:
Ipatasertib (RO5532961)
VERSION NUMBER:
2
IND NUMBER:
111051
EUDRACT NUMBER:
2016-004429-17
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, Ph.D.
DATE FINAL:
Version 1: 16 March 2020
DATE AMENDED:
Version 2: See electronic date stamp below.
Date and Time(UTC)        Reason for Signing
Name
23-Dec-2020 01:46:05
Company Signatory


Ipatasertib—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan CO39303, Version 2
STATISTICAL ANALYSIS PLAN AMENDMENT, VERSION 2
RATIONALE
The Statistical Analysis Plan (SAP) Version 1 for Protocol CO39303 (yielding Version 2, 
i.e., this document) has been amended to include an additional second overall survival 
(OS) interim analysis to provide more stable assessments on the key secondary 
endpoint OS as well as other secondary endpoints with longer patient follow-up following 
the primary progression-free survival (PFS) analysis, which is also the first OS interim 
analysis. Fewer OS events were observed at the time of primary analysis than originally 
projected (observed 140 OS events in 27% patients vs projected 196 OS events in 36% 
patients, in patients with PTEN loss tumors by IHC; and observed 267 OS events in 24% 
patients vs projected 363 OS events in 33% patients, in the ITT population). Changes to 
the SAP along with the rationale are summarized in the following sections:
In Section 2.4.2 (interim and final analysis timing for OS), an additional OS interim 
analysis has been added for Study CO39303. The overall type 1 error of OS analyses is 
controlled at 4% because only one of the co-primary endpoints, radiographic 
progression-free survival (rPFS) in patients with phosphatase and tensin homolog
(PTEN) loss tumors by immunohistochemistry (IHC), was met. A total of three analyses 
of OS in patients with PTEN loss tumors by IHC are to be performed according to the 
new analysis plan, including two interim analyses and one final analysis. The first OS 
interim analysis was already performed at the time of rPFS primary analysis. The 
second OS interim analysis has been added to the original interim analysis plan. The 
target number of OS events for the final OS analysis remains unchanged per the original 
SAP Version 1, the type I error for the final OS analysis will be adjusted based on the 
Lan-DeMets implementation of the O’Brien-Fleming alpha spending function. 
In Section 4.4.4.2, the weighted log-rank test has been added as a sensitivity analysis 
for OS due to the potential risk of non-proportional hazards due to delayed treatment 
effect.
Additional minor changes have been made to improve clarity and consistency.


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TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 9
2.2
Outcome Measures ................................................................. 9
2.3
Determination of Sample Size ............................................... 11
2.4
Analysis Timing ..................................................................... 14
2.4.1
Primary Analysis Timing for rPFS.......................................... 14
2.4.2
Interim and Final Analysis for OS .......................................... 15
3.
STUDY CONDUCT..................................................................................... 19
3.1
Randomization Issues ........................................................... 19
3.2
Independent Review Committee............................................ 19
3.3
Data Monitoring committee.................................................... 19
4.
STATISTICAL METHODS .......................................................................... 19
4.1
Analysis Populations ............................................................. 19
4.1.1
ITT Population ....................................................................... 19
4.1.2
Safety-Evaluable Population.................................................. 19
4.1.3
Pharmacokinetic-Evaluable Population ................................. 20
4.2
Analysis of Study Conduct..................................................... 20
4.2.1
PRO Completion Rates ......................................................... 20
4.3
Analysis of Treatment Group Comparability .......................... 20
4.4
Efficacy Analysis.................................................................... 20
4.4.1
Primary Efficacy Endpoint...................................................... 21
4.4.2
Secondary Efficacy Endpoints............................................... 22
4.4.2.1
Overall Survival ..................................................................... 22
4.4.2.2
Time to Pain Progression ...................................................... 23
4.4.2.3
Time to Initiation of Cytotoxic Chemotherapy ........................ 24
4.4.2.4
Time to Function Deterioration .............................................. 24
4.4.2.5
Time to Prostate-Specific Antigen Progression ..................... 25
4.4.2.6
Time to First Opioid Use........................................................ 25
4.4.2.7
Time to Symptomatic Skeletal Events ................................... 25




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4.9
Missing Data.......................................................................... 34
4.10
Interim Analyses .................................................................... 35
4.10.1
Planned Interim Safety Analyses........................................... 35
4.10.2
Planned Interim Efficacy Analyses ........................................ 35
4.10.3
Optional Interim Analysis....................................................... 35
5.
REFERENCES ........................................................................................... 37
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 10
Table 2
Primary Analysis for Radiographic Progression-Free Survival.... 15
Table 3
Timing of Overall Survival Analyses............................................ 16
Table 4
Efficacy Stopping Boundaries and Power for Overall Survival 
Analyses ..................................................................................... 17
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 6
Figure 2
Type I Error Control .................................................................... 12
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 38
Appendix 2
Schedule of Assessments........................................................... 48
Appendix 3
Schedule of Pharmacokinetic Samples and Exploratory 
Biomarker Samples..................................................................... 56


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6/Statistical Analysis Plan CO39303, Version 2
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for the Study CO39303 (IPATential150).  The analyses described in 
this SAP will supersede those specified in Protocol CO39303.
2.
STUDY DESIGN
This is a Phase III, multicenter, international, randomized, double-blind, 
placebo-controlled study.  This study is designed to evaluate the efficacy, safety, and 
pharmacokinetics of ipatasertib plus abiraterone and prednisone/prednisolone (Ipat+Abi) 
compared with placebo plus abiraterone and prednisone/prednisolone (PboAbi). The 
target patient population is asymptomatic or mildly symptomatic patients previously 
untreated for metastatic castration-resistant prostate cancer (mCRPC). The analysis will 
be based on the intent-to-treat (ITT) and phosphatase and tensin homolog (PTEN) loss
populations, the latter defined using the Ventana PTEN immunohistochemistry (IHC) 
assay. Patients must have a valid PTEN IHC result from tumor to be enrolled.
The study will enroll approximately 1100 patients at approximately 200 centers 
worldwide in about 20 months. The study schema is shown in Figure 1. 
Figure 1
Study Schema
BIDtwice daily; CRPCcastration-resistant prostate cancer; ECOGEastern Collaborative Oncology 
Group; FFPEformalin-fixed, paraffin-embedded; HbA1cglycosylated hemoglobin; 
IHCimmunohistochemistry; mCRPCmetastatic castration -resistant prostate cancer; PCWG3Prostate 
Cancer Working Group 3; PSperformance status; PSAprostate-specific antigen; QDonce daily; 
RECIST v1.1Response Evaluation Criteria in Solid Tumors, Version 1.1. 
a
Abiraterone (1000 mg QD)prednisone/prednisolone (5 mg BID).
b In the absence of radiographic disease progression, patients may continue single-agent treatment. 
c
If applicable, patients will return to clinic for tumor assessments (disease follow-up visit) until confirmed 
radiographic progression.


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Approximately 1100 patients will be enrolled to enable the primary analysis for the global 
study results.  After approximately 1100 patients have been randomized into the study, 
the global enrollment will be closed.
Patients who meet the eligibility criteria will be randomized in a 1:1 ratio to one of the 
following two treatment arms (each consisting of 28-day cycles of oral administration):

Arm 1:  ipatasertib (400 mg once daily [QD]) plus abiraterone (1000 mg QD) 
and prednisone/prednisolone (5 mg twice daily [BID])

Arm 2:  placebo (matched to ipatasertib appearance) plus abiraterone (1000 mg 
QD) and prednisone/prednisolone (5 mg BID)
A randomization scheme will be used across all study sites through a centralized 
interactive voice- or Web-based response system (IxRS).  In this study, randomization of 
patients will be stratified on the basis of the following factors:

Prior taxane-based therapy in the hormone-sensitive setting (yes vs. no)

Progression factor (prostate-specific antigen [PSA] only vs. other)

Presence of visceral metastasis (liver or lung; yes vs. no)

Tumor PTEN loss status by IHC assay (yes vs. no)

Geographic region (not a factor for stratified analysis)
Prior to enrollment, but after signing the Informed Consent Form, patients will have the 
PTEN loss status of their tumor assessed by the central laboratory using a validated 
IHC assay with defined criteria for PTEN loss. Patients whose tumor samples have no 
valid PTEN IHC test result will not be permitted to enroll in the study.
Study assessments (efficacy, safety, patient-reported outcomes, and pharmacokinetic 
[PK] measurements) and timing of those assessments during each 28-day cycle are
presented in Appendix 2. 
Radiographic tumor assessments, including computed tomography (CT) or magnetic 
resonance imaging (MRI), and bone scans will be evaluated locally by the investigators.  
Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) will be used to 
assess CT or MRI scans of lesions in soft tissues.  Bone lesions will be assessed by 
bone scan only, using the Prostate Cancer Working Group 3 (PCWG3) criteria to assess 
disease progression.  All scans will be prospectively collected and centrally archived.
Timely and complete disease assessments by imaging methods in this study are 
imperative.  Each tumor assessment will be performed as scheduled according to the 
calendar, regardless of any study treatment doses omitted, to prevent the introduction of 
bias into the assessment of efficacy.  Failure to perform any of the required disease 
assessments will result in the inability to determine disease status for that time point.


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In addition, an independent review committee (IRC) will provide an assessment of 
radiographically assessed disease progression as an exploratory endpoint to support the 
findings of the investigator assessed outcomes. The data will be collected from all 
patients.  IRC and IRF (independent review facility) are used interchangeably.  IRC will 
be used hereafter.
Patients will receive study treatment until radiographically assessed disease progression 
(as assessed by the investigator per RECIST v1.1 and/or PCWG3 criteria as applicable), 
intolerable toxicity, elective discontinuation of the study treatment, elective withdrawal 
from the study, initiation of new anti-cancer therapy, study completion or termination by 
F. Hoffmann‑La Roche Ltd (the Sponsor), or physician decision, whichever occurs first.  
For patients where disease progression is assessed only on the basis of bone scan 
findings, a confirmatory scan MUST be performed per PCWG3 criteria to establish 
disease progression.  Patients who discontinue one of the study treatments (i.e., 
ipatasertib/placebo or abiraterone) in the absence of radiographically assessed disease 
progression may continue the study and receive the remaining single-agent treatment 
(i.e., abiraterone if ipatasertib/placebo is discontinued or ipatasertib/placebo if 
abiraterone is discontinued) at the discretion of the investigator. 
Patients who discontinued from study treatment will return for a study treatment 
completion visit within 30 days after the last dose of study treatment.
A crossover between treatment arms is not allowed.
Following radiographically assessed disease progression (as assessed by the 
investigator per RECIST v1.1 and/or PCWG3 criteria as applicable) and study treatment 
discontinuation, patients will continue post-treatment follow-up for selected assessments 
supporting secondary and exploratory efficacy endpoints, until death, loss to follow-up, 
withdrawal of consent from study, or study termination by the Sponsor.
Sites should record for all patients who are in follow-up survival information including 
symptomatic skeletal events (SSEs), initiation of subsequent anti-cancer therapy 
(including the date of the first dose of agent, the date of the last dose of agent, patient’s 
best response, and date of disease progression), date of second radiographically 
assessed disease progression and any post-progression therapy for prostate cancer
(PC) as well as any serious adverse events considered by the investigator to be related 
to the study treatment (abiraterone and/or ipatasertib/placebo), and anti-diabetic 
medications for hyperglycemia related to study treatment and opioid consumption for 
cancer-related pain.
Patients who discontinue from study treatment for reasons other than radiographically 
assessed disease progression will be asked to return to the clinic for disease follow-up 
visits approximately every three months to complete tumor assessments until 


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radiographically assessed disease progression (per RECIST v1.1 and/or PCWG3 as 
applicable) or withdrawal from the study.
All patients who discontinue from study treatment because of radiographically assessed 
disease progression or any other reasons will be asked to report, via electronic 
provisioned device completed at home or at the clinic, pain medications (including dose 
and type of opioids used), pain severity (7-day recall), and other patient-reported 
outcome (PRO) measures approximately every 28 days until initiation of any 
post-progression therapy for PC or up to 1 year, whichever occurs first.
After initiation of the next-line of therapy or 1-year post study treatment discontinuation, 
whichever occurs first, patients will be asked to report pain severity, analgesic use (yes 
vs. no), EuroQol 5 Dimensions, 5 Levels (EQ-5D-5L); and three scales from the 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 (EORTC QLQ‑C30) every 3 months completed at home or at the 
clinic or via telephone calls.
An independent Data Coordinating Center (iDCC) will prepare all summaries and 
analyses for the independent Data Monitoring Committee’s (iDMC’s) review.  The safety 
summaries will include, but will not be limited to, demographic data, adverse events, 
serious adverse events, and relevant laboratory data (see iDMC charter for details).
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  Following the data review, the iDMC will provide 
a recommendation to the Sponsor whether to continue the study, amend the protocol, or 
stop the study.  The final decision will rest with the Sponsor.
Any outcomes of the iDMC’s reviews on the safety and benefit-risk balance that affect 
study conduct will be communicated in a timely manner to the investigators for 
notification of Institutional Review Boards and Ethics Committees (IRBs/ECs).
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
OUTCOME MEASURES
This study will evaluate the efficacy, safety, and pharmacokinetics of (IpatAbi), 
compared with PboAbi in asymptomatic or mildly symptomatic patients previously 
untreated for mCRPC.  Specific objectives and corresponding endpoints for the study 
are outlined below (see Table 1).






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The overall type I error (a) for this study is 0.05 (two-sided).  Type I error will be 
controlled for the following efficacy endpoints:
–
Co-primary efficacy endpoints:  Investigator-assessed radiographic progression-free 
survival (rPFS) per PCWG3 criteria in the ITT population and in patients with PTEN
loss tumors by IHC
–
Key secondary endpoints:  overall survival (OS) in the ITT population and in patients 
with PTEN loss tumors by IHC
Type I error will be controlled by comparing these endpoints between treatment arms 
according to the following testing procedure (Figure 2).
Figure 2
Type I Error Control
Dx+diagnostic positive; ITTintention-to-treat; rPFSradiographic progression-free survival; 
OSoverall survival.
Testing of rPFS
Both rPFS in the ITT population and in patients with PTEN loss tumors by IHC will be 
tested at the time of the primary analysis of rPFS in order as follows:
1.
Firstly, test the null hypothesis of no difference in rPFS between the two arms in 
patients with PTEN loss tumors by IHC using the stratified log-rank test with 
significance level of 0.05.
2.
If the null hypothesis of test 1 described above is rejected, of 0.05 will then be 
passed along and allocated between rPFS in the ITT population (0.01) and OS in 
patients with PTEN loss tumors by IHC (0.04).  That is, rPFS in the ITT population 
will be tested using the stratified log-rank test with significance level of 0.01.


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Testing of OS in patients with PTEN loss tumors by IHC
1.
OS in patients with PTEN loss tumors by IHC will be tested only if the test of rPFS in 
patients with PTEN loss tumors by IHC (i.e., test 1 described above) is positive with 
ɑ of 0.05.  If the test of rPFS in the ITT population (i.e., test 2 described above) is 
also positive with ɑ of 0.01, then the OS in patients with PTEN loss tumors by IHC 
will be tested with ɑ of 0.05; otherwise the OS in patients with PTEN loss tumors by 
IHC will be tested with ɑ of 0.04.  When the test of rPFS in patients with PTEN loss 
tumors by IHC (i.e., test 1 described above) is passed, at the time of the primary 
analysis of rPFS, an interim analysis of OS in patients with PTEN loss tumors by 
IHC will be performed.  The interim analysis boundary for statistical significance will 
be determined based on the Lan-DeMets implementation of the O’Brien-Fleming 
alpha spending function according to the type I error ɑ allocated to this endpoint 
(see Figure 2).
Testing of OS in the ITT population
1.
OS in the ITT population will be tested only if the test of OS in patients with PTEN
loss tumors by IHC (i.e., test 3 described above) is positive, and it will be tested with 
the same type I error that is used for the test of OS in patients with PTEN loss 
tumors by IHC.  At the time of the primary analysis of rPFS, if the interim analysis of 
OS in patients with PTEN loss tumors by IHC test is positive, an interim analysis of 
OS in the ITT population will be performed.  At the time of final OS analysis in 
patients with PTEN loss tumors by IHC, if the test of OS in patients with PTEN loss
tumors by IHC is positive, an interim analysis of OS in the ITT population will be 
performed.  The interim analysis boundary for statistical significance will be 
determined based on the Lan‑DeMets implementation of the O’Brien-Fleming alpha 
spending function according to the type I error allocated to this endpoint, which 
should be the same type I error that is used for the test of OS in patients with 
PTEN loss tumors by IHC.
The sample size of this study is based on the number of events required to demonstrate
efficacy with regard to both rPFS and OS for the comparison of treatment arms in ITT 
and PTEN loss population by IHC.
The estimates of the number of events required to demonstrate efficacy with regard to
rPFS in the comparison of treatment arms are based on the following assumptions:

In the PTEN loss population
–
A two-sided significance level of 0.05 
–
A power of 98.4% to detect a hazard ratio (HR) of 0.61, corresponding to an 
improvement in median rPFS from 14 months to 23 months 
–
No interim analysis for rPFS
–
A dropout rate of 10% per 12 months

In the ITT population
–
A two-sided significance level of 0.01


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–
A power of 94.6% to detect an HR of 0.70, corresponding to an improvement in 
median rPFS from 16.5 months to 23.6 months 
–
No interim analysis for rPFS
–
A dropout rate of 10% per 12 months
The estimates of the number of events required with regard to OS in the comparison of 
treatment arms are based on the following assumptions:

In the PTEN loss population:
–
A two-sided significance level of 0.04
–
A power of 63% to detect a HR of 0.76, corresponding to an improvement in 
median OS from 29 months to 38 months
–
First OS interim analysis performed at approximately 27% event-patient ratio 
(EPR), a second OS interim analysis to be performed at approximately 44% 
EPR and OS final analysis to be performed at approximately 63%EPR.
–
A dropout rate of 5% per 24 months

In the ITT population:
–
A two-sided significance level of 0.04.
–
A power of 60% to detect an HR of 0.83, corresponding to an improvement in 
median OS from 35 months to 42 months
–
First OS interim analysis was not performed due to the testing hierarchy with 
27% EPR. A second OS interim analysis to be performed at approximately 41% 
EPR, a third OS interim analysis to be performed at approximately 59% EPR
and OS final analysis to be performed at approximately 60% EPR.
–
A dropout rate of 5% per 24 months
With these assumptions, approximately 1100 patients in total will be randomized into this 
study, with approximately 550 patients with PTEN loss tumors by IHC.
2.4
ANALYSIS TIMING
2.4.1
Primary Analysis Timing for rPFS
The primary analysis of rPFS will occur when approximately 275 rPFS events in patients 
with PTEN loss tumors and approximately 550 rPFS events in the ITT population have 
been observed, whichever occurs later.  The primary analysis is expected to occur 
approximately 34 months after the first patient is randomized.
In the PTEN loss population, 275 events will allow for 98.4% power to detect an 
improvement in median rPFS from 14 months in the placebo arm to approximately 
23 months in the ipatasertib arm (HR0.61) at the 5% level of significance (two-sided).
These numbers of events correspond to a minimum detectable difference (MDD) in HR 
of approximately 0.79.


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In the ITT population, 550 events will allow for 94.5% power to detect an improvement in 
median rPFS from 16.5 months in the placebo arm to approximately 23.6 months in the 
ipatasertib arm (HR0.70) at the 1% level of significance (two-sided). These numbers of 
events correspond to an MDD in HR of approximately 0.80 (see Table 2).
Table 2
Primary Analysis for Radiographic Progression-Free Survival
PTEN Loss
ITT
Type of 
Analysis
Analysis 
Timing
(Months 
since 
FPI)
No. of 
Events 
(Event 
Ratio %)
MDD in
Hazard 
Ratio
Power %
No. of 
Events 
(Event 
Ratio %)
MDD in
Hazard 
Ratio
Power %
rPFS 
Primary 
Analysis
34
275 (50)
0.79
98.4
550 (50)
0.80
94.5
FPIfirst patient in; ITTintention-to-treat; MDDminimum detectable difference;
rPFSradiographic progression-free survival.
2.4.2
Interim and Final Analysis for OS
Following the type I error control diagram shown in Figure 2, since rPFS in patients with 
PTEN loss tumors by IHC passed the test with a significance level of 0.05 and rPFS in 
the ITT population did not pass the test with of 0.01 at the time of primary analysis of 
rPFS, the allocated to OS analysis is 0.04. OS in the patients with PTEN loss tumors 
by IHC will be tested firstly with of 0.04, followed by testing OS in the ITT population. 
A total of four analyses of OS are planned:
–
The first interim analysis of OS was performed at the time of primary analysis of 
rPFS.
–
The second interim analysis of OS will take place when approximately 229 OS 
events in the patients with PTEN loss tumors by IHC occur, or when the minimum 
follow-up time (from the last patient enrollment date of 17 January 2019) is 
approximately 32 months, whichever occurs later.
–
The third analysis of OS is the final analysis of OS in the patients with PTEN loss 
tumors by IHC and it is also the third interim analysis of OS in the ITT population. It 
is scheduled when there are approximately 327 OS events in patients with PTEN 
loss tumors by IHC occur. This target number of OS event is unchanged per the 
original SAP, Version 1.


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–
The fourth analysis of OS is the final analysis of OS in the ITT population. It is 
scheduled when there are approximately 660 OS events in the ITT population occur. 
This target number of OS event is unchanged per the original SAP, Version 1.
The projected analysis timing and the corresponding numbers of OS events for OS 
interim and final analyses in patients with PTEN loss tumors by IHC and in the ITT 
population are shown in Table 3. When the timing of the third and fourth analyses are 
very close, these two analyses could be combined and the alpha-spending will be 
adjusted using O’Brien-Fleming alpha-spending method.
Table 3
Timing of Overall Survival Analyses
PTEN Loss
ITT
Analysis
Time from FPI
(months)
Information
Fraction (%)
No. of Events
(EPR %)
Information
Fraction (%)
No. of Events
(EPR %)
OS 1st IA
33
43
140 (27)
40
267 (24)
OS 2nd IA
50
70
229 (44)
69
450 (41)
OS 3rd IA/ FA
78
100
327 (63)
98
646 (59)
OS FA
81
-
-
100
660 (60)
FAfinal analysis; FPIfirst patient in; ITTintent-to-treat; OSoverall survival; EPREvent-Patient-Ratio.
The efficacy stopping boundaries for OS interim and final analyses will be calculated 
using the Lan-DeMets approximation to the O’Brien-Fleming boundary in the patients 
with PTEN loss tumors by IHC and in the ITT population, respectively. The details of 
each OS analysis testing are described below, and the efficacy stopping boundaries are 
shown in Table 4. Crossing the p-value boundaries will be used to claim statistical 
significance. The projected HR or p-value boundaries in Table 4 are based on the 
observed (i.e., first OS interim analysis) or projected numbers of OS events listed in
Table 3, and the actual boundaries for HR or p-values will be calculated at the time of 
analysis based on the actual number of OS events observed in patients with PTEN loss 
tumors by IHC and in the ITT population, respectively. 


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Table 4
Efficacy Stopping Boundaries and Power for Overall Survival 
Analyses
Analysis
PTEN loss
ITT
OS 1st IA
spent0.0008
HR 0.567
p-value 0.0008
power4%
OS 1st IA in PTEN loss is negative 
of 0.0008 cannot be passed along*
OS 2nd IA
spent0.0106
HR 0.713
p-value 0.0106
power30%
OS 2nd IA in PTEN loss is positive, OS in ITT 
will be tested with of 0.0392.
spent0.0094
HR 0.783
p-value 0.0094
power25%
OS 2nd IA in PTEN loss is 
negative
of 0.0106 cannot be passed 
along*
OS 3rd IA/ FA
spent0.0286
HR 0.793
p-value 0.0359
power63%
spent0.0272
HR 0.846
p-value 0.0337
power58%
OS FA in PTEN loss is 
positive, OS in ITT will be 
tested with of 0.0286.
spent0.0266
HR 0.840
p-value 0.0266
power54%
OS FA
-
spent0.0026
HR 0.844
p-value 0.0293
power60%
spent0.0020
HR 0.837
p-value 0.0224
power56%
Based on number of events given in Table 3, power for patients with PTEN loss tumors by IHC is 
computed to detect an improvement in median OS from 29 months in the placebo arm to 
approximately 38 months in the ipatasertib arm (HR0.76), and power for the ITT population is 
computed to detect an improvement in median OS from 35 months in the placebo arm to 
approximately 42 months in the ipatasertib arm (HR0.83).
FAfinal analysis; IAinterim analysis; HRhazard ratio; OSoverall survival.
* Not formally tested due to testing hierarchy
FA in ITT population will not be formally tested if all tests are negative in patients with PTEN loss 
tumors by IHC.
At the first interim analysis of OS (i.e., the primary analysis of rPFS), following the rPFS 
analyses, OS in patients with PTEN loss tumors by IHC was tested with significance 
level of 0.04. A total of 140 (27% of 521 patients) OS events was observed in patients 
with PTEN loss tumors by IHC. This corresponds to 43% (140/327) information fraction 
of the final analysis of OS in patients with PTEN loss tumors by IHC, and the O’Brien-
Fleming p-value boundary was 0.0008. The first interim analysis for OS in patients with 
PTEN loss tumors by IHC did not pass the test. Therefore, of 0.0008 cannot be 
passed along to the first interim analysis for OS in the ITT population due to the testing 
hierarchy. 


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At the second interim analysis of OS, the OS in patients with PTEN loss tumors by IHC 
will be formally tested firstly. Given that of 0.0008 was spent at the first interim analysis 
of OS, the remaining of 0.0392 will be allocated to the second interim and final 
analyses of OS in patients with PTEN loss tumors by IHC. With 229 OS events which 
correspond to 70% (229/327) information fraction, the O’Brien-Fleming p-value boundary 
is 0.0106. That is, statistical significance will be declared if p ≤ 0.0106 for the OS in 
patients with PTEN loss tumors by IHC. The actual interim analysis boundary for 
statistical significance will be determined based on the actual OS events observed using 
the Lan-DeMets implementation of the O’Brien-Fleming alpha spending function.

If the test of the second interim OS analysis in patients with PTEN loss tumors by 
IHC is positive, then OS in the ITT population will be formally tested with the 
remaining of 0.0392 allocated to the second interim, the third interim and the final 
analyses based on the number of OS events observed using O’Brien-Fleming 
alpha-spending method. For example, based on the projected numbers of OS 
events listed in  Table 3, the spent, HR and p-value boundary for each analysis 
are presented in Table 4. The third interim analysis and final analysis for the OS in 
the ITT population could be combined and the alpha-spending will be adjusted using 
O’Brien-Fleming alpha-spending method.

If the test of the second interim OS analysis in patients with PTEN loss tumors by 
IHC is negative, of 0.0106 cannot be passed along to the OS in the ITT 
population. The second interim OS analysis in the ITT population will not be formally 
tested due to the testing hierarchy, and only the remaining of 0.0286 (=0.04-
0.008-0.106) will be used for the third interim analysis and final analysis for OS in 
the ITT population.
The final analysis of OS in patients with PTEN loss tumors by IHC is also the third 
interim analysis of OS in the ITT population.  

When both the first and second interim analyses of OS in patients with PTEN loss 
tumors by IHC are negative, the remaining will be used for the final analysis of OS 
patients with PTEN loss tumors by IHC. In the example shown in Table 4, of 
0.0286, p-value boundary of 0.0359 will be used. 

When the second interim analysis of OS in patients with PTEN loss tumors by IHC 
is positive and second interim analysis in the ITT population is negative, the final 
analysis of OS in patients with PTEN loss tumors by IHC becomes descriptive 
update and OS in the ITT populations will be formally tested with the remaining of 
0.0298 (=0.04-0.008-0.0094) will be allocated to the third interim and final analyses 
of OS in the ITT populations as shown in Table 4. The third interim analysis and 
final analysis for the OS in the ITT population could be combined and the alpha-
spending will be adjusted using O’Brien-Fleming alpha spending method.

When both the second interim analysis of OS in patients with PTEN loss tumors by 
IHC and the second interim analysis of OS in the ITT population are positive, the 
final analysis of OS in patients with PTEN loss tumors by IHC and the third and final 
analyses of OS in the ITT populations will become descriptive updates. 


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The final OS analysis in the ITT population will be formally tested with the remaining . 
As shown in Table 4, the value of depends on the testing results of the previous OS 
analyses in patients with PTEN loss tumors by IHC and in the ITT population. The actual 
will be recalculated based on the actual numbers of OS events observed. 
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Patients will be allocated to one of two treatment arms through use of a permuted block 
randomization algorithm with predefined stratification variables, prior taxane-based 
therapy in the hormone-sensitive setting (yes vs. no), progression factor (PSA only vs. 
other), presence of visceral metastasis (liver or lung; yes vs. no), and tumor PTEN loss 
status by IHC assay (yes vs. no). The stratification factor of geographic region will not
be a factor used for the stratified analysis.  A placebo for ipatasertib will be used in the 
control arm.  Patients, investigators, and the Sponsor will be blinded to treatment 
assignment.
3.2
INDEPENDENT REVIEW COMMITTEE
An independent Review Committee (IRC) will be set up to provide an assessment of 
radiographic progression as an exploratory endpoint to support the findings of the 
investigator-assessed outcomes.  The data will be collected from all patients.  Refer to 
the IRC charter and IRC audit plan for further detail.
3.3
DATA MONITORING COMMITTEE
An iDMC will evaluate safety during the study on a regular basis. All summaries and 
analyses by treatment arm for the iDMC review are prepared by an external iDCC. 
Members of the iDMC are external to the Sponsor and follow a separate iDMC Charter 
that outlines their roles and responsibilities, as well as a detailed monitoring plan. Refer 
to the iDMC charter for further detail.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
ITT Population
The ITT population is defined as all randomized patients, whether or not the patient 
received the assigned treatment. The ITT patients will be analyzed according to the 
treatment assigned at randomization by the IxRS.
4.1.2
Safety-Evaluable Population
The safety-evaluable population is defined as patients who received any amount of the 
study treatment. Patients will be analyzed according to the treatment arm associated 
with the actual regimen received. Patients who were randomized to the study but who 
did not receive any study drug will not be included in the safety-evaluable population.


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4.1.3
Pharmacokinetic-Evaluable Population
Pharmacokinetic (PK) analyses will be based on PK observations from all patients who 
received ipatasertib treatment with evaluable PK samples.
4.2
ANALYSIS OF STUDY CONDUCT
Enrollment, treatment discontinuation, treatment discontinuation reasons, major protocol 
deviations including major deviations of inclusion/exclusion criteria, and reasons for 
discontinuation from the study will be summarized by treatment arm for the ITT 
population.  
4.2.1
PRO Completion Rates
Completion rates for PRO measures in the ITT population and PTEN loss population will
be calculated as the number of patients who completed the assessment divided by the 
number of patients expected to complete the assessment at each time point for each 
treatment arm. Reasons for missing assessments, if available, will be summarized using 
frequencies and percentages. Completion rates will be reported for the following PRO 
measures: 7-day recall pain severity item (post-screening), the QLQ-C30 and key scales 
(role functioning [RF], physical functioning [PF], global health status [GHS]), and the 
EORTC Quality of Life Questionnaire Prostrate Cancer Module [QLQ-PR25] urinary 
scale.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including age, race, ethnicity, etc), and 
baseline disease characteristics such as presence of visceral metastasis (liver or lung; 
yes vs. no), progression factor (PSA only vs. other), prior taxane-based therapy in the 
hormone-sensitive setting (yes vs. no), tumor PTEN loss status by IHC assay (yes vs. 
no), progression criteria at enrollment (prostate-specific antigen only, radiographic only, 
prostate-specific antigen and radiographic), alkaline phosphatase and hemoglobin will 
be summarized by treatment arm. Descriptive statistics (mean, median, SD, and range) 
will be presented for continuous variables, and frequencies and percentages will be 
presented for categorical variables.
Baseline values are the last available data obtained prior to the patient receiving the first 
dose of any study treatments on Cycle 1, Day 1 visits unless otherwise noted.
4.4
EFFICACY ANALYSIS
The co-primary efficacy objective for this study is to evaluate the efficacy of IpatAbi
compared with PboAbi on the basis of rPFS in patients in the ITT population and in 
patients with PTEN loss tumors determined by IHC assay.
Efficacy analyses will include all patients who were included in the randomization, i.e. 
ITT population, except for the objective response rate (ORR) analysis.  ORR analysis 


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will include all patients with measurable disease at baseline only. For efficacy, patients 
will be analyzed according to the treatment arm to which they were randomized.
The stratification factors will be those used for randomization and will be obtained from 
the IxRS except for the factor “region”. Due to the potential risk of over-stratification 
(Akazawa et al. 1997), if at least one stratum (i.e., a combination of stratification factor 
levels across all stratification factors) has fewer than 10 rPFS events across treatment 
arms, the stratification factor which contains the level with the smallest number of 
patients will be removed from the stratified analyses. The removal of the stratification 
factors will continue until there is no stratum with fewer than 10 rPFS events. The final 
set of stratification factors used in stratified analyses will be applied to all endpoints 
where stratified analyses are planned.
4.4.1
Primary Efficacy Endpoint
The primary endpoint of rPFS is defined as the time from randomization to the first 
documented disease progression, as assessed by the investigator with use of the 
PCWG3 criteria (soft tissue by CT or MRI scans according to RECIST v1.1, and bone 
metastasis by bone scan according to the PCWG3 criteria) or death from any cause, 
whichever occurs first.
Data for patients without the occurrence of disease progression or death as of the 
clinical data cutoff date will be censored at the time of the last tumor assessment (or at 
the time of randomization plus 1 day if no tumor assessment was performed after the 
baseline visit).
Firstly, the primary efficacy analysis of rPFS in patients with PTEN loss tumors by IHC 
assay will be performed by the two-sided log-rank test (= 0.05) using the following 
factors in stratified analyses to compare rPFS between the two treatment arms:

Presence of visceral metastasis (liver or lung; yes vs. no)

Progression factor (PSA only vs. other) 

Prior taxane-based therapy in the hormone-sensitive setting (yes vs. no)
As pre-specified in the protocol, all randomization stratification factors will be used in the 
stratified analysis except for the factor “region”. Values for the stratification factors will 
be recorded in the IxRS at the time of randomization and will be used in the primary 
stratified analysis. 
A Cox proportional-hazards model stratified using the three factors above will be used to 
estimate the HR and 95% CI. The results from the unstratified log-rank test will also be 
provided.


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The Kaplan-Meier approach will be used to estimate median rPFS for each treatment 
arm, and the Kaplan-Meier curve will be constructed to provide a visual description of 
the difference between the treatment arms.
When the primary efficacy analysis of rPFS in patients with PTEN loss tumors by IHC 
assay is positive, (i.e., a p-value <0.05), similar methods will then be used for the 
primary efficacy analysis of rPFS in the ITT population. The two-sided log-rank test 
(0.01) stratified by the following factors will be used to compare rPFS between the 
two treatment arms:

Presence of visceral metastasis (liver or lung; yes vs. no)

Progression factor (PSA only vs. other)

Prior taxane-based therapy in the hormone-sensitive setting (yes vs. no)

Tumor PTEN status by IHC assay (loss vs. non-loss)
4.4.2
Secondary Efficacy Endpoints
The secondary efficacy objectives for this study are to evaluate the OS and additional 
measures of clinical benefit in the ITT population, and in patients with PTEN loss tumors 
by IHC and also to evaluate the efficacy in patients with PTEN loss tumors by next-
generation sequencing (NGS). 
All of the following secondary efficacy endpoints will be analyzed in the ITT population 
and in patients with PTEN loss tumors determined by IHC assay, unless stated 
otherwise.
4.4.2.1
Overall Survival
OS is defined as the time from randomization to death due to any cause. Data for 
patients who are not reported as having died at the time of analysis will be censored at 
the date when they were last known to be alive.  Data for patients who do not have 
post-baseline information will be censored at the randomization date plus 1 day. 
The OS analyses will be performed by stratified two-sided log-rank tests with the 
significance levels 0.04 or 0.05 depending on the results of co-primary efficacy analyses 
in the ITT population and patients with PTEN loss tumors by IHC. The key OS analyses 
will be performed by stratified two-sided log-rank tests with the significance levels as 
described in Section 2.3. The analyses will be conducted according to an analysis 
hierarchy and -spending algorithm to control for the type I error rate (see Figure 2) and 
to account for interim analyses (see Section 2.4.2).
The same analysis methods as described in Section 4.4.1 will also be performed for OS 
analyses. 


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4.4.2.2
Time to Pain Progression
Cancer-related pain progression refers to pain onset for those patients asymptomatic at 
baseline (i.e., patients with a score of 0 or 1 on pain severity at its worst on the 10-point 
numeric rating scale [NRS]) or pain worsening for those patients who are mildly 
symptomatic at baseline (score of 2 or 3). 
Time to pain progression will be defined as the time from randomization to the first 
occurrence of a confirmed clinically meaningful cancer-related pain progression event as 
defined below.
Pain progression is defined as a 2-point absolute increase from baseline, defined as 
Cycle 1 Day 1, or screening if missing. Pain progression at a given timepoint will be 
considered clinically meaningful if followed by any of the following:

A subsequent pain severity assessment within 1 cycle + 2-week window (28 days + 
14 days) showing that the score on pain severity at its worst is maintained or 
increased.

Initiation or increase in opiate analgesic as measured in the analgesic quantification 
algorithm (AQA) within 1 cycle + 2-week window (28 days + 14 days) following the 
initial pain event.

Initiation of palliative therapy within 1 cycle + 2-week window (28 days + 14 days) 
following the initial pain event.

An increase in prednisone/prednisolone usage for the intent of treating cancer pain 
within 1 cycle + 2-week window (28 days + 14 days) following the initial pain event; 
or a prescription for any other glucocorticosteroid for the intent of treating cancer 
pain within 1 cycle + 2-week window (28 days + 14 days) following the initial pain 
event.

In the absence of further pain assessments and initiation of analgesic or palliative 
therapy, documentation of death attributable to cancer progression (not death of 
other causes, including adverse events) within a 3-month interval following the initial 
pain event for these patients who might be lost at follow-up.
Note that an initiation of opioid analgesic use for cancer-related pain will be defined by a 
documentation of an opioid prescription for cancer-related pain followed by patient’s 
record of opioid intake or availability of an Analgesic Quantification Algorithm (AQA)
daily score.  For patients reporting use of opioid for cancer-related pain at baseline, the 
confirmatory event of opioid escalation will be defined as an increase in AQA daily score 
of one point or more.
All patients who underwent randomization will be included in the time to pain progression 
analysis.
The analysis for this secondary endpoint will include any pain progression event 
collected until initiation of the next line of therapy or up to one year following treatment 
discontinuation, whichever occurs first. Note that data collected post initiation of next 


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line of therapy will not be used for the analysis of the secondary endpoint but will be 
used to inform understanding of the disease burden post-progression in exploratory 
analyses.
Patients without occurrence of pain progression at the time of analysis will be censored 
at the last available pain severity assessment.
Patients whose death is not preceded by an increase in pain of 2 points will be 
censored at the latest date of the last pain severity assessment.
In addition, patients with pain severity score 3 at screening or at baseline, or patients 
who has missing baseline pain data will be censored at the randomization date plus 1 
day.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to pain progression endpoint.
4.4.2.3
Time to Initiation of Cytotoxic Chemotherapy
Time to initiation of cytotoxic chemotherapy is defined as the time from randomization to 
initiation of cytotoxic chemotherapy for PC. Cytotoxic chemotherapy was defined as the 
use of any of the following antineoplastic agents for PC: docetaxel, cabazitaxel, 
mitoxantrone, estramustine, cisplatin, carboplatin, cyclophosphamide, doxorubicin, 
mitomycin, irinotecan, 5-fluorouracil, gemcitabine, or etoposide.  Data for patients who 
do not receive cytotoxic chemotherapy will be censored at the last known date of no 
cytotoxic chemotherapy administered.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to initiation of cytotoxic chemotherapy endpoint.
4.4.2.4
Time to Function Deterioration
Time to confirmed function deterioration is defined as the time from the date of 
randomization to the date of 10-point or more decrease on either the EORTC QLQ-C30 
PF or RF scale scores (range, 0-100) held for two consecutive assessments, or a 
10-point or more score decrease followed by death (any cause) within 28 days, 
whichever occurs first.
Patients who do not have a confirmed function deterioration event as defined above will 
be censored at the last assessment date. Patients without a baseline or post-baseline 
PRO assessment will be censored at randomization.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to function deterioration endpoint.


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4.4.2.5
Time to Prostate-Specific Antigen Progression
PSA progression is defined as a PSA increase that is 25% and 2 ng/mL above the
baseline or nadir, which is confirmed by a second value 3 weeks later (per the PCWG3 
criteria).
Time to PSA progression is defined as the time from the date of randomization to the 
first occurrence of PSA progression.  Data for patients without the occurrence of PSA 
progression as of the clinical data cutoff date will be censored at the time of the last PSA 
assessment (or at the time of randomization plus 1 day if no PSA assessment was 
performed after the baseline visit). The analysis methods will be the same as for the 
primary efficacy endpoint (see Section 4.4.1).
4.4.2.6
Time to First Opioid Use
Time to first opioid use is defined as the documentation of the first opioid prescription for 
cancer-related pain followed by the patient’s record of opioid intake or availability of an 
Analgesic Quantification Algorithm (AQA) daily score.  Patients reporting use of opioid 
for cancer-related pain at baseline will be excluded from the analysis.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to first opioid use endpoint.
4.4.2.7
Time to Symptomatic Skeletal Events
An SSE is defined using one of the following: (1) use of external-beam radiotherapy to 
relieve skeletal symptoms (including initiation of radium-223 to treat symptoms of bone 
metastases); (2) occurrence of a new symptomatic pathological bone fracture (vertebral 
or non-vertebral), (3) clinically apparent occurrence of spinal cord compression, or (4) a 
tumor-related orthopedic surgical intervention. Descriptive statistics of the number and 
percentage of patients with SSE will be summarized by treatment group.
Time to SSE is defined as the time from randomization to the first occurrence of an SSE.  
Censoring rules will be applied as follows:

Observations from patients who do not have post-baseline information will be 
censored at the date of randomization plus 1 day.  

Patients for whom an SSE has not been observed will be censored at the last time 
known to be alive and without an SSE.

Observations from patients who died before having an event will be censored on the 
date of death.

Observations from patients who discontinued study without experiencing an SSE 
will be censored on the date of study discontinuation.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to first SSE endpoint.


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4.4.2.8
Objective Response Rate
An objective response is defined as a complete response (CR) or partial response (PR)
on two consecutive occasions 4 weeks apart, as determined by the investigator using 
RECIST v1.1 and PCWG3 criteria, in patients with measurable disease at baseline.  
Patients without a post-baseline tumor assessment will be considered non-responders.
Patients who have concurrent or prior bone progression by PCWG3 will not be 
considered to have had a response.
ORR is defined as the proportion of patients who have an objective response in patients 
with measurable disease at baseline.  An estimate of ORR will be calculated for each 
treatment arm, and its 95% CI will be calculated using the Clopper-Pearson method.
ORR will be compared between treatment arms using the stratified 
Cochran-Mantel-Haenszel test. The stratification factors will be the same as those 
described for the analysis of the primary endpoint (see Section 4.4.1).  The difference in 
ORR between treatment arms will be calculated, and its 95% CI will be calculated using 
the normal approximation to the binomial distribution.
4.4.2.9
Duration of Response
A duration of response (DOR) is defined for patients with an objective response as the 
time from the first documented objective response to documented disease progression 
as determined by the investigator using RECIST v1.1 and PCWG3 criteria, or death from 
any cause, whichever occurs first. Data for patients who are alive and who have not 
experienced disease progression at the time of analysis will be censored at the date of 
the last tumor assessment. If no tumor assessments were performed after the date of 
the first occurrence of the objective response (CR or PR), DOR will be censored at the 
date of the first occurrence of the objective response. Because the determination of 
DOR is based on a non-randomized subset of patients, formal hypothesis testing will not 
be performed. DOR will be estimated using the Kaplan-Meier methodology. 
Comparisons between treatment arms will be made using the stratified and unstratified 
log-rank test for descriptive purposes only.
4.4.2.10
Prostate-Specific Antigen Response Rate
PSA response rate is defined as the proportion of patients achieving a PSA 
decline 50% from baseline.  Patients without a post-baseline PSA assessment will be 
considered non-responders. The analysis population for PSA response rate will be all 
randomized patients. The analysis methods will be the same as for the ORR endpoint 
(see Section 4.4.2.8).
4.4.2.11
Investigator-Assessed rPFS in Patients with PTEN Loss 
Tumors by NGS
Investigator-assessed rPFS per PCWG3 criteria will be analyzed in patients with PTEN
loss tumors by NGS.  The same analysis methods as described in Section 4.4.1 for the 
primary endpoint rPFS will be used.


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4.4.3
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints will be analyzed in the ITT population and in patients 
with PTEN loss tumors determined by IHC assay, unless stated otherwise.  P-values will 
be reported for descriptive purposes.  The exploratory efficacy endpoints include IRC-
assessed radiographic progression, PFS on next-line therapy (PFS2), descriptive 
summaries for pain progression, descriptive PRO score summaries, time to deterioration 
in health-related quality of life, time to deterioration in urinary symptoms, time to 
deterioration in fatigue.
4.4.3.1
IRC-assessed Radiographic Progression
rPFS as assessed by the IRC (IRC-Assessed rPFS) is defined as the time from 
randomization to the first documented disease progression as determined by the IRC
using PCWG3 criteria (soft tissue by CT or MRI scans according to RECIST v1.1, and 
bone metastasis by bone scan according to the PCWG3 criteria) or death from any 
cause, whichever occurs first.  Refer to the IRC charter and IRC audit plan for further 
detail.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used.
4.4.3.2
Progression-Free Survival 2 (PFS2)
PFS2 is defined as the time from randomization to first disease progression, as 
assessed by the investigator on next-line treatment, or death from any cause, whichever 
occurs first. Specifically, next-line therapy is defined as the treatment received after the 
first disease progression. Patients who do not experience disease progression on next-
line therapy or death will be censored at the last time known to be alive without objective 
disease progression on next-line therapy. Observations from patients who do not have 
post-baseline information will be censored at the date of randomization plus 1 day.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for the PFS2 endpoint.  This analysis will be performed as data allows.
4.4.3.3
Descriptive Summaries for Pain Progression
The following descriptive summaries for the time to confirmed cancer-related pain 
progression endpoint (see Section 4.4.2.2) will be performed by treatment arm.
The number and percentage of patients and each of the confirmatory events for the time 
to pain progression endpoint will be summarized by treatment arm.
Pain severity scores will be summarized as frequencies and percentages at each time 
point by treatment arm, where a patient’s pain severity score is classified as either 
no/mild pain (scores of 0-4), moderate pain (scores of 5-6), or severe pain (scores of 
7-10).


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A table and/or stacked bar chart will be used to summarize the number and proportion of 
patients who reported meaningful pain increase, pain decrease, or stable pain at each 
time point by treatment arm. Specifically, patients who reported a 2-point absolute 
increase above baseline in pain severity score will be classified as “pain increase,” 
patients who reported a 2-point decrease from baseline in pain severity score will be 
classified as “pain decrease,” and patients who reported less than a 2-point change from 
baseline in pain severity score will be classified as “stable pain”.
Mean pain severity scores will be cross-tabulated with cancer-related opioid use by 
treatment arm and time point.
4.4.3.4
Descriptive PRO Score Summaries
Descriptive analyses will include summary statistics (mean, SD, median, interquartile 
range [IQR], minimum, maximum) of PRO scores and score changes from baseline at 
each assessment time point by treatment arm. For graphs of mean scores and/or score 
changes from baseline, two-sided 95% CIs will be presented. Descriptive summaries 
will be reported for the 7-day recall pain severity item (post-screening), each QLQ-C30 
scale, and the QLQ-PR25 urinary scale.
4.4.3.5
Time to Deterioration in health-related quality of life
Confirmed deterioration in GHS is defined as a 10-point or more decrease on the 
EORTC QLQ-C30 GHS scale score (range, 0-100) held for two consecutive 
assessments, or a 10-point or more score decrease followed by death (any cause) within 
28 days. 
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to deterioration in GHS endpoint.
4.4.3.6
Time to Deterioration in Urinary Symptoms
Confirmed deterioration in urinary symptoms is defined as a 10-point or more increase 
on the EORTC QLQ-PR25 urinary scale score (range, 0-100) held for two consecutive 
assessments, or a 10-point or more score increase followed by death (any cause) within 
28 days. 
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to deterioration in urinary symptoms endpoint 
4.4.3.7
Time to Deterioration in Fatigue
Confirmed deterioration in fatigue is defined as a 10-point or more increase on the 
EORTC QLQ-C30 fatigue scale score (range, 0-100) held for two consecutive 
assessments, or a 10-point or more score increase followed by death (any cause) within 
28 days. 
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to deterioration in fatigue endpoint.


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4.4.3.8
Time to Initiation of Subsequent Anticancer Therapy
Time to initiation of subsequent anticancer therapy is defined as the time from 
randomization to initiation of subsequent anticancer therapy post-study treatment for 
PC. Data for patients who do not receive anticancer therapy will be censored at the last 
known date of no anticancer therapy administered. The same analysis methods as 
described in Section 4.4.1 for the primary endpoint rPFS will be used for this time to 
initiation of first anticancer therapy endpoint.
4.4.3.9
Clinical PFS
Clinical PFS is defined as time from randomization to the earliest occurrence of one of 
the following:

First documented disease progression (as described in Section 4.4.1)

Patient-reported pain progression (as described in Section 4.4.2.2)

Symptomatic skeletal event (as described in Section 4.4.2.7)

Initiation of subsequent anticancer therapy (as described in Section 4.4.3.8)
4.4.4
Sensitivity Analyses
4.4.4.1
Radiographic Progression-Free Survival
Sensitivity analyses will be performed to evaluate the robustness of the primary analysis 
results. The following sensitivity analyses of rPFS will be performed in the ITT 
population and in patients with PTEN loss tumors by IHC.
rPFS censoring for missing visits
An analysis of rPFS censoring for missing visits will be performed. Data for patients with 
an rPFS event who missed two or more consecutive scheduled assessment immediately 
prior to the rPFS event will be censored at the last tumor assessment prior to the missed 
visits.  Due to the change in assessment schedule for both soft tissue and bone scans 
(assessments at the end of Cycles 2, 4, 6, and every 3 cycles thereafter), a cutoff of 
5 month (20 weeks) will be used to assess whether a patient missed two or more
consecutive scheduled assessment immediately prior to the rPFS event.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for rPFS censoring for missing visits analysis.
rPFS censoring for non-protocol therapy
Non-protocol therapy (NPT) is defined as any anti-cancer therapy other than study 
treatment. The impact of NPT on the primary endpoint of investigator-assessed rPFS by 
RECIST v1.1 will be evaluated. A sensitivity analysis will be performed in which data for 
patients who received NPT prior to the rPFS event will be censored at the last tumor 
assessment date before the patient received NPT.


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The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for rPFS censoring for non-protocol therapy analysis.
4.4.4.2
Delayed Treatment Effect
The weighted log-rank analysis (Fleming and Harrington 1991) that weighs more on late 
events (Fine 2007) will be conducted to assess a potential delayed treatment effect for 
OS.
Statistical methodologies analogous to those used in the analysis of OS as specified in 
Section 4.4.2.1 will be used for these sensitivity analyses. The sensitivity analysis is 
based on the stratified analyses.
4.4.4.3
Time to Pain Progression
The impact of alternative event definitions and the analysis population will be examined 
as follows, including but not limited to: 

Time to confirmed cancer-related pain progression will be evaluated as the time 
from randomization date to the date of a patient’s 2-point or more score increase on 
the pain severity item held for two consecutive assessments, or a 2-point or more 
score increase followed by death (any cause) within 1 cycle + 2-week window (28 
days + 14 days).

Radiographic disease progression (within 1 cycle + 2-week window of the patient’s 
2-point or more score increase) will be considered as a confirmatory pain 
progression event criterion. 

Time to confirmed cancer-related pain progression analysis will also be performed in 
the PRO-evaluable analysis population, defined as patients with a non-missing 
baseline assessment and at least one post-baseline assessment.

Instead of censoring patients with pain severity score > 3 at screening or at baseline
as specified in section 4.4.2.2, time to confirmed pain progression analyses will be 
performed to 
o
Exclude patients with pain severity score > 3 at screening or at baseline, 
or patients with missing baseline pain data from the analysis population
o
Include patients with pain severity score > 3 at screening or at baseline, 
and their post-baseline pain data in pain progression definition. Patients 
who have missing baseline pain data will be censored at the 
randomization date plus 1 day.
The same analysis methods as described in Section 4.4.1 for the primary endpoint rPFS 
will be used for this time to pain progression endpoint.
4.4.5
Subgroup Analyses
The consistency of the rPFS and OS results will be examined in subgroups defined by 
demographic and baseline characteristics and stratification factors. Summaries of rPFS 
and OS, including the unstratified HR estimated from a Cox proportional hazards model 


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and Kaplan-Meier estimates of median PFS and OS, will be produced by treatment arm 
for each of the defined subgroups, and displayed in a forest plot in the ITT population 
and in patients with PTEN loss tumors by IHC.
The subgroups to be considered include but are not limited to the following:

Age (<65, ≥65 and <75, ≥75 years) at randomization

Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Unknown)

Lactate dehydrogenase (LDH) (≤upper limit of normal [ULN], >ULN)

Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, 2)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown)

Prior taxane-based therapy in hormone-sensitive setting (yes, no)

Progression factor (PSA only, Other)

Presence of visceral metastasis (liver or lung) (yes, no)

Tumor PTEN-diagnostic status by IHC assay (PTEN loss, PTEN intact) for ITT 
population only

Geographic Region (EU, Asia-Pacific, North America, Rest of World)
4.5
SAFETY ANALYSES
Safety analyses will be conducted in all patients who were randomized and received any 
amount of ipatasertib, placebo, or abiraterone (the safety-evaluable population).
Patients will be analyzed accordingly to the treatment arm associated with the actual 
regimen received.  Specifically, a patient will be included in the IpatAbi arm in the 
safety analyses if this patient has received any amount of ipatasertib, regardless of the 
initial treatment assignment at randomization.
Sponsor-selected adverse events (AEs) will be presented in more detail including AE 
severity and AE seriousness.  Additionally, time to first AE onset and duration to AE 
resolution will also be presented for rash, diarrhea, and hyperglycemia. The Sponsor 
proposes to define the medical concepts representing the selected AEs by using Medical 
Dictionary for Regulatory Activities (MedDRA) SMQs, AEGTs, and manually selected 
groups of preferred terms (PTs).
Safety endpoints will include incidence, severity, and seriousness of adverse events, 
deaths, and clinically significant laboratory measurements. All safety endpoints will be 
analyzed in the safety-evaluable population by all patient population and PTEN loss 
population by IHC, unless stated otherwise. 


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4.5.1
Exposure of Study Medication
Study treatment exposure, including but not limited to treatment duration, number of 
doses, total cumulative dose, dose intensity with respect to total dose, and dose intensity
with respect to total number of doses will be summarized with descriptive statistics. The 
number of missed doses will also be displayed. Reasons for discontinuation from the 
study treatment will be summarized.
4.5.2
Adverse Events
Verbatim description of AEs will be mapped to the latest effective MedDRA thesaurus 
terms and graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). Adverse events will be 
summarized by mapped term, appropriate thesaurus level and NCI CTCAE Grade.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported, 
e.g. serious adverse events related to invasive procedures such as biopsies. 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 28 days after the last dose of study. After this period, investigators should 
report any serious adverse events (SAEs) and adverse events of special interest (AESI) 
that are believed to be related to prior treatment with study drug. 
Summary tables of the following will be provided, including, but not limited to: 

SAEs 

AEs leading to study treatment discontinuation 

AEs leading to dose reduction or interruption 

Treatment-related AEs 

Severe adverse events (Grade 3 or higher) 

AEs leading to death 

AEs by highest NCI CTCAE Grade 

Selected Adverse Events of Interest (including sponsor-defined AESI)
A summary table of common AEs, i.e., those occurring in at least 10% of patients, will be 
provided. 
Multiple occurrences of the same event will be counted once at the maximum severity. 
All listings of AEs will include all AEs with onset on or after the first study drug treatment 
up to the data cutoff date. 
All deaths and causes of death will be summarized.


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4.5.3
Laboratory Data
Laboratory data will be classified according to NCI CTCAE v 4.0 and will be summarized 
descriptively over time including change from baseline. Highest NCI CTCAE Grade 
post-baseline will also be reported and shift tables from baseline to worst value during 
the study post-baseline will be presented. Summary statistics (number of patients, 
mean, 95% CI, median, and range) of absolute values and mean changes from baseline 
will be calculated for HbA1c at each assessment time point for each arm within each 
cohort. 
A Hy’s law analysis will be provided. The potential Hy’s law quadrant is defined as 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increases above 
3-fold the ULN with concomitant total bilirubin increases above 2-fold the ULN.
4.5.4
Vital Signs and ECOG Performance Status
Vital signs will be summarized descriptively over time including change from baseline. 
ECOG performance status will also be summarized over time.
4.5.5
Electrocardiograms
The baseline ECG of the patients will be summarized and results of study drug 
discontinuation visits will be listed.
4.6
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Ipatasertib and its metabolite (G-037720) levels will be measured on Days 1 and 15 of 
Cycle 1, Day 1 of Cycle 3, and Day 1 of Cycle 6.  Ipatasertib and its metabolite plasma 
concentration versus time data, together with information on dosing and patient 
characteristics, will be pooled and analyzed using a population PK (PopPK) analysis 
approach, as appropriate.  Non-linear mixed-effect modeling will be used for the 
estimation of PopPK parameters for ipatasertib.  Covariates such as patient 
demographics (e.g., age, body size), may be tested for significance on PK parameters of 
interest.
The PK data may be combined with the safety, efficacy, and biomarker data for 
exposure-response modeling as an exploratory objective.  PK and PK/pharmacodynamic 
analyses may be reported in separate stand-alone reports.  Additional analyses may be 
explored as warranted by the data.
Abiraterone levels will be measured on Day 15 of Cycle 1 and Day 1 of Cycle 3.  
Abiraterone trough plasma concentrations will be compared between arms (ipatasertib 
vs. placebo).
4.7
Exploratory Biomarker Analyses
Exploratory biomarker analyses (in tumor tissues and plasma, whole blood, or serum) 
will be performed in an effort to understand the association of these markers with study 


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drug response, including efficacy and/or adverse events.  The results will be presented 
in a separate report.
Whole genome sequencing (WGS) data will be analyzed in the context of this study and 
explored in aggregate with data from other studies to increase researchers’ 
understanding of disease pathobiology and guide the development of new therapeutic 
approaches.
4.8
OTHER EXPLORATORY ANALYSES
4.8.1
Patient-Reported Symptomatic Adverse Events
Compliance rates in the safety-evaluable population will be summarized as the number 
of patients who completed the questionnaire (11 PRO-CTCAE items and the global 
assessment of treatment side effect bother item) divided by the number of patients 
expected to complete the questionnaire at each time point for each treatment arm.
Descriptive analysis of the overall side effect bother item will be performed by treatment 
arm at each visit in the safety-evaluable population.  Data will be summarized 
descriptively for on-study treatment visits in addition to a patient’s closest assessment in 
the 28 days prior to treatment discontinuation due to AEs.  Distribution of responses and 
change from baseline will be summarized by treatment arm as frequencies and 
percentages, where patients are considered either improved, no change, or worsened, 
at each time point.  Stacked bar charts or lollipop charts may be used to illustrate the 
distribution of responses and the change in response (either improved, no change, or 
worsened) at each time point by treatment arm.
Descriptive item-level analyses of the 11 PRO-CTCAE items may be performed by 
treatment arm at each visit in the safety population. The distribution of responses for 
each item attribute (“frequency”, “severity”, “interference”, “presence”) may be 
summarized as frequencies and percentages at each visit and by treatment arm. 
Change from baseline for each item may be summarized by treatment arm as 
frequencies and percentages, where patients are considered either improved [by 1, 2, 3, 
or 4], no change, or worsened [by 1, 2, 3, or 4], at each time point. For each item, the 
cumulative incidence of patients reporting scores of 3 or 4 may also be presented 
graphically by treatment arm during the study.
4.8.2
Health Utilities 
EQ-5D-5L health utilities will be used to inform pharmacoeconomic modeling. These 
results will be presented separately from the CSR. 
4.9
MISSING DATA
In safety analyses, all deaths are included, from all sources, regardless of completeness 
of death date; patients who died with only a partial death date available will be included.


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In efficacy analyses, a death is considered an event if and only if a complete death date 
is available; patients who died with only a partial death date available will be censored.
4.10
INTERIM ANALYSES
4.10.1
Planned Interim Safety Analyses
The iDMC will evaluate safety data (including SAEs, deaths, and AESI) during the study 
on a periodic basis, approximately every 3 months for the first year and approximately 
every 6 months thereafter, until the time of the rPFS primary analysis, according to the 
policies and procedures detailed in an iDMC charter.  The Sponsor will be blinded until 
the rPFS primary analysis.  No interim efficacy analyses are planned for the primary 
endpoint of rPFS.
An iDCC will prepare all summaries and analyses for the iDMC’s review.  The safety 
summaries will include demographic data, AEs, SAEs, and relevant laboratory data.
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities.  Following the data review, the iDMC will provide 
a recommendation to the Sponsor whether to continue the study, amend the protocol, or 
stop the study.  The final decision will rest with the Sponsor.
Any outcomes of the iDMC’s reviews on the safety and benefit-risk balance that affect 
study conduct will be communicated in a timely manner to the investigators for 
notification of IRBs/ECs and competent authorities as required.
4.10.2
Planned Interim Efficacy Analyses
No interim efficacy analyses are planned for the primary endpoint of rPFS.
As described in Section 2.3 if the test of rPFS in patients with PTEN loss tumors by IHC 
is positive, then OS in patients with PTEN loss tumors by IHC will be further tested.  An 
interim analysis will be performed at the time of rPFS primary analysis, which is 
approximately 34 months after the first patient in, and the final analysis will be performed 
approximately 24 months after the rPFS primary analysis.
As described in Section 2.3 if the test of OS in patients with PTEN loss tumors by IHC is 
positive, then OS in the ITT population will be further tested. Interim analyses will be 
performed at the time of rPFS primary analysis which is approximately 34 months after 
the first patient in, and at the time of the final analysis of OS in patients with PTEN loss 
tumors by IHC which is approximately 24 months after the rPFS primary analysis; and 
the final analysis will be performed approximately 9 months after the final analysis of OS 
in patients with PTEN loss tumors by IHC.
4.10.3
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one interim efficacy analysis for futility.  Below are the 


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specifications in place to ensure the study continues to meet the highest standards of 
integrity when an optional interim analysis is executed.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by an external statistical group and reviewed by the iDMC.
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
charter.
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis will be documented in the SAP, and the SAP will 
be submitted to relevant health authorities at least 2 months before the conduct of the 
interim analysis.  The iDMC charter will be updated to document potential 
recommendations the iDMC can make to the Sponsor as a result of the analysis (e.g., 
stop the study for futility), and the iDMC charter will also be made available to relevant 
health authorities.
If there is a potential for the study to be stopped for futility as a result of the interim 
analysis, the threshold for declaring futility will be included in the SAP.  Additional criteria 
for recommending that the study be stopped for futility may be added to the iDMC 
charter.  An interim analysis that might lead to stopping the study for futility will not occur 
before at least 67% of the information in both the ITT population and patients with PTEN
loss tumors has been accumulated.
After the primary analysis for PFS, additional OS interim analyses may be conducted to 
provide additional OS data, per the recommendation from health authorities.  If 
conducted, the Lan-DeMets-spending function with an O’Brien-Fleming boundary will be 
used to control the overall type I error for OS accounting for the additional OS interim 
analyses.


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5.
References
Akazawa K, Nakamura T, Palesch Y. Power of logrank test and Cox regression model in 
clinical trials with heterogeneous samples. Stat Med. 1997 16:583-97.
Fine GD. Consequences of delayed treatment effects on analysis of time-to-event 
endpoints. Ther Innov Regul Sci 2007;41:535−9.
Fleming TR and Harrington DP. Counting processes and survival analysis. New York: 
John Wiley & Sons, 1991.


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Appendix 1
Protocol Synopsis








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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:
General Inclusion Criteria

Signed Informed Consent Form(s)

Ages 18 years

Eastern Collaborative Oncology Group performance status of 0 or 1 at screening

Adequate hematologic and organ function within 28 days before the first study treatment, 
defined using the following (hematologic parameters must be assessed 14 days after a 
prior transfusion, if any):
Neutrophils:  ANC 1500 cells/L (1.5 109/L)
Hemoglobin 10 g/dL
Platelet count 100,000 cells/L
Total bilirubin 1.5 the upper limit of normal (ULN) with the following exception:

Patients with known Gilbert disease who have serum bilirubin 3 ULN may 
be enrolled.
AST and ALT 1.5 ULN, with the exception that patients with liver metastasis may 
have AST and/or ALT 2.5 ULN and total bilirubin 1.5 ULN
Serum creatinine 1.5 ULN and creatinine clearance 50 mL/min based on 
CockroftGault glomerular filtration rate estimation:  
(140 age in years) (weight in kg)
72 (serum creatinine in mg/dL)
Serum albumin 3.5 g/dL
Serum potassium 3.5 mmol/L
Fasting glucose 150 mg/dL (8.3 mmol/L) and hemoglobin A1c 7.5% (58 mmol/mol)

Ability to comply with the study protocol, in the investigator's judgment

Willingness and ability of patients to use the electronic device to report selected study 
outcomes (e.g. symptom severity).  Caregivers and site staff can assist with patient diary 
input but patient must be able to independently comprehend and answer the 
questionnaires.

Life expectancy of at least 6 months

Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive 
measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom along with another effective contraceptive method 
during the treatment period and for at least 28 days after the last dose of study 
treatment to avoid exposing the embryo.  Men must refrain from donating sperm during 
this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.

For enrollment into the China extension cohort, residence in the People's Republic of China


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Disease-Specific Inclusion Criteria

Histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or 
small-cell features

Consent to provide a formalin-fixed, paraffin-embedded (FFPE) tissue block (preferred) or a 
minimum of 15 (20 preferred) freshly cut unstained tumor slides from the most recently 
collected, available tumor tissue accompanied by an associated pathology report (with 
tumor content information, Gleason score, and disease staging) for PTEN IHC and 
next-generation sequencing (NGS) testing and for other protocol-mandated secondary and 
exploratory assessments.  If only 1214 slides are available, the patient may still be eligible 
for the study, after discussion with and approval by the Medical Monitor.  Cytologic or 
fine-needle aspiration samples are not acceptable.  Tumor tissue from bone metastases is 
not acceptable.

A valid PTEN IHC result (central laboratory tested with results directly sent to interactive 
voice-or Web-based response technology [IxRS]), patients with an “invalid” or “failed” PTEN 
IHC result are not permitted to enroll

Metastatic disease documented prior to randomization by clear evidence of bone lesions on 
bone scan and/or measurable soft tissue disease by CT and/or MRI (at least one target 
lesion) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1)
Patients whose spread of disease is limited only to regional pelvic lymph nodes are not 
eligible.

Asymptomatic or mildly symptomatic form of prostate cancer
A score of 0 or 1 on the pain at its worst (24-hour recall) 10-point Numeric Rating Scale 
will be considered asymptomatic, and a score of 2 or 3 will be considered mildly 
symptomatic.

Progressive disease before initiating study treatment, defined using at least one of the 
following criteria:
Two rising PSA levels measured 1 week apart, with second result 1 ng/mL
according to PCWG3 criteria 

Patients who have received an anti-androgen therapy must have PSA 
progression after withdrawal (4 weeks since last flutamide or 6 weeks since 
last treatment of bicalutamide or nilutamide).
Radiographic evidence of disease progression in soft tissue according to RECIST v1.1 
and/or bone scan according to PCWG3 criteria

Ongoing androgen deprivation with gonadotropin-releasing hormone (GnRH) analog or 
bilateral orchiectomy, with serum testosterone 50 ng/dL (1.7 nmol/L)  within 28 days 
before randomization  
Patients on GnRH analog must have therapy initiated at least 4 weeks before 
Cycle 1, Day 1 and treatment must be continued throughout the study.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:
General Exclusion Criteria

Inability or unwillingness to swallow whole pills  

History of malabsorption syndrome or other condition that would interfere with enteral 
absorption  

Clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including cirrhosis, current alcohol abuse, or current known active infection with hepatitis B 
virus (HBV) or hepatitis C virus (HCV)


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Active infection is defined as requiring treatment with antiviral therapy or presence of 
positive test results for hepatitis B (hepatitis B surface antigen [HBsAg] and/or total 
hepatitis B core antibody [anti-HBc]) or HCV antibody.  Unless required by local 
regulations, patients are not required to have HIV, HBV, or HCV assessments at 
screening if these assessments have not been previously performed.
Patients who are positive for anti-HBc are eligible only if test results are also negative 
for HBsAg and polymerase chain reaction is negative for HBV DNA.
Patients who are positive for HCV serology are eligible only if testing for HCV RNA is 
negative.

Need of more than 10 mg/day of prednisone or an equivalent dose of other 
anti-inflammatory corticosteroids as a current systemic corticosteroid therapy to treat a 
chronic disease (e.g., rheumatic disorder)
Concurrent use of inhaled corticosteroids is allowed. 

Active infection requiring intravenous antibiotics within 14 days before Cycle 1, Day 1

Immunocompromised status because of current known active infection with HIV or because 
of the use of immunosuppressive therapies for other conditions  

Major surgical procedure or significant traumatic injury within 28 days prior to 
Cycle 1, Day 1, or anticipation of the need for major surgery during study treatment  

History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as 
structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular 
hypertrophy), untreated coronary heart disease (symptomatic or with ischemia 
demonstrated by diagnostic testing), myocardial infarction or atrial thrombotic events within 
the past 6 months, severe or unstable angina, New York Heart Association Class III and IV 
heart disease or depressed left ventricular ejection fraction (LVEF; previously documented 
LVEF < 50% without documentation of recovery), clinically significant electrolyte 
abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of 
sudden unexplained death or long QT syndrome

History of another malignancy within 5 years prior to randomization, except for either 
adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma 
in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder (Tis, Ta 
and low grade T1 tumors), or other malignancies where the patient has undergone 
potentially curative therapy with no evidence of disease and are deemed by the treating 
physician to have a recurrence rate of <5% at 5 years. 

Any other diseases; cardiovascular, pulmonary, or metabolic dysfunction; physical 
examination finding; or clinical laboratory finding giving reasonable suspicion of a disease 
or condition that contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or renders the patients at high risk from treatment complications
Disease-Specific Exclusion Criteria

Pathologic findings consistent with small-cell or neuroendocrine carcinoma of the prostate

Use of opioid medication for cancer-related pain, including codeine and 
dextropropoxyphene, currently or any time within 4 weeks of Cycle 1, Day 1

Any therapy including chemotherapy (e.g. docetaxel) or biological therapy (e.g., vaccine, 
immunotherapy) for the treatment of castration-resistant prostate cancer. Previous 
treatment with flutamide, steroidal anti-androgens, androgens, estrogens, bicalutamide, 
nilutamide, or 5-reductase inhibitor is permitted.
In the setting of hormone-sensitive prostate cancer, chemotherapy (e.g., docetaxel) is 
permitted provided that it is initiated within 6 months from the time of first castration 
(i.e., concurrent initiation of chemotherapy and ADT for HSPC).  Patient should not 
have progressed during or within 3 months after the completion of 
chemotherapy-based treatment (i.e., rapid progression on chemotherapy for HSPC).


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
Prior treatment with abiraterone or other known potent CYP17 inhibitors 
(e.g., ketoconazole, orteronel) or investigational agents that block androgen synthesis.  
Previous treatment with itraconazole and fluconazole is permitted.

Prior treatment with enzalutamide or other potent androgen-receptor blockers, approved or 
experimental (e.g., ARN-509, ODM-201, or galeterone) 

Prior treatment with flutamide (Eulexin®), steroidal anti-androgens (e.g., cyproterone 
acetate, chlormadinone acetate), androgens, or estrogens treatment within 4 weeks of 
Cycle 1, Day 1

Prior treatment with bicalutamide (Casodex®) or nilutamide (Nilandron®) within 6 weeks of 
Cycle 1, Day 1

Prior treatment with 5-reductase inhibitors within 4 weeks of Cycle 1, Day 1

Prior treatment with systemic radiopharmaceuticals (e.g., radium-223 and strontium-89).  
Radiopharmaceuticals for the purpose of imaging are permitted.  Focal palliative radiation to 
treat cancer-related pain is permitted provided that the last treatment with radiation is at 
least 14 days prior to Cycle 1, Day 1.

Prior treatment with approved or experimental therapeutic agents with known inhibition of 
the PI3K pathway, including PI3K inhibitors, AKT inhibitors, and mTOR inhibitors

Administration of an investigational therapeutic agent within 28 days of Cycle 1, Day 1

Known untreated or active CNS metastases (progressing or requiring anticonvulsant 
medications or corticosteroids for symptomatic control); a CT or MRI scan of the brain will 
be performed at screening if required by the local health authority.

Patients with a history of treated CNS metastases are eligible, provided they meet all of the 
following criteria:  
An evaluable or measurable disease according to the inclusion criteria outside the CNS
Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic study 
No history of intracranial hemorrhage or spinal cord hemorrhage 
Minimum of 2 weeks between completion of radiotherapy and Cycle 1, Day 1, and 
recovery from significant (Grade 3) acute toxicity, with no ongoing requirement for 
10 mg/day of prednisone or an equivalent dose of another corticosteroid

Any chronic therapy or use of food supplements that are strong CYP3A4/5 inducers or 
inhibitors or sensitive substrates of CYP3A or CYP2D6 with a narrow therapeutic window
Abiraterone-Specific Exclusion Criteria

Uncontrolled hypertension (systolic blood pressure 160 mmHg or diastolic blood pressure 
95 mmHg) 
Patients with a history of hypertension are eligible, provided blood pressure is 
controlled by anti-hypertensive treatment prior to or within the 28 days of screening 
period.

History of pituitary or adrenal dysfunction

Any ongoing cardiac arrhythmias (including atrial fibrillation) that require medical therapy
Ipatasertib-Specific Exclusion Criteria

Type 1 or Type 2 diabetes mellitus requiring insulin at study entry
Patients who are on a stable dose of oral diabetes medication 4 weeks prior to 
initiation of study treatment may be eligible for enrollment.

History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis), active 
bowel inflammation (e.g., diverticulitis)


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End of Study
The end of this study is defined as the date when the last patient, last visit occurs (i.e., the date 
at which the last data point required for statistical analysis or safety follow-up is received).
Length of Study
The total length of the study, from randomization of the first patient to the end of the study, is 
expected to be approximately 7 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Ipatasertib drug product will be supplied by the Sponsor as 100-mg and 200-mg tablets 
packaged in bottles.  Ipatasertib tablets are given once daily beginning on Cycle 1, Day 1 until 
disease progression or intolerable toxicity.  
For information on the formulation, packaging, and handling of abiraterone acetate, see the 
local prescribing information.
Comparator
The placebo drug product will be supplied by the Sponsor as a tablet formulation and will be 
matched in size, color, and shape to ipatasertib tablets to maintain the study blind.  Placebo 
tablets are given once daily beginning on Cycle 1, Day 1 until disease progression or intolerable 
toxicity.  
Non-Investigational Medicinal Product
For information on the formulation, packaging, and handling of prednisone/prednisolone, see 
the local prescribing information.
Statistical Methods
Primary Analysis
This study has two co-primary endpoints:  rPFS in the ITT population and rPFS in patients with 
PTEN-loss tumors by IHC. At the time of primary analysis of rPFS, rPFS in patients with PTEN-
loss tumors by IHC will be firstly tested with of 5%.  If the test is positive, then rPFS in the ITT 
population will be tested with of 1%.
The primary analysis of rPFS will occur when approximately 275 rPFS events in patients with 
PTEN-loss tumors and approximately 550 rPFS events in the ITT population have been 
observed, whichever occurs later.  The primary analysis is expected to occur approximately 
34 months after the first patient is randomized.
In the PTEN-loss population, 275 events will allow for 98.4% power to detect an improvement in 
median rPFS from 14 months in the placebo arm to approximately 23 months in the ipatasertib 
arm (HR = 0.61) at the 5% level of significance (two-sided).  The largest hazard ratio deemed to 
be statistically significant will be approximately 0.79 (with median rPFS improvement from 
14 months in the placebo arm to approximately 17.7 months in the ipatasertib arm). 
In the ITT population, 550 events will allow for 94.5% power to detect an improvement in 
median rPFS from 16.5 months in the placebo arm to approximately 23.6 months in the 
ipatasertib arm (HR =0.70) at the 1% level of significance (two-sided).  The largest hazard ratio 
deemed to be statistically significant will be approximately 0.80 (with median rPFS improvement 
from 16.5 months in the placebo arm to approximately 20.6 months in the ipatasertib arm.
Determination of Sample Size
Approximately 1100 patients in total will be randomized into this study in about 20 months.
Assuming 50% prevalence of IHC PTEN-loss tumors in all patients, it’s estimated that 
approximately 550 patients will have PTEN loss tumors.


Ipatasertib—F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan CO39303, Version 2
Interim Analysis
An iDMC will evaluate safety data (including, but not limited to, serious adverse events, death, 
and adverse events of special interest) during the study on a periodic basis, approximately 
every 3 months for the first year and approximately every 6 months thereafter, until the time of 
the rPFS primary analysis, according to the policies and procedures detailed in an iDMC 
charter.  The Sponsor will be blinded until the rPFS primary analysis. 
No interim efficacy analyses are planned for the primary endpoint of rPFS.
A total of four analyses of OS are planned:

The first interim analysis of OS was performed at the time of primary analysis of rPFS.

The second interim analysis of OS will take place when approximately 229 OS events in the 
patients with PTEN loss tumors by IHC occur, or when the minimum follow-up time (from 
the last patient enrollment date of 17 January 2019) is approximately 32 months, whichever 
occurs later.

The third analysis of OS is the final analysis of OS in the patients with PTEN loss tumors by 
IHC and it is also the third interim analysis of OS in the ITT population. It is scheduled when 
there are approximately 327 OS events in patients with PTEN loss tumors by IHC occur. 
This target number of OS event is unchanged per the original Protocol Version 6, section 
6.1.3.

The fourth analysis of OS is the final analysis of OS in the ITT population. It is scheduled 
when there are approximately 660 OS events in the ITT population occur. This target 
number of OS event is unchanged per the original Protocol Version 6, section 6.1.3.
The projected analysis timing and the corresponding numbers of OS events for OS interim and 
final analyses in patients with PTEN loss tumors by IHC and in the ITT population are presented 
in the Section 6.8.2 of the Protocol Version 7.  When the timing of the third and fourth analyses 
are very close, these two analyses could be combined and the alpha-spending will be adjusted 
using O’Brien-Fleming alpha-spending method.


Ipatasertib—F. Hoffmann-La Roche Ltd
48/Statistical Analysis Plan CO39303, Version 2
Appendix 2
Schedule of Assessments
Assessment/Procedure
(Window)
Screening a
Cycle 1
Cycle 2
Cycle3
Cycles 
4
Study
Treatment 
Discontinuation b
Disease 
Follow-Up
c
Post-
Treatment 
Follow-Up d
Days –28 
to –1
Day
1
Day
4
(1)
Day
8
(2)
Day
15 e
(2)
Da
y
1
Day
15 e
Da
y
1
Day
15 e
Day
1
Within 30 days 
of the Last Study 
Treatment
Every 3 
(1) 
Months
Every 3 
(1) 
Months
Informed consent(s)
x f
Demographic data (age, sex, 
and self-reported race/ethnicity)
x
Medical history and baseline 
conditions g
x
Archival FFPE tumor tissue
x h
PTEN IHC results
x
Patient randomization number 
assignment (IxRS)
x
Concomitant medications i
x
x
x
x
x
x
x
x
x
x
x j
Adverse events k
x
x
x
x
x
x
x
x
x
x
x
x
x
Complete physical examination l
x a
x
Limited physical examination m
x
x
x
x
x
x
x
ECOG performance status
x a
x
x
x
x
x
x
x
Vital signs n
x
x
x
x
x
x
x
x
x
x
x
Weight and height (height at 
screening only)
x
x
x
x
x
x
Electrocardiogram o
x o
As clinically indicated
x o
Historic values for PSA velocity
x p
PSA p
x p, q
x r
x r
x r
x r
x


Ipatasertib—F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan CO39303, Version 2
Appendix 2
Schedule of Assessments (cont.)
Assessment/Procedure
(Window)
Screening a
Cycle 1
Cycle 2
Cycle3
Cycles 
4
Study
Treatment 
Discontinuation b
Disease 
Follow-Up
c
Post-
Treatment 
Follow-Up d
Days –28 
to –1
Day
1
Day
4
(1)
Day
8
(2)
Day
1
Da
y
1
Day
15 e
Da
y
1
Day
15 e
Day
1
Within 30 days 
of the Last Study 
Treatment
Every 3 
(1) 
Months
Every 3 
(1) 
Months
Serum testosterone s
x
x
Hematology t
x
x r
x r
x r
x r
x r
x r
x r
x r
x
Fasting blood glucose u 
x
x
x
x
x
x
x
x
x
x
x
Home glucose monitoring v
Post-meal blood glucose measurement and recording in daily 
glucose log 
(while receiving ipatasertib/placebo treatment)
Chemistry panel w
x
x r
x r
x r
x r
x r
x r
x r
x r
x
Urinalysis x
x
As clinically indicated
x
Coagulation:  aPTT, PT, and 
INR 
x
As clinically indicated
x
Amylase and lipase
x
x
Day 1 of 
Cycles 4, 
6, 9, 12, 
and 
every 3 
cycles 
thereafte
r
x
Fasting lipid profile
x
x
x
Hemoglobin A1c
x
x
Tumor assessment of soft 
tissue per RECIST v1.1 y
x a
End of Cycles 2, 4, 6, 
and every 3 cycles
thereafter aa
x
x
Tumor assessment:  bone scan
z
x a
x
x
Pain severity at its worst NRS 
(24h recall) bb
x


Ipatasertib—F. Hoffmann-La Roche Ltd
50/Statistical Analysis Plan CO39303, Version 2
Appendix 2
Schedule of Assessments (cont.)
Assessment/Procedure
(Window)
Screening a
Cycle 1
Cycle 2
Cycle3
Cycles 
4
Study
Treatment 
Discontinuation b
Disease 
Follow-Up
c
Post-
Treatment 
Follow-Up d
Days –28 
to –1
Day
1
Day
4
(1)
Day
8
(2)
Day
15 e
(2)
Da
y
1
Day
15 e
Da
y
1
Day
15 e
Day
1
Within 30 days 
of the Last Study 
Treatment
Every 3 
(1) 
Months
Every 3 
(1) 
Months
Pain severity at its worst NRS 
(7-day recall) bb
x
x
x
x
x
x
x
EORTC QLQ-C30, Urinary 
Scale from EORTC PR-25 bb
x
x
x
x
x
x
x
EQ-5D-5L bb
x
x
x
x
x
x
x
PRO-CTCAE (selected items) 
bb
x
x
x
x
x
x
x
x
Medication log cc
Record per medication consumption
x
x
Study treatment administration 
dd
Daily administration of ipatasertib/placebo, abiraterone plus 
prednisone/prednisolone
Symptomatic skeletal events ee
Record any symptomatic 
skeletal events
x
x
x
Drug accountability
x
x
x
x
Plasma PK sample ff
See Appendix 3
Blood sample for NGS control gg
See Appendix 3
Blood sample for 
pharmacogenomics gg
See Appendix 3
Plasma sample for somatic 
tumor mutations gg
See Appendix 3
Plasma sample for exploratory 
biomarkers gg
See Appendix 3




Ipatasertib—F. Hoffmann-La Roche Ltd
52/Statistical Analysis Plan CO39303, Version 2
Appendix 2
Schedule of Assessments (cont.)
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit within 30 (3) days after the last dose of 
study treatment.  The visit at which response assessment shows progressive disease may be used as the treatment discontinuation visit, 
provided that all tests required at the treatment discontinuation visit are performed.  Tumor assessments at the treatment discontinuation visit 
may be omitted if the most recent prior assessment was performed less than 28 days ago or the patient has already had confirmation of 
radiographic disease progression.
c After treatment discontinuation, patients who discontinue study treatment in the absence of radiographically assessed disease progression will 
return to the clinic for tumor assessment follow-up visits approximately every 3 months from the last tumor assessment (CT or MRI scan and 
bone scans) until radiographically assessed disease progression.  Refer to Section 4.5.5 of the protocol and PCWG3 guidelines.  Following 
initiation of a new anti-cancer therapy for prostate cancer, information on disease progression from patient’s medical records may be used to 
complete disease follow-up via telephone calls and/or clinic visits.  
d After treatment discontinuation and radiographically assessed disease progression, unless the patient requests to be withdrawn from survival 
follow-up, the required information will be collected via telephone calls and/or clinic visits, or patients’ medical records, approximately every 
3 months until death, loss to follow-up, or study termination by the Sponsor. 
e Day 15 clinical visit and assessments up to Cycle 3 only.  During subsequent cycles, site personnel may contact the patient by telephone to 
assess the occurrence of adverse events as described in footnote "k".  The rationale for the telephone call is to allow proactive medical 
management of adverse events and to minimize delayed reporting by patient, owing to the monthly clinic visit schedule.
f
Informed consent, including optional consent, must be documented before any study-specific screening procedure is performed and may be 
obtained more than 28 days before initiation of study treatment.
g Medical history includes clinically significant diseases within the previous 5 years, surgeries, complete cancer history (including prior cancer 
therapies and procedures), complete cardiovascular history, reproductive status, smoking history, use of alcohol, and drugs of abuse
(see Section 4.5.2 of the protocol).
h A tumor tissue block or a minimum of 15 (20 preferred) freshly cut, unstained slides from patients will be collected at screening.  If only 
1214 slides are available, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor.  A valid PTEN
IHC test result (from the central laboratory) must be available prior to initiation of study treatment on Cycle 1, Day 1.  If archival tissue is 
insufficient, a fresh tumor biopsy meeting the minimum requirement may be used.
i
Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient from 7 days prior to screening (or 28 days prior to initiation of study treatment on Cycle 1, Day 1, whichever occurs first) until 
28 days after the last dose of study treatment.  
j
Opioid consumption for cancer-related pain and anti-diabetic medications for hyperglycemia related to study treatment should be recorded in the 
eCRF from Cycle 1, Day 1 to initiation of the next line of prostate cancer therapy.


Ipatasertib—F. Hoffmann-La Roche Ltd
53/Statistical Analysis Plan CO39303, Version 2
Appendix 2
Schedule of Assessments (cont.)
k After informed consent has been obtained but prior to initiation of study treatment, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the last dose of study 
treatment. After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be 
related to prior study treatment.  The investigator should follow each adverse event until the event has resolved to baseline grade or better, the 
event is assessed by the investigator as stable and no further changes are expected, the patient is lost to follow-up, or the patient withdraws 
consent.  Every effort should be made to follow all serious adverse events considered by the investigator to be related to study treatment or trial-
related procedures until a final outcome can be reported.
l
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At study discontinuation visit, record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF.
m Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
n Vital signs include respiratory rate, pulse (heart) rate, and systolic and diastolic blood pressures while the patient is in a seated position, and 
temperature.  Oxygen saturation per pulse oximetry (optional).  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
o ECG recordings will be obtained as part of the screening assessment as clinically indicated during study treatment, and at the end of treatment 
visit.  ECGs will be reviewed by the investigator to determine patient eligibility at screening.  Baseline evaluation of LVEF by MUGA or ECHO 
should be considered for patients with cardiac risk factors and/or history of coronary artery disease.
p If the progression disease will be based on PSA at screening, at least two PSA samples (obtained at least 1 week apart) will be assessed locally 
at screening for confirmation of eligibility (if no data are available prior to screening). 
q Regardless of PSA used for confirmation of progression disease at screening, historic values of PSA will be collected as available for calculation 
of PSA velocity per PCWG3 criteria (at least three PSA values with each values 0.2 ng/dL, including the most recent value during androgen-
derivation therapy, and the interval between first and last PSA value to be 8 weeks but 12 months).  A central laboratory sample should also 
be submitted at screening and at all other timepoints.  If medically indicated, additional PSA samples may be collected and tested locally.  An 
increase in PSA, without evidence of radiographic progression or unequivocal clinical progression, should not be used as a criterion to start a 
new systemic anti-cancer therapy during the study.
r
May be performed 96 hours prior to dosing for each clinic visit during study treatment, screening assessments performed 96 hours prior to 
dosing on Cycle 1, Day 1 do not have to be repeated on Cycle 1, Day 1.  PSA may be performed 96 hours prior to dosing at each Day 1 visit.
s Serum testosterone samples will be assessed locally and centrally at screening for determination of eligibility and at study treatment 
discontinuation to confirm testosterone remains at castration level. 


Ipatasertib—F. Hoffmann-La Roche Ltd
54/Statistical Analysis Plan CO39303, Version 2
Appendix 2
Schedule of Assessments (cont.)
t
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, bands [optional]
eosinophils, basophils, monocytes, lymphocytes, and other cells).  
u For all clinic visits during study treatment, the glucose level of the patient must be performed 96 hours prior to dosing, except for Cycle 1, Day 
4, which must be done ≤ 24 hours prior to the visit, and must be reviewed prior to further ipatasertib/placebo administration and prior to 
discharge from the clinic.  Blood glucose may be obtained by a glucometer (fingerstick). For fasting blood glucose, patients should fast 8 hours 
prior to testing.  
v Patients enrolled will be supplied with a blood glucose meter and a blood glucose log to record blood glucose at least once daily.  Self-monitoring 
should be performed at least once daily by the patient after "a bigger meal" throughout the study treatment period (i.e., until discontinuation of 
ipatasertib/placebo).   
w Chemistry panel includes sodium, potassium, chloride, magnesium, bicarbonate, BUN (or urea), creatinine, total protein, albumin, phosphorus, 
calcium, uric acid, and liver function test panel (total and direct bilirubin, alkaline phosphatase, ALT, AST, and LDH).  The occurrence of 
Grade 3 abnormalities should be monitored at a minimum of every 2 weeks.  
x Includes dipstick (pH, specific gravity, glucose, protein, ketones, blood).
y Tumor assessments should include the chest, abdomen, and pelvis (and other body regions if clinically indicated) at screening and at 
subsequent tumor assessments, even if there are no detectable lesions at baseline.  CT scans are the preferred imaging modality for tumor 
assessments.  MRI scans may be substituted for CT scans and the same imaging method used at screening must be used throughout the study.  
Soft tissue responses will be assessed locally by the investigator (and/or radiologists) according to RECIST v1.1 for patient management.  All 
films should be submitted for central archive to enable radiologic review if determined by the Sponsor to be necessary for the primary endpoint 
analysis.
z A technetium bone scan will be performed at screening (within 42 days before Cycle 1, Day 1) to evaluate for the presence of bone metastases.  
In cases of ambiguous findings on bone scan, an X-ray or CT/MRI confirmatory scan should performed at baseline, to ensure that ambiguous 
findings on bone scan are related to cancer and not healing bone.  For adequate assessment of bone lesions, it is expected that the radiologist 
will adjust the window leveling accordingly (refer to the Imaging Charter).  In case of isotope shortage, the Sponsor or Medical Monitor should be 
contacted if the scan cannot be performed within 1 week from the allowable window.  All films should be submitted for central archive, to enable 
radiologic review if determined necessary for primary endpoint analysis by the Sponsor.
aa Tumor assessments should be performed 7 days of the scheduled cycles.  




Ipatasertib—F. Hoffmann-La Roche Ltd
56/Statistical Analysis Plan CO39303, Version 2
Appendix 3
Schedule of Pharmacokinetic Samples and Exploratory 
Biomarker Samples
Study Visit
Timepoint(s)
Sample Type
Cycle 1, Day 1
Prior to ipatasertib/placebo and 
abiraterone
Blood for NGS control
Plasma (somatic tumor mutations)
Plasma (exploratory biomarkers)
Pharmacogenetic blood sample
Optional blood for RBR 
(for DNA extraction) a
13 hours postipatasertib/placebo 
and abiraterone administration
PK plasma sample for
ipatasertib/placebo
Cycle 1, Day 15
(3 days)
Prior to ipatasertib/placebo and 
abiraterone
PK plasma sample for 
ipatasertib/placebo and abiraterone 
13 hours postipatasertib/placebo 
and abiraterone administration
PK plasma sample for 
ipatasertib/placebo
Cycle 3, Day 1
Prior to ipatasertib/placebo and 
abiraterone
Plasma (somatic tumor mutations)
Plasma (exploratory biomarkers)
PK plasma sample for 
ipatasertib/placebo and abiraterone 
13 hours postipatasertib/placebo 
and abiraterone administration
PK plasma sample for 
ipatasertib/placebo
Cycle 6, Day 1
Prior to ipatasertib/placebo and 
abiraterone administration
PK plasma sample for 
ipatasertib/placebo
Cycle 12, Day 1
At visit
Plasma (somatic tumor mutations)
Plasma (exploratory biomarkers)
SDDV
At visit
Plasma (somatic tumor mutations)
Plasma (exploratory biomarkers)
NGSnext-generation sequencing; PKpharmacokinetic; RBRResearch Biosample 
Repository; SDDVstudy drug discontinuation visit.
Notes:  After Cycle 1, Day 1, all study visits and assessments during the treatment period 
should be performed within 3 days of the scheduled date.  Study assessments may be 
delayed or moved ahead of the window to accommodate holidays, vacations, and unforeseen 
delays.  PK samples will be collected in both arms. 
If ipatasertib/placebo (either alone or with abiraterone) has been on temporary hold for 
2 days prior to PK assessment timepoint, then PK sampling for both ipatasertib/placebo and 
abiraterone may be rescheduled to another day within that cycle after ipatasertib/placebo has 
been administered for at least 3 consecutive days prior to the visit day. If only abiraterone is 
held for any number of days prior to PK sampling time point, continue sampling of 
ipatasertib/placebo as per schedule; do not collect abiraterone PK sample and resume 
abiraterone sampling at the next scheduled timepoint.  If ipatasertib/placebo is permanently
discontinued, PK sampling for ipatasertib/placebo and abiraterone can be discontinued.
a Requires additional informed consent and can be collected at any time during the course of 
the study.