A Phase II, Randomized, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of GDC-9545 Compared With Physician's Choice of Endocrine Monotherapy in Patients With Previously Treated Estrogen Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer
Phase: PHASE2
Conditions: Estrogen Receptor-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer
Sponsor: Hoffmann-La Roche

 
 
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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
 
GDC-9545—F. Hoffmann-La Roche Ltd 
Protocol WO42312, Version 4  
PROTOCOL 
TITLE: 
A PHASE II, RANDOMIZED, OPEN-LABEL, 
MULTICENTER STUDY EVALUATING THE 
EFFICACY AND SAFETY OF GDC-9545 
COMPARED WITH PHYSICIAN'S CHOICE OF 
ENDOCRINE MONOTHERAPY IN PATIENTS WITH 
PREVIOUSLY TREATED ESTROGEN 
RECEPTOR-POSITIVE, HER2-NEGATIVE 
LOCALLY ADVANCED OR METASTATIC BREAST 
CANCER 
PROTOCOL NUMBER: WO42312 
STUDY NAME: 
acelERA Breast Cancer 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-001984-10 
IND NUMBER: 
132,673 
NCT NUMBER: 
NCT04576455 
TEST PRODUCT: 
GDC-9545 (RO7197597) 
MEDICAL MONITOR: 
, PharmD Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of the document. 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
2/ Protocol WO42312, Version 4 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
4 
See electronic signature and date 
stamp on the final page of the 
document 
3 
09 July 2021 
2 
21 October 2020 
1 
15 May 2020 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
3/ Protocol WO42312, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol WO42312 has been amended to include recent GDC-9545 safety 
information as per Investigator’s Brochure version 6 (IB v6).  In addition, Protocol 
WO42312 has been amended following the results of drug-drug interaction study 
(GP44001), which showed that giredestrant is a moderately sensitive CYP3A 
substrate.  Changes to the protocol, along with a rationale for each change, are 
summarized below: 
 
Clinical and Safety Data has been updated to reflect recent clinical 
information as per IB v6.  Identified and potential safety risks associated with 
giredestrant have been updated accordingly (Sections 1.2.2, 5.1.1, and 
5.1.2). 
 
Cautionary use of medications associated with QT interval prolongation for 
patients receiving giredestrant has been removed from Section 4.4.2 based 
on IB v6 updates, due to the fact that QT prolongation has been formally 
refuted as a potential risk with giredestrant. 
 
Moderate CYP3A inducers has been added to cautionary therapy (Section 
4.4.2.4), and language added to prohibited therapy and prohibited food 
(Sections 4.4.3 and 4.4.4) based on the results of study GP44001 showing 
that giredestrant is a moderately sensitive CYP3A substrate (Section 4.4). 
Since the study has already completed enrollment, no further updates have 
been made to the study eligibility criteria.  Contraception requirements have 
been updated to ensure complete washout of GDC-9545, considering its 
embryo-fetal toxicity (Sections 4.1.1, 4.1.2 and 5.4.3). 
 
The email address for withdrawal from the Research Biosample Repository 
after site closure has been corrected (Section 4.5.12.6). 
 
Personal identifiable information (i.e., name and telephone number) for the 
Medical Monitors has been removed from the protocol.  Medical Monitor 
contact information has been replaced with a sentence indicating that this 
information will be provided separately to sites (Section 5.4.1). 
 
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). 
 
“Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form” was changed to “Clinical Trial Adverse Event/Special 
Situations Form” throughout the document.  
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents 
cumulative changes to protocol version 3.0. 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
4/ Protocol WO42312, Version 4 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 26 
1.1 
Background on Estrogen ReceptorPositive, 
HER2-Negative Breast Cancer ................................................ 26 
1.2 
Background on GDC-9545 ...................................................... 28 
1.2.1 
Nonclinical Data ....................................................................... 28 
1.2.2 
Clinical Data ............................................................................. 29 
1.2.2.1 
Study GO39932 ....................................................................... 29 
1.2.2.2 
Study WO42312 ...................................................................... 30 
1.2.2.3 
Study BO41843 ....................................................................... 31 
1.2.2.4 
Study GO40987 ....................................................................... 31 
1.2.2.5 
Study WO42133 ...................................................................... 32 
1.2.2.6 
Study GO42784 ....................................................................... 32 
1.3 
Study Rationale and Benefit–Risk Assessment ....................... 32 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 35 
2.1 
Efficacy Objectives .................................................................. 35 
2.1.1 
Primary Efficacy Objective ....................................................... 35 
2.1.2 
Secondary Efficacy Objective .................................................. 35 
2.1.3 
Exploratory Efficacy Objective ................................................. 36 
2.2 
Safety Objectives ..................................................................... 36 
2.3 
Pharmacokinetic Objective ...................................................... 37 
2.4 
Biomarker Objective ................................................................ 37 
2.5 
Health Status Utility Objective .................................................. 37 
3. 
STUDY DESIGN ........................................................................... 38 
3.1 
Description of the Study ........................................................... 38 
3.1.1 
Overview of the Study .............................................................. 38 
3.1.2 
Independent Review Committee .............................................. 41 
3.1.3 
Internal Monitoring Committee ................................................. 41 
3.2 
End of Study and Length of Study ........................................... 41 

 
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3.3 
Rationale for Study Design ...................................................... 42 
3.3.1 
Rationale for GDC-9545 Dose and Schedule .......................... 42 
3.3.2 
Rationale for Patient Population .............................................. 43 
3.3.3 
Rationale for Control Group ..................................................... 43 
3.3.4 
Rationale for Primary Endpoint of Investigator-Assessed 
Progression-Free Survival ....................................................... 44 
3.3.5 
Rationale for Biomarker Assessments ..................................... 45 
3.3.5.1 
Rationale for the Collection of Plasma Samples for 
Somatic Tumor Mutation Analysis ........................................... 45 
3.3.5.2 
Rationale for the Collection of Tissue Samples ....................... 46 
3.3.6 
Rationale for Clinical Outcome Assessments .......................... 47 
4. 
MATERIALS AND METHODS ...................................................... 48 
4.1 
Patients .................................................................................... 48 
4.1.1 
Inclusion Criteria ...................................................................... 48 
4.1.2 
Exclusion Criteria ..................................................................... 53 
4.2 
Method of Treatment Assignment and Blinding ....................... 55 
4.2.1 
Treatment Assignment ............................................................. 55 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 56 
4.3.1 
Study Treatment Formulation and Packaging .......................... 56 
4.3.1.1 
GDC-9545................................................................................ 56 
4.3.1.2 
Physician's Choice of Endocrine Monotherapy ........................ 56 
4.3.1.3 
Luteinizing HormoneReleasing Hormone Agonist ................. 56 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 57 
4.3.2.1 
GDC-9545................................................................................ 57 
4.3.2.2 
Physician's Choice of Endocrine Monotherapy ........................ 58 
4.3.2.3 
Luteinizing HormoneReleasing Hormone Agonist ................. 58 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 58 
4.3.4 
Continued Access to GDC-9545 .............................................. 59 
4.4 
Concomitant Therapy .............................................................. 59 
4.4.1 
Permitted Therapy ................................................................... 60 
4.4.2 
Cautionary Therapy for Patients Receiving GDC-9545 ........... 60 
4.4.2.1 
Medications Associated with Bradycardia ................................ 60 

 
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4.4.2.2 
Surgery .................................................................................... 60 
4.4.2.3 
Herbal Therapies ..................................................................... 61 
4.4.2.4 
Moderate CYP3A Inducers ...................................................... 61 
4.4.3 
Prohibited Therapy .................................................................. 61 
4.4.4 
Prohibited Food ........................................................................ 63 
4.5 
Study Assessments ................................................................. 63 
4.5.1 
Informed Consent Forms and Screening Log .......................... 63 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 64 
4.5.3 
Physical Examinations ............................................................. 64 
4.5.4 
Vital Signs ................................................................................ 64 
4.5.5 
ECOG Performance Status...................................................... 64 
4.5.6 
Tumor and Response Evaluations ........................................... 65 
4.5.6.1 
Baseline Tumor Assessments ................................................. 66 
4.5.6.2 
Postbaseline Tumor Assessments ........................................... 67 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 67 
4.5.8 
Electrocardiograms .................................................................. 70 
4.5.9 
Clinical Outcome Assessments ............................................... 71 
4.5.9.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 71 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments ....... 72 
4.5.9.3 
Optional Patient Interviews ...................................................... 74 
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................ 74 
4.5.11 
Optional Tumor Biopsy (Patients at Participating Sites) .......... 76 
4.5.12 
Optional Samples for Research Biosample Repository ........... 76 
4.5.12.1 
Overview of the Research Biosample Repository .................... 76 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 77 
4.5.12.3 
Sample Collection .................................................................... 77 
4.5.12.4 
Confidentiality .......................................................................... 78 
4.5.12.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 78 
4.5.12.6 
Withdrawal from the Research Biosample Repository ............. 79 

 
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4.5.12.7 
Monitoring and Oversight ......................................................... 79 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 80 
4.6.1 
Study Treatment Discontinuation ............................................. 80 
4.6.2 
Patient Discontinuation from the Study .................................... 81 
4.6.3 
Study Discontinuation .............................................................. 81 
4.6.4 
Site Discontinuation ................................................................. 82 
5. 
ASSESSMENT OF SAFETY ......................................................... 82 
5.1 
Safety Plan .............................................................................. 82 
5.1.1 
Identified Risks of GDC-9545 .................................................. 82 
5.1.1.1 
Arthralgia ................................................................................. 82 
5.1.1.2 
Bradycardia ............................................................................. 83 
5.1.1.3 
Diarrhea ................................................................................... 83 
5.1.1.4 
Dizziness ................................................................................. 83 
5.1.1.5 
Headache .................................................................................. 83 
5.1.1.6 
Hepatotoxicity ......................................................................... 83 
5.1.1.7 
Hot flush .................................................................................. 83 
5.1.1.8 
Fatigue ..................................................................................... 83 
5.1.1.9 
Musculoskeletal pain ............................................................... 84 
5.1.1.10 
Nausea .................................................................................... 84 
5.1.1.11 
Vomiting ................................................................................... 84 
5.1.2 
Potential Risks Associated with GDC-9545 ............................. 84 
5.1.2.1 
Venous Thromboembolic Events (Including Pulmonary 
Embolism) ................................................................................ 84 
5.1.2.2 
Renal Toxicity or Increased Creatinine .................................... 84 
5.1.2.3 
Changes in Female Reproductive Organs and Menopausal 
Symptoms ................................................................................ 85 
5.1.2.4 
Female and Male Fertility ........................................................ 85 
5.1.2.5 
Embryofetal Toxicity ................................................................ 85 
5.1.3 
Management of Patients Who Experience Adverse Events ..... 86 
5.1.3.1 
Dose Modifications .................................................................. 86 
5.1.3.2 
Treatment Interruption ............................................................. 86 
5.1.3.3 
Management Guidelines .......................................................... 86 
5.1.3.4 
Management of Increases in QT Interval ................................. 89 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
8/ Protocol WO42312, Version 4 
5.2 
Safety Parameters and Definitions .......................................... 89 
5.2.1 
Adverse Events ........................................................................ 89 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 90 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 91 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 91 
5.3.1 
Adverse Event Reporting Period .............................................. 92 
5.3.2 
Eliciting Adverse Event Information ......................................... 92 
5.3.3 
Assessment of Severity of Adverse Events ............................. 92 
5.3.4 
Assessment of Causality of Adverse Events............................ 93 
5.3.5 
Procedures for Recording Adverse Events .............................. 94 
5.3.5.1 
Injection Reactions (for Patients Receiving Fulvestrant or 
Formestane) ............................................................................ 94 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 94 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 95 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 95 
5.3.5.5 
Abnormal Laboratory Values ................................................... 96 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 96 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 97 
5.3.5.8 
Deaths ..................................................................................... 97 
5.3.5.9 
Preexisting Medical Conditions ................................................ 98 
5.3.5.10 
Lack of Efficacy or Worsening of Breast Cancer ...................... 98 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 98 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 99 
5.3.5.13 
Patient-Reported Outcome Data ............................................ 101 
5.3.5.14 
Safety Biomarker Data ........................................................... 101 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 101 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............. 102 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 102 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 102 

 
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5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 103 
5.4.3 
Reporting Requirements for Pregnancies .............................. 103 
5.4.3.1 
Pregnancies in Female Patients ............................................ 103 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 104 
5.4.3.3 
Abortions................................................................................ 104 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 104 
5.5 
Follow-Up of Patients after Adverse Events........................... 105 
5.5.1 
Investigator Follow-Up ........................................................... 105 
5.5.2 
Sponsor Follow-Up ................................................................ 105 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 105 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 105 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 107 
6.1 
Determination of Sample Size ............................................... 107 
6.2 
Summaries of Conduct of Study ............................................ 108 
6.3 
Summaries of Treatment Group Comparability ...................... 108 
6.4 
Efficacy Analyses ................................................................... 108 
6.4.1 
Primary Efficacy Endpoint ...................................................... 108 
6.4.2 
Secondary Efficacy Endpoints ............................................... 109 
6.4.2.1 
Overall Survival ...................................................................... 109 
6.4.2.2 
Objective Response Rate ...................................................... 109 
6.4.2.3 
Duration of Response ............................................................ 109 
6.4.2.4 
Clinical Benefit Rate .............................................................. 110 
6.4.2.5 
PFS by ESR1 Mutation Status ............................................... 110 
6.4.2.6 
Patient-Reported Outcomes .................................................. 110 
6.4.3 
Exploratory Efficacy Endpoints .............................................. 111 
6.5 
Safety Analyses ..................................................................... 111 
6.5.1 
Analyses of Exposure, Adverse Event, Laboratory, and 
Vital Sign Data ....................................................................... 111 
6.5.2 
Exploratory Safety Analyses of PRO-CTCAE and GP5 
Data ....................................................................................... 112 
6.6 
Pharmacokinetic Analyses ..................................................... 112 
6.7 
Biomarker Analyses ............................................................... 113 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
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6.8 
Health Status Utility Analyses ................................................ 113 
6.9 
China Subpopulation Analyses .............................................. 113 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 114 
7.1 
Data Quality Assurance ......................................................... 114 
7.2 
Electronic Case Report Forms ............................................... 114 
7.3 
Electronic Patient-Reported Outcome Data ........................... 115 
7.4 
Source Data Documentation .................................................. 115 
7.5 
Use of Computerized Systems .............................................. 116 
7.6 
Retention of Records ............................................................. 116 
8. 
ETHICAL CONSIDERATIONS .................................................... 117 
8.1 
Compliance with Laws and Regulations ................................ 117 
8.2 
Informed Consent .................................................................. 117 
8.3 
Institutional Review Board or Ethics Committee .................... 118 
8.4 
Confidentiality ........................................................................ 119 
8.5 
Financial Disclosure ............................................................... 120 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 120 
9.1 
Study Documentation ............................................................ 120 
9.2 
Protocol Deviations ................................................................ 120 
9.3 
Management of Study Quality ................................................ 120 
9.4 
Site Inspections ..................................................................... 121 
9.5 
Administrative Structure ......................................................... 121 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 121 
9.7 
Protocol Amendments ........................................................... 122 
10. 
REFERENCES............................................................................ 122 
 
 
LIST OF TABLES 
Table 1 
Guidelines for Management of Patients Who Experience 
Adverse Events Associated with GDC-9545 ............................... 86 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 93 
Table 3 
Causal Attribution Guidance ....................................................... 94 
 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
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LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 41 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 129 
Appendix 2 
 Schedule of Pharmacokinetic Samples for Patients in 
GDC-9545 Arm ......................................................................... 135 
Appendix 3 
 Schedule of Biomarker Samples .............................................. 137 
Appendix 4 
 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1)........................................................ 138 
Appendix 5 
 European Organisation for Research and Treatment of 
Cancer QLQ-C30 Questionnaire (EORTC QLQ-C30) ............... 147 
Appendix 6 
 European Organisation for Research and Treatment of 
Cancer QLQ-BR23 Questionnaire (EORTC QLQ-BR23) .......... 149 
Appendix 7 
 Brief Pain InventoryShort Form (BPI-SF) "Worst Pain" Item .. 151 
Appendix 8 
 National Cancer Institute Patient-Reported Outcomes 
Common Terminology Criteria for Adverse Events (NCI 
PRO-CTCAE) Items .................................................................. 152 
Appendix 9 
 EQ-5D-5L ................................................................................. 154 
Appendix 10 
 FACT-G Single-Item GP5, Overall Treatment Burden ............. 157 
Appendix 11 
 Eastern Cooperative Oncology Group (ECOG) Performance 
Status Scale .............................................................................. 158 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
12/ Protocol WO42312, Version 4 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, RANDOMIZED, OPEN-LABEL, 
MULTICENTER STUDY EVALUATING THE 
EFFICACY AND SAFETY OF GDC-9545 
COMPARED WITH PHYSICIAN'S CHOICE OF 
ENDOCRINE MONOTHERAPY IN PATIENTS WITH 
PREVIOUSLY TREATED ESTROGEN 
RECEPTOR-POSITIVE, HER2-NEGATIVE LOCALLY 
ADVANCED OR METASTATIC BREAST CANCER 
PROTOCOL NUMBER: WO42312  
STUDY NAME: 
acelERA Breast Cancer 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-001984-10 
IND NUMBER: 
132,673 
NCT NUMBER: 
NCT04576455 
TEST PRODUCT: 
GDC-9545 (RO7197597) 
MEDICAL MONITOR: 
, PharmD, PhD 
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. 
 

 
GDC-9545—F. Hoffmann-La Roche Ltd 
13/ Protocol WO42312, Version 4 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, RANDOMIZED, OPEN-LABEL, MULTICENTER 
STUDY EVALUATING THE EFFICACY AND SAFETY OF 
GDC-9545 COMPARED WITH PHYSICIAN'S CHOICE OF 
ENDOCRINE MONOTHERAPY IN PATIENTS WITH PREVIOUSLY 
TREATED ESTROGEN RECEPTOR-POSITIVE, HER2-NEGATIVE 
LOCALLY ADVANCED OR METASTATIC BREAST CANCER 
PROTOCOL NUMBER: 
WO42312 
STUDY NAME: 
acelERA Breast Cancer 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-001984-10 
IND NUMBER: 
132,673 
NCT NUMBER: 
NCT04576455 
TEST PRODUCT: 
GDC-9545 (RO7197597) 
PHASE: 
II 
INDICATION: 
Estrogen receptorpositive, HER2-negative locally advanced or 
metastatic breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of GDC-9545 compared with physician's choice 
of endocrine monotherapy in patients with previously treated estrogen receptor (ER)positive, 
HER2-negative locally advanced or metastatic breast cancer who have received one or two 
prior lines of systemic therapy in the locally advanced or metastatic setting.  
Endocrine monotherapy is defined as either fulvestrant or an aromatase inhibitor.  Specific 
objectives and corresponding endpoints for the study are outlined below. 
 
EFFICACY OBJECTIVES 
PRIMARY EFFICACY OBJECTIVE 
The primary efficacy objective for this study is to evaluate the efficacy of GDC-9545 compared 
with physician's choice of endocrine monotherapy on the basis of the following endpoint: 
 
Progression-free survival (PFS), defined as the time from randomization to the first 
occurrence of disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
SECONDARY EFFICACY OBJECTIVE 
The secondary efficacy objective for this study is to evaluate the efficacy of GDC-9545 
compared with physician's choice of endocrine monotherapy on the basis of the following 
endpoints: 
 
Overall survival (OS), defined as the time from randomization to death from any cause 

 
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 
Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) on two consecutive occasions  4 weeks apart, as 
determined by the investigator according to RECIST v1.1 
 
Duration of response (DOR), defined as the time from the first occurrence of a documented 
objective response to disease progression or death from any cause (whichever occurs 
first), as determined by the investigator according to RECIST v1.1 
 
Clinical benefit rate (CBR), defined as the proportion of patients with stable disease for 
 24 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1 
 
Investigator-assessed PFS, in subgroups categorized by baseline ESR1 mutation status 
 
Time to deterioration (TTD) in pain severity after randomization, defined as the time from 
randomization to the first documentation of a  2-point increase from baseline on the "worst 
pain" item score from the Brief Pain InventoryShort Form (BPI-SF)  
 
TTD in pain presence and interference after randomization, defined as the time from 
randomization to the first documentation of a  10-point increase from baseline in the 
European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 linearly 
transformed pain scale score 
 
TTD in physical functioning (PF) after randomization, defined as the time from 
randomization to the first documentation of a  10-point decrease from baseline in the 
EORTC QLQ-C30 linearly transformed PF scale score 
 
TTD in role functioning (RF) after randomization, defined as the time from randomization to 
the first documentation of a  10-point decrease from baseline in the EORTC QLQ-C30 
linearly transformed RF scale score 
 
TTD in global health status (GHS) and quality of life (QoL) after randomization, defined as 
the time from randomization to the first documentation of a  10-point decrease from 
baseline in the EORTC QLQ-C30 linearly transformed GHS/QoL scale score 
EXPLORATORY EFFICACY OBJECTIVE 
The exploratory efficacy objective for this study is to evaluate the efficacy of GDC-9545 
compared with physician's choice of endocrine monotherapy on the basis of the following 
endpoints: 
 
Mean scores and mean change from baseline in functional scores (physical, role, cognitive, 
emotional, and social), GHS/QoL, and disease- and treatment-related symptom scores, as 
assessed through use of the QLQ-C30 and QLQ-BR23 scales at specified timepoints 
Patient interviews will also explore patients’ experience of study drug, therapeutic context and 
disease journey among a subset of patients treated with GDC-9545. 
 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of GDC-9545 compared with 
physician's choice of endocrine monotherapy on the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0  
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 
The exploratory safety objective for this study is to evaluate the tolerability of GDC-9545 
compared with physician's choice of endocrine monotherapy on the basis of the following 
endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference with daily 
function of selected symptomatic treatment toxicities, as assessed through use of the 
NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE)  

 
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 
Overall tolerability (i.e., bother experienced due to side effects of treatment), as assessed 
through the General Population, Question 5 (GP5) item from the Functional Assessment of 
Cancer TherapyGeneral (FACT-G) questionnaire 
 
Change from baseline in symptomatic treatment toxicities and overall tolerability/side-effect 
burden, as assessed through use of the PRO-CTCAE and the GP5 item, respectively 
 
PHARMACOKINETIC OBJECTIVE 
The pharmacokinetic (PK) objective for this study is to characterize the GDC-9545 PK profile 
( LHRH agonist) on the basis of the following endpoint: 
 
Plasma concentration of GDC-9545 at specified timepoints 
 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to GDC-9545 (i.e., predictive biomarkers), are early surrogates of 
efficacy, are associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), are associated with acquired resistance to GDC-9545, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event monitoring 
or investigation (i.e., safety biomarkers), can provide evidence of GDC-9545 activity (i.e., PD 
biomarkers), or can increase the knowledge and understanding of disease biology and drug 
safety, on the basis of the following endpoint: 
 
Relationship between biomarkers in blood, plasma, and tumor tissue and efficacy, safety, 
PK, disease biology, or other biomarker endpoints 
 
HEALTH STATUS UTILITY OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with GDC-9545 compared with physician's choice of endocrine 
monotherapy on the basis of the following endpoint: 
 
Health utility and visual analog scale score of the EQ-5D-5L for pharmacoeconomic 
modeling at specified timepoints 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This Phase II, randomized, open-label, multicenter study will evaluate the efficacy and safety of 
GDC-9545 compared with physician's choice of endocrine monotherapy in patients with 
ER positive, HER2-negative locally advanced or metastatic breast cancer who have received 
one or two prior lines of systemic therapy in the locally advanced or metastatic setting. 
This study will initially enroll approximately 300 patients across all sites in a global enrollment 
phase.  After completion of the global enrollment phase, additional patients may be enrolled in 
an extended China enrollment phase at sites in mainland China, and/or Taiwan.  The global 
population will include all patients enrolled during the global enrollment phase (including 
patients enrolled in mainland China, Hong Kong, and/or Taiwan during that phase), and the 
China subpopulation will include all patients enrolled in mainland China, and/or Taiwan (i.e., 
during both the global enrollment phase and the extended China enrollment phase). 
Eligible patients will be randomly assigned in a 1:1 ratio to either an experimental arm 
to receive GDC-9545 or a control arm to receive physician's choice of endocrine monotherapy.  
Patients will be stratified by site of disease, assessed locally (visceral [any lung and/or liver 
involvement] vs. non-visceral [absence of any lung and/or liver involvement]), prior treatment 
with cyclin-dependent kinase (CDK)4/6 inhibitor (yes vs. no); and prior treatment with 
fulvestrant (yes vs. no).  The number of premenopausal/perimenopausal patients and male 
patients enrolled will be limited to approximately 20% of the study population.  The cap of 20% 
has been chosen to ensure that the mix of patients in this study approximates global clinical 
practice patterns. 

 
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Patients who withdraw from the study or who discontinue study treatment will not be replaced.  
However, patients who withdraw from the study after screening, but before randomization, will 
be replaced. 
Patients may continue to receive study treatment until disease progression or unacceptable 
toxicity, whichever occurs first.  An exception will be made for patients who have developed 
isolated brain metastases that are treatable with radiation, provided the patients have 
experienced a PR, CR, or stable disease for  24 weeks.  These patients will be allowed to 
continue to receive study treatment until systemic progression of disease and/or further 
progression in the brain.   
After the date of randomization, tumor assessments will be performed every 8 weeks for the 
first 18 months, then every 12 weeks thereafter, with the exception of bone scans, which will be 
performed every 24 weeks or as clinically indicated. 
Efficacy analyses will be based on the local radiologist's or investigator's tumor assessments.  
Radiographic images, photographs, and clinical information will be sent to a blinded, 
independent core imaging laboratory to enable a retrospective evaluation of disease response 
and progression by an Independent Review Committee. 
All patients will be closely monitored for adverse events throughout the study, and adverse 
events will be graded according to NCI CTCAE v5.0.  An Internal Monitoring Committee will 
also provide safety oversight. 
 
NUMBER OF PATIENTS 
This study will initially enroll approximately 300 patients across all sites in a global 
enrollment phase. 
 
TARGET POPULATION 
INCLUSION CRITERIA 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
For women:  postmenopausal or premenopausal/perimenopausal status, defined as 
follows: 
Postmenopausal, as defined by at least one of the following criteria: 
– 
Age  60 years 
– 
Age  60 years and  12 months of amenorrhea without an alternative 
medical cause plus follicle-stimulating hormone and plasma estradiol levels 
within postmenopausal range by local laboratory assessment, in the absence of 
oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing 
hormone agonist or antagonist. 
– 
Documented bilateral oophorectomy ( 14 days prior to first treatment on Day 1 of 
Cycle 1 and recovery from surgery to baseline) 
Premenopausal or perimenopausal, defined as not meeting the criteria for 
postmenopausal, and willing to undergo and maintain treatment with approved 
LHRH-agonist therapy for the duration of study treatment  
LHRH-agonist therapy may be initiated 28 days prior to Day 1 of Cycle 1 (or 
according to clinical practice for the selected agent).  To minimize the potential of 
exposure to the medication decreasing to sub-therapeutic levels towards the end 
of the treatment cycle, monthly injections of LHRH agonist are preferred and to be 
synchronized with Day 1 of each 28-day cycle. 
 
For men:  willing to undergo and maintain treatment with approved LHRH-agonist therapy 
for the duration of study treatment 
LHRH-agonist therapy may be initiated 28 days prior to Day 1 of Cycle 1 (or 
according to clinical practice for the selected agent).  To minimize the potential of 
exposure to the medication decreasing to sub-therapeutic levels towards the end 

 
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of the treatment cycle, monthly injections of LHRH agonist are preferred and to be 
synchronized with Day 1 of each 28-day cycle. 
 Locally advanced or metastatic adenocarcinoma of the breast, not amenable to treatment 
with curative intent  
 
Disease progression after treatment with one or two lines of systemic therapy in the locally 
advanced or metastatic setting 
One of the prior lines of systemic therapy may have included chemotherapy. 
Patients may not have received more than one prior targeted therapy regimen in the 
locally advanced or metastatic setting.  Targeted therapies may include, but are not 
limited to CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors or PARP inhibitors. 
One of the prior lines of systemic therapy must have included endocrine therapy, 
which must have been administered continuously for a minimum of 6 months in the 
locally advanced or metastatic setting prior to disease progression. 
Patients who were intolerant to their last systemic anti-cancer regimen may be 
considered eligible if all other eligibility criteria are met (including a minimum of 
6 months continuous endocrine therapy). 
Intolerance is defined as any treatment-related Grade 4 adverse event, or any 
treatment-related Grade 2 or 3 adverse event that is unacceptable to the patient 
and persists despite standard countermeasures.  The reason for intolerance must 
be fully documented. 
 
Documented ER-positive tumor according to American Society of Clinical Oncology/College 
of American Pathologists (ASCO/CAP) or ESMO guidelines, assessed locally and defined 
as  1% of tumor cells stained positive based on the most recent tumor biopsy (or archived 
tumor sample) 
Patient must be considered appropriate for endocrine therapy. 
 
Documented HER2-negative tumor assessed locally and defined as meeting criteria 
according to ASCO/CAP guidelines. 
 
Confirmed availability of the most recently collected and representative tumor tissue 
specimen (i.e., archived formalin-fixed paraffin-embedded tissue block [preferred] or 
1520 slides containing unstained, freshly cut, serial sections), Whenever possible, tumor 
tissue from a metastatic site of disease is preferred, but archival tumor tissue from the 
primary tumor is acceptable if it is the most recently collected or most suitable for testing.   
If tumor tissue is not available, a newly collected, pre-treatment biopsy will be required 
for patient participation.  In general, a minimum of three cores per block is preferred. 
If the aforementioned minimum tissue requirements cannot be met because of local 
regulatory requirements, patient may still be eligible for the study and study team is 
available for advice. 
 
Measurable disease as defined per RECIST v.1.1 or bone only disease which must have at 
least one predominantly lytic bone lesion confirmed by computed tomography or magnetic 
resonance imaging which can be followed. 
Tumor lesions previously irradiated or subjected to other locoregional therapy will be 
deemed measurable only if disease progression at the treated site after completion of 
therapy is clearly documented. 
 
Eastern Cooperative Oncology Group Performance Status 01 
 
Life expectancy of  6 months 
 
Adequate organ function as defined by the following criteria: 
– 
ANC  1.5  109/L (1500/L)  
– 
Platelet count  100  109/L (100,000/L) 
– 
AST and serum ALT  3  upper limit of normal (ULN)  
For patients with documented liver metastasis:  AST and ALT  5  ULN 

 
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– 
Hemoglobin  90 g/L (9 g/dL) 
The blood counts are to meet the specified criteria without transfusion or growth factor 
support, unless it is clear that the bone marrow function is adequate and that any 
aberration has a clear and correctable cause, and the correction undertaken. 
– 
Serum bilirubin  1.5  ULN, with the following exception: 
Patients with known Gilbert syndrome:   3   ULN 
– 
Serum creatinine  1.5  ULN or estimated creatinine clearance  60 mL/min as 
calculated per institutional guidelines 
 
INR (or PT)  1.5  ULN and PTT (or aPTT)  1.5  ULN (except for patients receiving 
anticoagulation therapy) 
For patients receiving warfarin, a stable INR between 2 and 3 is required. 
For patients receiving heparin, PTT (or aPTT) between 1.5 and 2.5  ULN (or patient's 
value before starting heparin treatment) is required. 
If anticoagulation therapy is required for a prosthetic heart valve, stable INR between 
2.5 and 3.5 is permitted. 
 
Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to 
NCI CTCAE v5.0 Grade  1 (except alopecia, Grade  2 peripheral neuropathy, or other 
toxicities not considered a safety risk for the patient per investigator's judgment) 
 
For women of childbearing potential:  agreement to take precautions as outlined below for 
each treatment arm: 
– 
If assigned to the control arm (physician's choice of endocrine monotherapy), 
agreement to comply with local prescribing guidelines regarding contraception for the 
chosen endocrine monotherapy  
– 
If assigned to the GDC-9545 arm:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, and agreement to refrain from donating 
eggs, as defined below: 
Women must remain abstinent or use non-hormonal contraceptive methods with 
a failure rate of  1% per year during the treatment period and for 10 days after 
the final dose of GDC-9545 or for the time period according to local prescribing 
guidelines.  Women must refrain from donating eggs during this same period. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis).  The definition 
of childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
Examples of non-hormonal contraceptive methods with a failure rate of  1% per 
year include bilateral tubal ligation, male sterilization, and copper intrauterine 
devices. 
For women of childbearing potential, hormonal contraceptive methods are not 
allowed in this study. 
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 postovulation methods) 
and withdrawal are not adequate methods of contraception.  LHRH agonists are 
not adequate contraception.  If required per local guidelines or regulations, locally 
recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
For men:  agreement to take precautions as outlined below for each treatment arm: 

 
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– 
If assigned to the control arm (physician's choice of endocrine monotherapy), 
agreement to comply with local prescribing guidelines regarding contraception for the 
chosen endocrine monotherapy 
– 
If assigned to the GDC-9545 arm:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods, and agreement to refrain from 
donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant, men must 
remain abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of 1% per year during the treatment period and 
for 10 days after the final dose of GDC-9545 or for the time period according to 
local prescribing guidelines.  Men must refrain from donating sperm during this 
same period. 
With a pregnant female partner, men must remain abstinent or use a condom 
during the treatment period and for 10 days after the final dose of GDC-9545 or 
for the time period according to local prescribing guidelines 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 postovulation methods) 
and withdrawal are not adequate methods of contraception.  If required per local 
guidelines or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
For female partners of male patients, hormonal contraceptive methods 
supplemented by a barrier method are permitted. 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Willing and able to use an electronic device for PRO data collection 
 
For patients enrolled in an extended China enrollment phase:  current resident of mainland 
China, or Taiwan, and of Chinese ancestry 
 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Prior treatment with a SERD, with the exception of fulvestrant, if fulvestrant treatment was 
terminated at least 28 days prior to randomization  
 
Treatment with any investigational therapy within 28 days prior to randomization  
 
Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days 
prior to randomization 
Patient must have recovered from any resulting acute toxicity (to Grade 1 or better) 
prior to randomization. 
Anticipation of need for a major surgical procedure during the course of the study is 
exclusionary. 
 
History of any other malignancy other than breast cancer within 5 years prior to screening, 
except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, or Stage I endometrial cancer 
For participants with a history of other non-breast cancers within 5 years from the date of 
randomization and considered of very low risk of recurrence per investigator’s judgment 
(e.g., papillary thyroid cancer treated with surgery), eligibility is to be discussed with the 
Sponsor. 
 
Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in 
the short term (including massive uncontrolled effusions [pleural, pericardial, peritoneal] or 
pulmonary lymphangitis) 

 
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 
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or 
leptomeningeal disease 
 
Patients with a history of CNS metastases or cord compression are eligible if 
have been definitively treated with local therapy (e.g., radiotherapy, surgery), are 
clinically stable, and have not been treated with anticonvulsants or corticosteroids 
within 2 weeks prior to randomization. 
 
Active cardiac disease or history of cardiac dysfunction, including any of the following: 
– 
History (within 2 years of screening) or presence of idiopathic symptomatic bradycardia 
or resting heart rate  50 bpm at screening 
Patients on stable dose of a -blocker or calcium channel antagonist for 
preexisting baseline conditions (e.g., hypertension) may be eligible if resting heart 
rate is at least 50 bpm. 
– 
History of angina pectoris or symptomatic coronary heart disease within 12 months 
prior to study entry 
– 
History of documented congestive heart failure (New York Heart Association 
Class IIIV) or cardiomyopathy 
– 
QT interval corrected through use of Fridericia's formula  470 ms, for women,  450 
ms for men, history of long or short QT syndrome, Brugada syndrome or known history 
of corrected QT interval prolongation, or torsades de pointes  
– 
Presence of an abnormal ECG that is clinically significant in the investigator's opinion, 
including complete left bundle branch block, second- or third-degree heart block, sick 
sinus syndrome. 
o 
Participants with first-degree heart block may be considered for inclusion 
following consultation with a cardiologist and determination that no additional 
cardiac risks are present. 
o 
Patients with history of well-controlled atrial fibrillation are eligible. 
– 
History (within 12 months) or presence of ventricular dysrhythmias or risk factors for 
ventricular dysrhythmias such as significant structural heart disease (e.g., severe left 
ventricular systolic dysfunction, restrictive cardiomyopathy, hypertrophic 
cardiomyopathy, infiltrative cardiomyopathy, moderate to severe valve disease) or 
family history of long QT syndrome 
 Clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia) should be corrected prior to enrollment. 
 
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, 
including active viral or other hepatitis virus (e.g., hepatitis B or hepatitis C), current alcohol 
abuse, or cirrhosis 
Active viral infection is clinically defined as requiring treatment with antiviral therapy or the 
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.  Patients are not required to 
have HBV, or HCV assessments at screening if these assessments have not been 
previously performed. 
Patients that have tested positive for anti-HBc would be eligible if tests for HBsAg and 
polymerase chain reaction (PCR) are HBV DNA are negative. 
Patients who have been cured of their HCV infection (must have an undetectable viral load 
i.e., a sustained virologic response for 3 months after completing treatment) are eligible to 
enroll.  Patients that have tested positive for the HCV antibody would be eligible if tests for 
HCV RNA are negative.  If the patient is a carrier of HCV and tests positive for HCV RNA, 
they would not be considered eligible. 
For patients who have been successfully treated for viral hepatitis, the possibility of 
re-activation of the virus or reinfection with viral hepatitis should be considered by the 
Investigator and the overall potential benefits associated with study treatment for the patient 
should be deemed to exceed the overall risks. 

 
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 
Known HIV infection 
 
Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper 
gastrointestinal surgery, including gastric resection, potentially affecting enteral absorption  
 
Serious infection requiring oral or IV antibiotics, or other clinically significant infection, within 
14 days prior to randomization.  Patients who fully recovered from serious and clinically 
significant infections within 14 days prior to randomization are eligible. 
 
Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator's judgment, precludes the patient's safe participation in and completion of the 
study 
 
Known allergy or hypersensitivity to any of the study drugs or any of their excipients  
 
For premenopausal/perimenopausal patients or male patients:  known hypersensitivity to 
LHRH agonists 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within 
10 days after the final dose of GDC-9545, or within the time period specified per local 
prescribing guidelines after the final dose of physician's choice of endocrine monotherapy 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study treatment. 
 
END OF STUDY 
The end of this study (global phase and potential China extension phase combined) is defined 
as the date when the last patient, last visit occurs or the date at which the last data point 
required for statistical analysis or overall survival follow-up is received from the last patient, 
whichever occurs later.  The end of the study is expected to occur at least 25 months after the 
last patient is enrolled in the global study.  In addition, the Sponsor may decide to terminate the 
study at any time. 
 
LENGTH OF STUDY 
The total length of the global phase of the study, from screening of the first patient to the end of 
the study, is expected to be approximately 40 months.  In the event enrollment is initiated in a 
China extension phase, timelines will be extended as applicable 
 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal products (IMPs) for this study are GDC-9545 and physician's 
choice of endocrine monotherapy. 
Patients will receive open-label study drug as follows, beginning on Day 1 of Cycle 1: 
 
Patients in the experimental arm will receive GDC-9545 30 mg taken orally once a day on 
Days 128 of each 28-day cycle. 
 
Patients in the control arm will receive physician's choice of endocrine monotherapy in 
accordance with local prescribing guidelines. 
 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
The non-IMPs for this study are LHRH agonists.  
 
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary efficacy objective for this study is to evaluate the efficacy of GDC-9545 compared 
with physician's choice of endocrine monotherapy on the basis of investigator-assessed PFS.  
The analysis population for the efficacy analyses will consist of all randomized patients, with 
patients grouped according to their assigned treatment.  The primary analysis of PFS will be 
conducted when approximately 166 PFS events from both arms are observed. 
 

 
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DETERMINATION OF SAMPLE SIZE   
Approximately 300 patients will be enrolled and randomized in a 1:1 ratio to receive either 
GDC-9545 (experimental arm) or physician's choice of endocrine monotherapy (control arm).  
The sample size is determined by the primary endpoint, investigator-assessed PFS, comparing 
the two treatment arms. 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AI 
aromatase inhibitor 
ALT 
alanine aminotransferase 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
BPI-SF 
Brief Pain InventoryShort Form 
CCCA 
CBR 
complete cell cycle arrest 
clinical benefit rate 
CCOD 
clinical cutoff date 
CDK4/6 
cyclin-dependent kinase 4/6 
CR 
complete response 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DDI 
drug-drug interaction 
DOR 
duration of response 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of 
Cancer 
ER 
estrogen receptor 
ESO-ESMO 
European School of OncologyEuropean Society for 
Medical Oncology 
FACT-G 
Functional Assessment of Cancer TherapyGeneral  
FDA 
Food and Drug Administration 
FES 
16 -fluoroestradiol 
FFPE 
formalin-fixed, paraffin-embedded 
FSH 
follicle-stimulating hormone 
GHS 
global health status 
GI 
gastrointestinal 
GP5 
General Population, Question 5 
HR 
hormone receptor 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IHC 
immunohistochemistry 

 
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Abbreviation 
Definition 
IM 
intramuscular 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
intent-to-treat (population) 
IxRS 
interactive voice or web-based response system 
LBD 
ligand-binding domain 
LHRH 
luteinizing hormonereleasing hormone 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
next-generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PCET 
physician’s choice of endocrine therapy 
PD 
pharmacodynamic 
PET  
positron emission tomography  
PF 
Physical Functioning (scale) 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
by mouth; orally 
PR 
partial response 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes Common Terminology Criteria 
for Adverse Events 
QD 
once a day 
QoL 
quality of life 
QTcF 
QT interval corrected through use of Fridericia's formula 
RBR 
Research Biosample Repository 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RF 
Role Functioning (scale) 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SD 
stable disease 

 
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Abbreviation 
Definition 
SERD 
selective estrogen receptor degrader 
TTD 
time to deterioration 
ULN 
upper limit of normal 
VAS 
visual analogue scale 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON ESTROGEN RECEPTORPOSITIVE, 
HER2-NEGATIVE BREAST CANCER 
Breast cancer is the most commonly diagnosed cancer in women, with an 
estimated global incidence of 2,088,849 new cases and 626,679 deaths reported 
in 2018 (Bray et al. 2018; IARC 2018).  Breast cancer in men is rare; in 2019, 
less than 1% of new breast cancer diagnoses in the United States occurred in 
men (American Cancer Society 2019).  Hormone receptor (HR)-positive, HER2-
negative breast cancer accounts for 60%70% of all breast cancers.   
The role of estrogen in breast cancer etiology and disease progression is well 
established (Colditz et al. 1995).  Modulation of estrogen activity and/or synthesis 
is the mainstay of therapeutic approaches in patients with estrogen receptor 
(ER)positive breast cancer.  
Standard-of-care treatment options for patients with ER-positive, HER2-negative 
locally advanced or metastatic disease include endocrine therapy, endocrine and 
targeted therapy combinations, or chemotherapy.  Chemotherapy is indicated in 
patients with symptomatic visceral disease or in patients with disease 
progression after multiple consecutive endocrine therapy regimens.  Additionally, 
guidelines generally recommend that premenopausal women undergo ovarian 
ablation or suppression and that men be treated using the same approaches as 
women (Cardoso et al. 2018; NCCN 2020).  Current treatments focus on 
prolonging life and improving or maintaining quality of life. 
Despite the effectiveness of available therapies such as ER antagonists 
(e.g., tamoxifen), aromatase inhibitors (AIs; e.g., anastrozole, letrozole, 
and exemestane), selective ER degraders (SERDs; e.g., fulvestrant), cyclin-
dependent kinase 4/6 (CDK4/6) inhibitors (e.g., abemaciclib, palbociclib, 
ribociclib), and other targeted agents such as PI3K inhibitors (e.g., alpelisib), 
many patients ultimately relapse or develop resistance to these agents and 
therefore require further treatment for optimal disease control.  However, growth 
and survival of the majority of tumors are thought to remain dependent on ER 
signaling, despite becoming refractory to AIs or tamoxifen; therefore, patients 
with ER-positive breast cancer can still respond to second- or third-line endocrine 
treatment after progression on prior therapy (Di Leo et al. 2010; 
Baselga et al. 2012).  Importantly, there is growing evidence that in the 
endocrine-resistant state, the ER can signal in a ligand-independent manner 
(Miller et al. 2010; Van Tine et al. 2011).  An agent capable of targeting both 
ligand-dependent and ligand-independent ER signaling has the potential to 
improve treatment outcomes in patients with ER-positive breast cancer. 

 
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ESR1 mutations appear to be a major mechanism of acquired resistance to AIs 
and are associated with poorer outcomes (Schiavon et al. 2015; Chandarlapaty 
et al. 2016; Fribbens et al. 2016).  The prevalence of ESR1 mutation ranges from 
25%40% after AI exposure but only in 2%3% of endocrine therapy-naive 
patients (Chandarlapaty et al. 2016), illustrating that ESR1 becomes an important 
oncogenic driver under AI-selection pressure.  Studies have identified mutations 
in ESR1 that encode ER (primarily Y537S and D538G) affecting the 
ligand-binding domain (LBD) of the ER (Segal and Dowsett 2014).  The Y537S 
and D538G mutations have been most commonly detected in metastatic breast 
cancer clinical samples and are hypothesized to contribute to the resistance to AI 
therapy (Li et al. 2013; Merenbakh-Lamin et al. 2013; Robinson et al. 2013; 
Toy et al. 2013; Alluri et al. 2014; Jeselsohn et al. 2015; Niu et al. 2015; 
Schiavon et al. 2015; Chu et al. 2016).  In nonclinical models, mutant receptors 
are able to drive ER-dependent transcription and proliferation in the absence of 
estrogen, suggesting that LBD-mutant forms of ER are involved in mediating 
clinical resistance to endocrine therapy (Li et al. 2013; Robinson et al. 2013; 
Toy et al. 2013; Segal and Dowsett 2014).  ER antagonists that are efficacious 
against these ligand-independent, constitutively active ERmutated receptors 
may be of substantial therapeutic benefit.  
Notably, circulating free DNA analysis of the SoFEA clinical trial (NCT00253422) 
showed that postmenopausal patients harboring ESR1 mutations have an 
improved progression-free survival (PFS) when treated with fulvestrant as 
compared with exemestane after disease progression following nonsteroidal AI 
therapy (hazard ratio  0.52; p  0.02) (Fribbens et al. 2016).  
SERDs have the potential to block endocrine-dependent and endocrine-
independent ER signaling and have been recognized to offer a therapeutic 
approach to ER‑positive metastatic breast cancer.  Fulvestrant, a first-generation 
SERD, binds, blocks, and degrades the ER, leading to inhibition of estrogen 
signaling through the ER.  Fulvestrant has also shown benefit over anastrozole in 
frontline patients, as demonstrated in the FALCON study (NCT01602380), a 
Phase III, randomized, double-blind trial that treated de novo patients with HR-
positive, locally advanced or metastatic breast cancer with either fulvestrant or 
anastrozole (Robertson et al. 2016).  Fulvestrant was associated with a 
statistically significant improvement in PFS compared with anastrozole (hazard 
ratio  0.797; 95% CI: 0.637 to 0.999; p  0.0486).  Median PFS was 16.6 months 
(95% CI: 13.83 to 20.99 months) with fulvestrant and 13.8 months (95% CI: 
11.99 to 16.59 months) with anastrozole. 
Although demonstrating clinical benefit, fulvestrant has unfavorable 
pharmacokinetic (PK) properties, requiring intramuscular (IM) injection.  New 
agents with superior bioavailability, pharmacokinetics, and more potent activity 
against the ER (including ESR1 mutations) are warranted. 

 
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Notwithstanding the multiple advances in improving the clinical benefit of 
endocrine therapy, there is a need for new ER-targeting therapies with increased 
anti-tumor activity to further delay disease progression and/or overcome 
resistance to the currently available endocrine therapies and ultimately prolong 
survival in patients with ER-positive, HER2-negative breast cancer.  
1.2 
BACKGROUND ON GDC-9545  
GDC-9545 is a potent, orally bioavailable, small molecule therapeutic agent that 
is being developed for the treatment of patients with ER-positive breast cancer.  
GDC-9545 antagonizes the effects of estrogens via competitive binding to the 
LBD of both wild-type and mutant ER, with nanomolar potency.  Upon binding, 
GDC-9545 induces an inactive conformation to the ER LBD, as measured by 
displacement of co-activator peptides.  In addition to its direct antagonist 
properties, the mechanism of action of GDC-9545 includes reducing levels of 
ER protein through proteasome-mediated degradation.  GDC-9545 enables full 
suppression of ER signaling, which is not achieved by first-generation ER 
therapeutics such as tamoxifen that display partial agonism.  GDC-9545 potently 
inhibits the proliferation of multiple ER-positive breast cancer cell lines in vitro, 
including cells engineered to express clinically relevant mutations in ER.  
1.2.1 
Nonclinical Data 
Nonclinical studies comparing drug exposure and in vitro potency of GDC-9545 
versus fulvestrant demonstrated that human steady-state total drug exposure of 
GDC-9545 at 30 mg once a day (QD) is approximately 10-fold higher than the 
steady-state exposure of fulvestrant 500 mg IM monthly.  Furthermore, the lower 
plasma protein binding of GDC-9545 provides higher free concentration of GDC-
9545 than fulvestrant.  In in vitro cell and biochemical assays, GDC-9545 
exhibited up to 10-times higher potency than fulvestrant both in wild-type and 
ESR1mutant contexts. 
In vivo, GDC-9545 exhibited dose-dependent anti-tumor activity in xenograft 
models of ER-positive breast cancer, including in a patient-derived xenograft 
model that harbors an activating ESR1 mutation (ER.Y537S).  The efficacious 
dose range was 0.110 mg/kg/day, and all doses were well tolerated.  On the 
basis of in vivo xenograft models, maximal activity of GDC-9545 occurs at human 
dose equivalents greater than 10 mg.  In three patient-derived xenograft models, 
increasing ER depletion and inhibition of ER transcriptional activity was observed 
with the increase of doses up to 20 mg/kg, corresponding to clinical exposures of 
30 mg.  No further depletion or inhibition was observed from further increasing 
the dose up to 80 mg/kg (corresponding to a 100-mg clinical dose).  Fulvestrant, 
when dosed according to a clinically relevant dosing scheme, was less 
efficacious than GDC-9545 in the assessed xenograft models.  Taken together, 

 
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GDC-9545 data demonstrated robust nonclinical activity in ER-positive breast 
cancer models of both ESR1wild type and ESR1-mutationbearing disease. 
Refer to the GDC-9545 Investigator's Brochure for details on toxicology and 
safety pharmacology studies. 
1.2.2 
Clinical Data 
Giredestrant is being assessed in three metastatic breast cancer studies 
(GO39932, WO42312 and BO41843), in two neoadjuvant studies (GO40987 and 
WO42133) and in one adjuvant study (GO42784). 
Overall, the identified risks of giredestrant include gastrointestinal toxicity 
(nausea, vomiting, diarrhea), arthralgia, musculoskeletal pain, dizziness, 
bradycardia, hepatotoxicity, headache, hot flushes, and fatigue.  The potential 
risks of giredestrant include venous thromboembolism, renal dysfunction, 
menopausal symptoms, infertility and embryofetal toxicity. 
Refer to IB v6 for information on clinical studies, on identified and potential 
risks for giredestrant and risk-mitigation measures, including guidelines for 
managing adverse events associated with giredestrant. 
1.2.2.1 
Study GO39932 
Study GO39932 is a first-in-human, Phase Ia/Ib, multicenter, open-label study 
evaluating the safety, pharmacokinetics, and activity of GDC-9545 as a single 
agent or in combination with palbociclib (with or without [] luteinizing 
hormonereleasing hormone [LHRH] agonist) in patients with ER-positive 
(HER2-negative) locally advanced or metastatic breast cancer. 
As of the clinical cutoff date (CCOD) of 17 September 2021, 175 patients in 
Study GO39932 had received treatment as follows:  111 patients had been 
treated with single-agent GDC-9545 at doses of 10 mg, 30 mg, 90/100 mg, and 
250 mg ( LHRH agonist), and 64 patients had been treated with GDC-9545 
100 mg in combination with palbociclib 125 mg ( LHRH agonist) (given Days 
121 with 7 days off).   
At the CCOD, 47 patients (26.9%) were ongoing in the study (19 patients 
[17.1%] in the single-agent cohorts and 28 patients [43.8%] in the combination 
cohort with palbociclib [ LHRH agonist]). 
 
As of the CCOD, of the 111 patients treated with single-agent GDC-9545, the 
majority of patients enrolled had visceral (65%) and measurable disease (73%) 
at baseline, and a small proportion (19.5%) had bone-only disease at baseline.  
Baseline ESR1 mutation status of wild type or mutant was reported in 50% and 
47% of patients, respectively.  The remaining patients (3%) had unknown ESR1 

 
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mutation status.  Twenty-three patients (21%) received prior therapy with 
fulvestrant and 71 patients (64.0%) with a CDK4/6 inhibitor.  
Based on the CCOD, clinical benefit, as measured by either radiographic partial 
response (PR) or at least 6 months of stable disease (SD), was observed at all 
four single-agent GDC-9545 doses tested.  Clinical benefit was reported in 
106/175 patients (60.6%) overall and in 54/111 patients (48.6%) in the single-
agent cohorts (doses ranging from 10-250 mg giredestrant [  LHRH agonist]).  
In the 30 mg single-agent cohort, a clinical benefit was reported in 22/41 
patients (53.7%). 
Furthermore, pharmacodynamic (PD) modulation of specified markers ER, 
progesterone receptor, and Ki67 could not be differentiated by dose as on-
treatment changes were similarly observed. 
In the safety-evaluable population, giredestrant was well tolerated and the 
observed safety profile of the combination of giredestrant and palbociclib was 
consistent with the known safety profile of the individual drugs.  No patients 
experienced dose-limiting toxicities and the MTD was not reached. 
 
1.2.2.2 
Study WO42312 
Study WO42312 (acelERA Breast Cancer) is a Phase II, randomized, open-label 
multicenter study evaluating the efficacy and safety of giredestrant compared 
with 
physician's choice of endocrine monotherapy (PCET [fulvestrant or an aromatase 
inhibitor]) in patients with ER-positive , HER2-negative mBC who have received 
one or two prior lines of systemic therapy in the locally advanced or metastatic 
setting.  
As of the CCOD (18 February 2022) for the primary analysis, of the 303 patients 
enrolled, 15.2% patients had discontinued from the study and the majority of 
those remaining had discontinued treatment; median duration of follow-up was 
7.89 months. 
Study WO42312 did not meet its primary endpoint of investigator-assessed PFS. 
Giredestrant showed a numerical improvement relative to physician’s choice of 
endocrine therapy (PCET) in terms of PFS hazard ratio of 0.81 (95% CI: 0.60 to 
1.10), which was not statistically significant (p   0.1757).  Median PFS was 
similar between both arms: 5.55 months (95% CI: 4.93 to 7.36) with giredestrant 
and 5.36 months (95% CI%: 3.71 to 5.55) with PCET and PFS benefit was more 
pronounced in the subset of patients with baseline ESR1 mutations (hazard ratio: 
0.60 [95% CI: 0.35 to 1.03]). The OS data were still immature (   10% events).  
Numerical increases in other secondary endpoints were observed with 
giredestrant, for both CBR (31.8% vs. 21.1%) and ORR (12.6% vs. 7.2%). 
 

 
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Giredestrant treatment was well tolerated and considered to have comparable 
safety to PCET. Overall, 84.7% of giredestrant patients experienced at least one 
adverse event compared to 71.1% in patients treated with PCET.  AEs leading to 
dose modification or interruption occurred in 13.3% of giredestrant patients and 
8.6% of PCET patients. Few events led to treatment withdrawal, with 2 (1.3%) 
in the giredestrant arm and 3 (2%) in the PCET arm. 
 
1.2.2.3 
Study BO41843 
Study BO41843 (persevERA) is a Phase III randomized, double-blind 
placebo-controlled, multicenter study evaluating the efficacy and safety of 
giredestrant combined with palbociclib compared with letrozole combined with 
palbociclib in patients with ER-positive, HER2-negative locally advanced 
(recurrent or progressed) or mBC.   
 
Approximately 978 patients are expected to be enrolled in the study.  Enrollment 
of Study BO41843 is ongoing and no efficacy data is available at this point. 
Preliminary safety data for the study is provided in the IB v6 only for overall 
patients and in an aggregate format and not by study treatment arm since 
treatment information is not known for this double blinded study. 
 
1.2.2.4 
Study GO40987 
 
Study GO40987 was a Phase I, open-label, multicenter, preoperative study to 
assess relative changes in Ki67 levels and to evaluate the pharmacodynamics, 
pharmacokinetics, safety, and biologic activity of giredestrant in patients with 
Stage I–III operable ER-positive, HER2-negative untreated breast cancer.  All 
patients provided a pre-treatment and post-treatment tumor tissue sample. 
Patients received giredestrant for approximately 14 days at one of three 
treatment cohorts (10, 30, and 100 mg). 
Seventy-five patients enrolled in this study, of which sixty-five were efficacy 
evaluable.  As of 25 May 2021, the study has been completed.  
 
The overall post-treatment geometric mean relative Ki67 reduction with 
giredestrant compared with baseline was 78%.  Complete cell cycle arrest 
(CCCA; Ki67 ≤2.7%) after approximately 2 weeks of treatment with giredestrant 
was achieved in 56.9% of all tumors.  These results were consistent across all 
three dose levels (10 mg, 30 mg, and 100 mg).  
 
Overall, giredestrant was well tolerated at all dose levels: the majority of adverse 
events reported were mild (Grade 1) or moderate (Grade 2) in maximum severity 
and there were no Grade   4 adverse events reported in this study.  No serious 
adverse events or Grade   3 adverse events were assessed as related to 
giredestrant by the investigator. 
No deaths were reported in the study and no new safety signal were detected. 
 

 
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1.2.2.5 
Study WO42133 
Study WO42133 (coopERA) was a Phase II randomized, open-label, two arm, 
multicenter study evaluating the efficacy, safety, and pharmacokinetics of 
giredestrant versus anastrozole (for 14 days in the window-of opportunity phase) 
and giredestrant plus palbociclib compared with anastrozole plus palbociclib (for 
16 weeks in the neoadjuvant phase) in postmenopausal patients with untreated 
ER-positive and HER2negative early breast cancer. 221 patients were enrolled 
in this study, of which 201 were efficacy evaluable.  
In this study, the primary endpoint of relative changes in Ki67 scores from 
baseline to Week 2 for giredestrant versus anastrozole was met.  Giredestrant 30 
mg showed a statistically superior reduction of Ki67 over anastrozole.  The 
geometric mean of Ki67 reduction after 2 weeks of treatment with giredestrant 
was 75% (95% confidence interval [CI]: 80% to 70%) and 67% (95% CI: 
73% to 59%) with anastrozole (p 0.043).  A greater rate of CCCA was 
achieved in patients treated with giredestrant (20%) compared with patients 
treated with anastrozole (13%), demonstrating superior antiproliferative activity 
of giredestrant over anastrozole.  
Giredestrant was well tolerated both as a single agent and in combination with 
palbociclib. 
 
1.2.2.6 
Study GO42784 
Study GO42784 (lidERA) is a Phase III, global, randomized, open-label, 
multicenter study evaluating the safety of giredestrant compared with endocrine 
therapy of physician’s choice in participants ERpositive and HER2negative 
early breast cancer.   
Enrollment of Study GO42784 is ongoing and no efficacy data is available at this 
point.  Preliminary safety data for the study is internally blinded and therefore, 
is provided only for overall patients and in an aggregate format and not by study 
treatment arm. 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
Despite treatment advances in ER-positive, HER2-negative breast cancer, it 
remains a disease with significant unmet need, particularly after disease 
progression with first-line therapy.  HR-positive tumors represent the most 
common form of breast cancer, yet despite adjuvant endocrine therapy, a 
significant proportion of patients (approximately 30%) remain at risk of relapse.  
With the development of metastatic disease and subsequent treatment with 
endocrine therapies, most patients develop resistance to endocrine therapy, and 
the majority of all breast cancer deaths are due to ER-positive disease.   

 
GDC-9545—F. Hoffmann-La Roche Ltd 
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GDC-9545 is a potent, orally bioavailable ERα antagonist and inducer of ERα 
degradation that competes with estrogens for binding to the ER, with low 
nanomolar potency; it is being developed for the treatment of patients with ER-
positive breast cancer.  GDC-9545 has demonstrated robust nonclinical activity 
in ER-positive breast cancer models of ESR1wild type and ESR1mutation 
bearing disease.  Furthermore, fulvestrant, an approved SERD molecule, when 
dosed according to a clinically relevant dosing scheme, was less efficacious than 
GDC-9545 in the assessed xenograft models (see Section 3.3.1).  As described 
in Section 1.2, GDC-9545 was tolerated in safety pharmacology studies.  
The proposed Phase II Study WO42312 is designed to demonstrate a statistically 
significant and clinically meaningful PFS benefit of GDC-9545 compared with 
physician's choice of endocrine monotherapy (fulvestrant or an AI) for patients 
with previously treated ER-positive, HER2-negative locally advanced or 
metastatic breast cancer.  
The present study has incorporated key design elements that are critical to an 
adequate assessment of benefit versus risk for GDC-9545 in a single Phase II 
pivotal study.  These elements include use of a randomized, multicenter, 
international study with a primary endpoint of investigator-assessed PFS, 
supported by key secondary endpoints and adequate power and type I error 
control to allow the demonstration of robust and clinically meaningful 
improvement in the primary endpoint.  The eligibility criteria are designed to 
minimize potential risks associated with GDC-9545 (see Sections 4.1.1 
and 4.1.2).  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  Safety 
monitoring and risk mitigation strategies, including detailed management 
guidelines for treatment-related symptoms or potential risks, are described in 
Section 5.1.  The potential safety issues associated with administration of GDC-
9545 therapy are expected to be clinically monitorable and manageable. 
An Internal Monitoring Committee (IMC) will review cumulative safety data 
throughout the study as outlined in a separate charter (see further details in 
Section 3.1.3). 
In the setting of the COVID-19 pandemic, patients with comorbidities including 
those with HR-positive metastatic breast cancer are a more vulnerable 
population.  In some retrospective analysis, infection with severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with 
higher morbidity and mortality in patients with cancer. 
Based on the mechanism of action and the observed clinical safety profile, it is 
not anticipated that treatment with GDC-9545 will compromise the immune 
system nor increase the likelihood or the severity of infection with SARS-CoV-2.  

 
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There is an increased risk of exposure to SARS-CoV-2 associated with hospital 
visits.  This risk can be minimized by complying with local guidelines and hospital 
policies.  Metastatic cancer is a life-threatening disease, and treatment with 
GDC-9545 is expected to provide a clinically meaningful improvement in PFS; 
therefore, the anticipated benefitrisk of this study remains positive in the setting 
of the COVID-19 pandemic. 
Given that the study drug, GDC-9545, is not expected to increase the risk or 
severity of COVID-19, no specific SARS-CoV-2 safety management guidelines 
are deemed necessary, and patients should be treated as per institutional 
standards of care with decisions for interruptions of study drugs taken by the 
sites based on the severity of the infection.  Please also refer to the guidelines 
provided for GDC-9545 for the management of non-hematological toxicity in 
Section 5.1.3.3 and the local labels for other study drugs.  Patients with serious 
infection within 14 days prior to randomization are excluded; however, no testing 
for SARS-CoV-2 is required.  Investigational sites will be specifically trained in 
the reporting of any occurrences of COVID-19, and the safety of patients will 
continue to be monitored regularly by both the Sponsor and IMC.  
At this time, there is insufficient experience with SARS-CoV-2 vaccines to 
support concrete recommendations concerning the use of SARS-CoV-2 vaccines 
in patients receiving GDC-9545 or other endocrine therapies for breast cancer.  
SARS-CoV-2 vaccines must be given in accordance with the 
approved/authorized vaccine label and official immunization guidance.  The 
decision of administration of a SARS-CoV-2 vaccine should be individualized 
based on a patient’s SARS-CoV-2 infection/complication risk, the general 
condition of the patient as well as the epidemiology of COVID-19 in the patient’s 
given area or region. 
Based on the data available to date regarding adverse reactions reported in 
patients receiving SARS-CoV-2 vaccines, the risk of serious or severe 
overlapping toxicities is low.  Based on the mechanism of action and current 
knowledge, it seems unlikely that GDC-9545 might have an impact on SARS-
CoV-2 vaccine efficacy or that mRNA (e.g., Pfizer/ BioNTech BNT162b2, 
Moderna), inactivated (e.g., Sinopharm, Sinovac, Bharat) replication deficient 
viral vector (e.g., AstraZeneca/Oxford, Johnson and Johnson, Gamaleya) or 
protein subunit vaccines (e.g., Anhui Zhifei Longcom, FBRI SRC VB Vector) 
could impact the safety or efficacy of GDC-9545. 
Please check the specific label of any vaccine to ensure compatibility prior to 
use.  

 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of GDC-9545 compared with 
physician's choice of endocrine monotherapy (as defined below) in patients with 
previously treated ER-positive, HER2-negative locally advanced or metastatic 
breast cancer who have received one or two prior lines of systemic therapy in the 
locally advanced or metastatic setting.  Specific objectives and corresponding 
endpoints for the study are outlined below.  
In this protocol, "study drug" refers to test product or the comparator assigned to 
patients (i.e., GDC-9545 or physician's choice of endocrine monotherapy).  
Endocrine monotherapy is defined as either fulvestrant or an AI.  In addition, 
premenopausal/perimenopausal patients and male patients will receive an LHRH 
agonist (e.g., goserelin, leuprolide acetate, or triptorelin). 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of GDC-
9545 compared with physician's choice of endocrine monotherapy on the basis of 
the following endpoint: 
 
PFS, defined as the time from randomization to the first occurrence of 
disease progression or death from any cause (whichever occurs first), as 
determined by the investigator according to RECIST v1.1 
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective for this study is to evaluate the efficacy of GDC-
9545 compared with physician's choice of endocrine monotherapy on the basis of 
the following endpoints: 
 
Overall survival (OS), defined as the time from randomization to death from 
any cause 
 
ORR, defined as the proportion of patients with a complete response (CR) or 
PR on two consecutive occasions  4 weeks apart, as determined by the 
investigator according to RECIST v1.1 
 
Duration of response (DOR), defined as the time from the first occurrence of 
a documented objective response to disease progression or death from any 
cause (whichever occurs first), as determined by the investigator according 
to RECIST v1.1 
 
CBR, defined as the proportion of patients with stable disease for  24 weeks 
or a CR or PR, as determined by the investigator according to RECIST v1.1 
 
Investigator-assessed PFS, in subgroups categorized by baseline ESR1 
mutation status 

 
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 
Time to deterioration (TTD) in pain severity after randomization, defined as 
the time from randomization to the first documentation of a  2-point increase 
from baseline on the "worst pain" item score from the Brief Pain 
InventoryShort Form (BPI-SF)  
 
TTD in pain presence and interference after randomization, defined as the 
time from randomization to the first documentation of a  10-point increase 
from baseline in the European Organisation for Research and Treatment of 
Cancer (EORTC) QLQ-C30 linearly transformed pain scale score 
 
TTD in Physical Functioning (PF) after randomization, defined as the time 
from randomization to the first documentation of a  10-point decrease from 
baseline in the EORTC QLQ-C30 linearly transformed PF scale score 
 
TTD in Role Functioning (RF) after randomization, defined as the time from 
randomization to the first documentation of a  10-point decrease from 
baseline in the EORTC QLQ-C30 linearly transformed RF scale score 
 
TTD in global health status (GHS) and quality of life (QoL) after 
randomization, defined as the time from randomization to the first 
documentation of a  10-point decrease from baseline in the EORTC QLQ-
C30 linearly transformed GHS/QoL scale score 
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of 
GDC-9545 compared with physician's choice of endocrine monotherapy on the 
basis of the following endpoints: 
 
Mean scores and mean change from baseline in functional scores (physical, 
role, cognitive, emotional, and social), GHS/QoL, and disease- and 
treatment-related symptom scores, as assessed through use of the QLQ-C30 
and QLQ-BR23 scales at specified timepoints  
 
Patient interviews will also explore patients’ experience of study drug, therapeutic 
context, and disease journey among a subset of patients treated with GDC-9545. 
2.2 
SAFETY OBJECTIVES 
The safety objective for this study is to evaluate the safety of GDC-9545 
compared with physician's choice of endocrine monotherapy on the basis of the 
following endpoints: 
 
Incidence and severity of adverse events, with severity determined according 
to National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE), Version 5.0  
 
Change from baseline in targeted vital signs 
 
Change from baseline in targeted clinical laboratory test results 
 

 
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The exploratory safety objective for this study is to evaluate the tolerability of 
GDC-9545 compared with physician's choice of endocrine monotherapy on the 
basis of the following endpoints: 
 
Presence, frequency of occurrence, severity, and/or degree of interference 
with daily function of selected symptomatic treatment toxicities, as assessed 
through use of the NCI Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events (PRO-CTCAE)  
 
Overall tolerability (i.e., bother experienced due to side effects of treatment), 
as assessed through the General Population, Question 5 (GP5) item from the 
Functional Assessment of Cancer TherapyGeneral (FACT-G) questionnaire 
 
Change from baseline in symptomatic treatment toxicities and overall 
tolerability/side-effect burden, as assessed through use of the PRO-CTCAE 
and the GP5 item, respectively 
 
2.3 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is to characterize the GDC-9545 PK profile ( 
LHRH agonist) on the basis of the following endpoint: 
 
Plasma concentration of GDC-9545 at specified timepoints 
 
2.4 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to GDC-9545 (i.e., predictive 
biomarkers), are early surrogates of efficacy, are associated with progression to 
a more severe disease state (i.e., prognostic biomarkers), are associated with 
acquired resistance to GDC-9545, are associated with susceptibility to 
developing adverse events or can lead to improved adverse event monitoring or 
investigation (i.e., safety biomarkers), can provide evidence of GDC-9545 activity 
(i.e., PD biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following endpoint: 
 
Relationship between biomarkers in blood, plasma, and tumor tissue (listed 
in Section 4.5.7) and efficacy, safety, PK, disease biology, or other biomarker 
endpoints 
 
2.5 
HEALTH STATUS UTILITY OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health 
status utility scores of patients treated with GDC-9545 compared with physician's 
choice of endocrine monotherapy on the basis of the following endpoint: 
 
Health utility and visual analog scale (VAS) score of the EQ-5D-5L for 
pharmacoeconomic modeling at specified timepoints 
 

 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of the Study 
This Phase II, randomized, open-label, multicenter study will evaluate the 
efficacy and safety of GDC-9545 compared with physician’s choice of endocrine 
monotherapy (as defined in Section 2) in patients with ER-positive, HER2-
negative locally advanced or metastatic breast cancer who have received one or 
two prior lines of systemic therapy in the locally advanced or metastatic setting. 
One of the prior lines of systemic therapy must have included endocrine therapy, 
which must have been administered continuously for a minimum of 6 months in 
the locally advanced or metastatic setting prior to disease progression.  Patients 
who received prior treatment with a SERD will be excluded from this study.  
An exception will be made for prior treatment with fulvestrant, if fulvestrant 
treatment was terminated at least 28 days prior to randomization.  Patients who 
do not meet the criteria for participation in this study (screen failure) may qualify 
for one re-screening opportunity (for a total of two screenings per participant) at 
the investigator's discretion.  Patients must re-sign the consent form prior to 
re-screening.  The investigator will record reasons for screen failure in the 
screening log (see Section 4.5.1).  
This study will initially enroll approximately 300 patients across all sites in a 
global enrollment phase.  After completion of the global enrollment phase, 
additional patients may be enrolled in an extended China enrollment phase at 
sites in mainland China and/or Taiwan.  The global population will include all 
patients enrolled during the global enrollment phase (including patients enrolled 
in mainland China, Hong Kong, and/or Taiwan during that phase), and the China 
subpopulation will include all patients enrolled in mainland China and/or Taiwan 
(i.e., during both the global enrollment phase and the extended China enrollment 
phase). 
Eligible patients will have histologically or cytologically confirmed diagnosis of 
adenocarcinoma of the breast with evidence of locally advanced or metastatic 
disease.  Patients must have measurable disease as per RECIST v.1.1 or 
evaluable bone disease.  Adequate archival or fresh tumor tissue availability is 
required for patient participation.  
Eligible patients will be randomly assigned in a 1:1 ratio to either an experimental 
arm to receive GDC-9545 or a control arm to receive physician's choice of 
endocrine monotherapy (as defined in Section 2).  Patients will be stratified by 
site of disease, assessed locally (visceral [any lung and/or liver involvement] vs. 
non-visceral [absence of any lung and/or liver involvement]), prior treatment with 
CDK4/6 inhibitor (yes vs. no); and prior treatment with fulvestrant (yes vs. no).  

 
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The number of premenopausal/perimenopausal patients and male patients 
enrolled will be limited to approximately 20% of the study population.  The cap of 
20% has been chosen to ensure that the mix of patients in this study 
approximates global clinical practice patterns. 
Patients will receive open-label study drug as follows, beginning on Day 1 of 
Cycle 1: 
 
Patients in the experimental arm will receive GDC-9545 30 mg taken orally 
(PO) QD on Days 128 of each 28-day cycle 
 
Patients in the control arm will receive physician's choice of endocrine 
monotherapy in accordance with local prescribing guidelines 
 
In addition, premenopausal/perimenopausal patients and male patients in both 
arms will receive an LHRH agonist.  To minimize the potential of exposure to the 
medication decreasing to sub-therapeutic levels towards the end of the treatment 
cycle, monthly injections of LHRH agonist are preferred and to be synchronized 
with Day 1 of each 28-day cycle (or according to clinical practice for the selected 
agent). 
Crossover between treatment arms will not be permitted in the study. 
Patients who withdraw from the study or who discontinue study treatment will not 
be replaced.  However, patients who withdraw from the study after screening, but 
before randomization, will be replaced. 
Patients may continue to receive study treatment until disease progression or 
unacceptable toxicity, whichever occurs first.  An exception will be made for 
patients who have developed isolated brain metastases that are treatable with 
radiation, provided the patients have experienced a PR, CR, or SD for 
 24 weeks.  These patients will be allowed to continue to receive study treatment 
until systemic progression of disease and/or further progression in the brain.   
Patients will be followed for safety for 30 days after the final dose of study 
treatment, including a treatment discontinuation visit at 30 days after the final 
dose (unless final dose resulted in a dose delay prior to decision to discontinue).  
For the control arm, the upper limit of the visit window will be dependent upon 
maximum dosing delay as permitted per local guidelines.  Thereafter, information 
on survival and new anti-cancer therapy will be collected every 6 months until 
death (unless the patient withdraws consent or the Sponsor terminates the 
study).  The survival follow-up period for patients remaining in the study will 
conclude at the time of the final OS analysis.   
After the date of randomization, tumor assessments will be performed every 
8 weeks for the first 18 months, then every 12 weeks thereafter, with the 

 
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exception of bone scans, which will be performed every 24 weeks or as clinically 
indicated (see Section 4.5.6.2 for detailed information). 
Efficacy analyses will be based on the local radiologist's or investigator's tumor 
assessments.  Radiographic images, photographs, and clinical information will be 
sent to a blinded, independent core imaging laboratory to enable a retrospective 
evaluation of disease response and progression by an Independent Review 
Committee (IRC) (see Section 3.1.2). 
To evaluate the PK properties of GDC-9545, sparse PK samples will be collected 
at various timepoints before and after dosing from all patients in the GDC-9545 
arm; a subset of patients in the GDC-9545 arm will be enrolled for intensive 
GDC-9545 PK sampling (see Appendix 2). 
Patient-reported outcome (PRO) instruments will be completed by patients to 
evaluate the treatment impact from the patient's perspective. 
Optional patient interviews will be performed among a subset (up to 30) of 
patients receiving GDC-9545, to explore patients’ experience of study drug, 
therapeutic context, and disease journey. 
All patients will be closely monitored for adverse events throughout the study, 
and adverse events will be graded according to NCI CTCAE v5.0.  An IMC will 
also provide safety oversight as outlined in Section 3.1.3. 
Figure 1 presents an overview of the study design.  A schedule of activities is 
provided in Appendix 1. 

 
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Figure 1 Study Schema 
 
ER  estrogen receptor; HER2  human epidermal growth factor receptor 2; LHRH  luteinizing 
hormone-releasing hormone; PO  orally; QDonce a day; R  randomization. 
a Premenopausal/perimenopausal patients and male patients in both arms will receive an 
LHRH agonist.  To minimize the potential of exposure to the medication decreasing to 
sub-therapeutic levels towards the end of the treatment cycle, monthly injections of LHRH 
agonist are preferred and to be synchronized with Day 1 of each 28-day cycle (or according to 
clinical practice for the selected agent). 
b An exception will be made for patients who have developed isolated brain metastases that are 
treatable with radiation, provided the patients have experienced a partial response, complete 
response, or stable disease for  24 weeks (see Section 4.4.3). 
  
3.1.2 
Independent Review Committee 
All radiological data (e.g., computed tomography [CT] scan, magnetic resonance 
imaging [MRI], bone scan), photographs of skin lesions, and any additional 
clinical information required will be sent to a blinded, independent, core imaging 
laboratory (contracted by the Sponsor) to facilitate a retrospective evaluation of 
disease response and progression by an IRC.  Details about IRC membership 
and procedures (e.g., tumor assessments) will be outlined in a separate IRC 
Charter. 
3.1.3 
Internal Monitoring Committee 
An IMC will provide additional safety oversight throughout the study.  The IMC 
will include representatives from Clinical Science, Safety Science, and 
Biostatistics.  In addition to the ongoing assessment of the incidence, nature, and 
severity of adverse events, serious adverse events, deaths, and vital sign and 
laboratory abnormalities performed by the Medical Monitor, the IMC will 
periodically review cumulative data during the study.  Specific operational details 
such as the committee's composition, frequency and timing of meetings, and 
members' roles and responsibilities will be detailed in the IMC Charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study (global phase and potential China extension phase 
combined) is defined as the date when the last patient, last visit occurs or the 

 
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date at which the last data point required for statistical analysis or overall survival 
follow-up is received from the last patient, whichever occurs later.  The end of the 
study is expected to occur at least 25 months after the last patient is enrolled in 
the global study.  In addition, the Sponsor may decide to terminate the study at 
any time. 
The total length of the global phase of the study, from screening of the first 
patient to the end of the study, is expected to be approximately 40 months.  In 
the event enrollment is initiated in a China extension phase, timelines will be 
extended as applicable. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for GDC-9545 Dose and Schedule 
This study will evaluate GDC-9545 30 mg PO QD administered on Days 128 of 
each 28-day cycle, beginning on Day 1 of Cycle 1. 
The Phase Ia/Ib study GO39932 evaluated escalating doses of GDC-9545 from 
10 to 250 mg PO QD (see Section 1.2.2).  Overall, GDC-9545 was shown to be 
well-tolerated at all dose levels with no clear trend for an increase in frequency or 
severity of events, except for Grade 1 asymptomatic bradycardia/heart rate 
decrease that was dose-related.  No adverse events of bradycardia were 
reported with doses  90 mg.  No Grade  3 bradycardia adverse events have 
been reported at any dose level up to 250 mg.  Indeed, with the exception of one 
Grade 2 adverse event; all bradycardia adverse events have been Grade 1 in 
maximum intensity, and no dose reductions have been necessary at any dose 
level. 
Nonclinical in vivo xenograft models reveal that the maximal activity is saturated 
at doses above 10 mg human dose equivalents.  Human steady-state total drug 
exposure of GDC-9545 at 30 mg QD is approximately 10-fold higher than the 
steady-state exposure of fulvestrant 500 mg IM monthly, with higher in vitro 
potency.  F-18 16 -fluoroestradiolpositron emission tomography (PET) showed 
 90% suppression of FES uptake to background levels at 10250 mg PO QD, 
regardless of ESR1 mutation status, indicating target saturation across all dose 
levels.  Clinical activity as measured by CBR was approximately 50% at 30 mg 
QD.  No evidence of additional benefit was observed at doses above 30 mg. 
Based on the totality of the available nonclinical and clinical data, GDC-9545 
30 mg PO QD has been selected as the most appropriate Phase II dose and 
schedule to maximize efficacy while ensuring tolerability. 
Please refer to the GDC-9545 Investigator's Brochure for additional information. 

 
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3.3.2 
Rationale for Patient Population 
The target patient population for this study is women and men with ER-positive, 
HER2-negative locally advanced or metastatic breast cancer who have received 
one or two prior lines of systemic therapy in the locally advanced or metastatic 
setting. 
Endocrine therapies are the mainstay of treatment for HR-positive breast cancer, 
but many patients relapse during endocrine therapy, which ultimately limits the 
use of these agents.  However, tumors continue to depend on ER activity for 
growth, and ER remains an important target in the endocrine-resistant setting, 
emphasizing the need for more effective endocrine treatment.  Patients 
previously treated with fulvestrant are eligible for this study, given that GDC-9545 
was more efficacious than fulvestrant in xenograft models of ER-positive breast 
cancer, when dosed according to a clinically relevant dosing scheme.  
Furthermore, as of the CCOD of 31 January 2021 in Study GO39932, clinical 
benefit (confirmed CR, PR, or the first occurrence of PD on or after 24 weeks) 
was observed for 8 of 26 (30.8%) clinical benefit-evaluable patients treated with 
single-agent GDC-9545 at various dose levels after prior treatment with 
fulvestrant. 
Hence, the patient population defined by the eligibility criteria reflects patients for 
whom there is an unmet medical need, as the current standard of care treatment 
options are limited. 
Both postmenopausal and premenopausal/perimenopausal women will be 
included in the study.  Premenopausal/perimenopausal women will receive an 
LHRH agonist for ovarian function suppression.  Male patients will also receive 
an LHRH agonist. 
3.3.3 
Rationale for Control Group 
Patients with HR-positive recurrent or metastatic breast cancer who respond to 
an endocrine treatment should receive additional endocrine therapy at disease 
progression (Cardoso et al. 2018; Thill et al. 2109; NCCN 2020).  After first-line 
endocrine therapy, little high-level evidence exists to assist in selecting the 
optimal sequence of endocrine therapy, but many premenopausal and 
postmenopausal patients with HR-positive breast cancer still benefit from 
sequential use of endocrine therapies at disease progression.  Additional 
endocrine therapies for second-line and subsequent therapies for 
postmenopausal women with ER-positive recurrent or progressed metastatic 
breast cancer typically include nonsteroidal AIs (e.g., anastrozole, letrozole), 
steroidal AIs (e.g., exemestane), ER antagonists (tamoxifen or toremifene), or 
SERDs (e.g., fulvestrant).  In premenopausal women who received a prior 
endocrine therapy, the preferred treatment includes ovarian ablation or 

 
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suppression, followed by endocrine therapy.  The third-generation AIs (i.e., 
anastrozole, letrozole, and exemestane) have shown superiority to tamoxifen in 
the metastatic breast cancer setting as well as in the adjuvant setting. 
Fulvestrant is clinically effective in patients with ER-positive breast cancer, both 
in patients naive to and resistant to endocrine therapy.  In the first-line setting, 
fulvestrant is more efficacious than AIs in patients naive to endocrine therapy, 
both in terms of PFS and OS (FIRST study [NCT00274469]; Ellis et al. 2015) and 
of PFS (FALCON study [NCT01602380]; Robertson et al. 2016).  Fulvestrant has 
been shown to be effective in patients who have disease progression after 
receiving tamoxifen.  Fulvestrant is also effective after previous treatment with 
third-generation AIs.  Hence, fulvestrant is generally reserved for second-line 
patients or those first-line patients recurring during or soon after treatment with 
adjuvant AIs (Robertson et al. 2009; Di Leo et al. 2010).  Recently, several new 
combination therapies with novel agents have become available as second-line 
and subsequent therapies, such as exemestane with everolimus (Baselga et al. 
2012; Yardley et al. 2013) or palbociclib with fulvestrant (Cristofanilli et al. 2016). 
In this study, the experimental arm consists of single-agent GDC-9545, and 
patients in the control group will receive single-agent endocrine therapy per 
physician's choice.  Endocrine monotherapy will be limited to fulvestrant or an AI.  
The choice of endocrine treatment is at the discretion of the investigator and 
should be based on various clinical considerations (e.g., age, tumor burden, 
symptoms, toxicity considerations, as well as appropriateness for targeted 
therapy) and local practice. 
3.3.4 
Rationale for Primary Endpoint of Investigator-Assessed 
Progression-Free Survival 
PFS is regarded as a clinically relevant measure of treatment benefit and, in 
recent years, has been shown to be an approvable endpoint in the setting of HR-
positive, HER2-negative metastatic breast cancer for several drugs.  In the 
PALOMA-3 study of patients with previously treated HR-positive, HER2-negative 
advanced or metastatic breast cancer (NCT01942135), median PFS for 
palbociclib plus fulvestrant versus fulvestrant were 9.5 months (95% CI: 9.2 to 
11.0 months) and 4.6 months (95% CI: 3.5 to 5.6 months), respectively (hazard 
ratio  0.461; 95% CI: 0.360 to 0.591; p  0.0001) (Cristofanilli et al. 2016).   
Data from the Phase III BOLERO-2 study (NCT00863655) of exemestane plus 
everolimus versus exemestane, in postmenopausal women with HR-positive 
advanced breast cancer that had progressed or recurred during treatment with a 
nonsteroidal AI, demonstrated a median PFS of 11.0 versus 4.1 months, 
respectively (hazard ratio  0.38; 95% CI: 0.31 to 0.48; p  0.0001) (Baselga et al. 
2012; Yardley et al. 2013). 

 
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In the Phase III CONFIRM study (NCT00099437), median PFS for fulvestrant 500 
mg versus fulvestrant 250 mg was 7.9 versus 6.3 months, respectively (hazard 
ratio  0.80; 95% CI: 0.70 to 1.10; p 0.068) for HR-positive locally advanced or 
metastatic breast cancer in the second-line setting (patients who relapsed more 
than 12 months after completion of adjuvant therapy, or who had previously 
presented with de novo locally advanced or metastatic breast cancer and were 
required to have a prior line of endocrine therapy [anti-estrogen or AI] for 
advanced disease) (Di Leo et al. 2010; Di Leo et al. 2018).  
Based on the data from these Phase III studies, PFS has been chosen as the 
primary endpoint for this proposed Phase II study, which aims to demonstrate an 
improvement in median PFS for GDC-9545 compared with physician's choice of 
endocrine monotherapy. 
PFS will be determined by the investigator according to RECIST v1.1; a 
retrospective, blinded, independent central evaluation of disease response and 
progression may be conducted by an IRC as outlined in Section 3.1.2. 
3.3.5 
Rationale for Biomarker Assessments 
ER-positive, HER2-negative breast cancer is a heterogeneous disease (Koboldt 
et al. [The Cancer Genome Atlas Network] 2012).  Therefore, all patients may not 
be equally likely to benefit from treatment with GDC-9545.  Predictive biomarker 
samples collected prior to dosing will be assessed in an effort to identify those 
patients who are most likely to respond to GDC-9545.  PD biomarkers will be 
assessed to demonstrate evidence of biologic activity of GDC-9545 in patients 
and to inform potential revisions to the PK samplecollection schedule.  As these 
biomarkers may also have prognostic value, their potential association with 
disease progression will also be explored.  Biomarker data will not inform clinical 
decisions and patient management. 
Exploratory research on safety biomarkers may be conducted to support future 
drug development.  Research may include further characterization of a safety 
biomarker or identification of safety biomarkers that are associated with 
susceptibility to developing adverse events or can lead to improved adverse 
event monitoring or investigation.  Adverse event reports will not be derived from 
safety biomarker data by the Sponsor, and safety biomarker data will not be 
included in the formal safety analyses for this study.  In addition, safety 
biomarker data will not inform decisions on patient management. 
3.3.5.1 
Rationale for the Collection of Plasma Samples for Somatic 
Tumor Mutation Analysis 
There is increasing evidence that circulating-tumor DNA (ctDNA) obtained from 
blood specimens of patients with cancer may be representative of the DNA and 
mutational status of tumor cells (Diehl et al. 2008; Maheswaran et al. 2008).  

 
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Recent nonclinical and clinical data suggest that mutations in ESR1 and PIK3CA 
are associated with endocrine-resistant breast cancer (Shou et al. 2004; Miller 
et al. 2010; Robinson et al. 2013; Toy et al. 2013; Jeselsohn et al. 2014; Bosch 
et al. 2015).  To gain insights into potential causal relationships between the 
clinical activity of GDC-9545 and resistance mechanisms, genes related to PI3K 
signaling and endocrine resistance as well as reported and unreported 
chromosomal alterations resulting from the tumorigenesis process may be 
assessed in ctDNA isolated from plasma using digital polymerase chain reaction 
and/or next-generation sequencing (NGS). 
3.3.5.2 
Rationale for the Collection of Tissue Samples 
Archival or fresh tumor tissue (preferred) will be collected.  A specimen from the 
most recently obtained tumor tissue will be requested to obtain the most accurate 
reflection of a patient's current disease, while minimizing burden.  Tumor tissues 
may be assessed for ER, progesterone receptor, and HER2 protein levels, and 
proliferative index (Ki67).  In addition, tumor tissue may enable assessment of 
ER pathway activity using RNA analysis of ER target genes (Guan et al. 2019).  
NGS techniques such as targeted exome sequencing may offer a unique 
opportunity to identify biomarkers of response and/or resistance to GDC-9545 in 
tumor tissue.  For example, genes related to PI3K signaling and endocrine 
resistance as well as reported and unreported chromosomal alterations resulting 
from the tumorigenesis process may be assessed.  Mutations in the ESR1 gene 
are more prevalent in metastatic ER-positive tumors and have been correlated 
with resistance to anti-estrogen therapies (Robinson et al. 2013; Toy et al. 2013; 
Jeselsohn et al. 2014).  Tumor tissue analysis offers the opportunity to perform 
molecular subtyping that may inform breast cancer biology and response to 
GDC-9545 or endocrine therapy.  The collection of tissue samples may also 
support future diagnostic development. 
Tissue samples will be collected for DNA extraction to enable whole genome 
sequencing (WGS) or whole exome sequencing (WES) to identify variants that 
are predictive of response to study drug, are associated with progression to a 
more severe disease state, are associated with acquired resistance to study 
drug, are associated with susceptibility to developing adverse events, can lead to 
improved adverse event monitoring or investigation, or can increase the 
knowledge and understanding of disease biology and drug safety.  Genomics is 
increasingly informing researchers' understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and 
exome, respectively, and, along with clinical data collected in this study, may 
increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more 
likely to respond to a drug or develop adverse events.  Data will be analyzed in 
the context of this study but may also be explored in aggregate with data from 

 
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other studies.  The availability of a larger dataset will assist in identification and 
characterization of important biomarkers and pathways to support future drug 
development. 
3.3.6 
Rationale for Clinical Outcome Assessments 
As metastatic breast cancer is not curable with currently approved and available 
therapies, the primary focus for patients is prolonging life and delaying the 
progression of cancer, while maintaining quality of life and the ability to carry out 
daily activities (Cardoso et al. 2012).  Research indicates that a higher proportion 
of HR-positive patients have bone metastases compared with other subtypes, 
which is often associated with pain (Irvin et al. 2011; Wood et al. 2016); thus, 
disease-related pain may be an important variable to assess during treatment.  
Limited data are available characterizing the clinical presentation of disease in 
this population; however, it is hypothesized that progression of disease would be 
associated with an increase in pain symptoms.  Hence, examining and 
measuring patients' disease-related pain and interference with functioning is 
important. 
Additionally, cancer treatments, particularly combination therapies, can produce 
significant symptomatic adverse events.  Recent research has shown that 
clinicians may underreport the incidence and severity of symptoms experienced 
by patients receiving treatment for cancer (Fromme et al. 2004; Trotti et al. 2007; 
Pakhomov et al. 2008; Basch 2010; Quinten et al. 2011; Atkinson et al. 2012; 
Basch et al. 2014).  Collecting tolerability information directly from patients can 
provide a better understanding of treatment characteristics and their effects.   
These issues will be assessed using validated PRO assessments in patients 
enrolled in the study.  The QLQ-C30 will be administered to patients to assess 
disease and treatment-related symptoms, functioning, and GHS/QoL.  The QLQ-
BR23 will provide an additional assessment of some treatment-related symptoms 
and symptoms that may occur with advanced disease.  The "worst pain" item 
from the BPI-SF will be used to gain further insight into increase in pain severity.  
For evaluation of the tolerability of GDC-9545, patients will be asked to report on 
their experience related to diarrhea, nausea, vomiting, decreased appetite, 
fatigue, mouth sores, and rash selected from the validated PRO-CTCAE item 
bank.  These symptoms were identified as being salient to patients' experience 
with GDC-9545 and/or common endocrine therapies on the basis of preliminary 
and published safety data, respectively.  An additional exploratory safety 
endpoint has been specified to evaluate the overall treatment burden patients 
may experience, which will be assessed by analyzing the proportion of patients 
who select each response option at each assessment timepoint by treatment arm 
for the single-item GP5 ("I am bothered by side effects of treatment") from the 
Physical Well-Being subscale of the validated and reliable FACT-G instrument, 

 
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Version 4 (Cella et al. 1993; Webster et al. 1999).  The EQ-5D-5L will also be 
collected and utilized to derive health states for use in economic models; 
therefore, the results will not be reported in the Clinical Study Report.  
See Section 4.5.9 and Appendix 5Appendix 10 for additional details on PRO 
instruments used in this study. 
The PRO data collected in the study will be supplemented by (optional) 
interviews conducted among a subset (up to 30) of patients treated with GDC-
9545 to further understand the experiences of study treatment, therapeutic 
context, and disease journey from the patient perspective. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
Approximately 300 patients with ER-positive, HER2-negative locally advanced or 
metastatic breast cancer who have received one or two prior lines of systemic 
therapy in the locally advanced or metastatic setting will be enrolled during the 
global enrollment phase of this study.  After completion of the global enrollment 
phase, additional patients may be enrolled in an extended China 
enrollment phase. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age  18 years at time of signing Informed Consent Form 
 
For women:  postmenopausal or premenopausal/perimenopausal status, 
defined as follows: 
Postmenopausal, as defined by at least one of the following criteria:  
– 
Age  60 years 
– 
Age  60 years and  12 months of amenorrhea without an 
alternative medical cause plus follicle-stimulating hormone (FSH) and 
plasma estradiol levels within postmenopausal range by local 
laboratory assessment, in the absence of oral contraceptive pills, 
hormone replacement therapy, or gonadotropin-releasing hormone 
agonist or antagonist.  
– 
Documented bilateral oophorectomy ( 14 days prior to first treatment 
on Day 1 of Cycle 1 and recovery from surgery to baseline) 
Premenopausal or perimenopausal, defined as not meeting the criteria 
for postmenopausal, and willing to undergo and maintain treatment with 
approved LHRH-agonist therapy for the duration of study treatment  
LHRH-agonist therapy may be initiated 28 days prior to Day 1 of 
Cycle 1 (or according to clinical practice for the selected agent).  To 

 
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minimize the potential of exposure to the medication decreasing to 
sub-therapeutic levels towards the end of the treatment cycle, 
monthly injections of LHRH agonist are preferred and to be 
synchronized with Day 1 of each 28-day cycle. 
 
For men:  willing to undergo and maintain treatment with approved LHRH-
agonist therapy for the duration of study treatment 
LHRH-agonist therapy may be initiated 28 days prior to Day 1 of 
Cycle 1 (or according to clinical practice for the selected agent).  To 
minimize the potential of exposure to the medication decreasing to 
sub-therapeutic levels towards the end of the treatment cycle, 
monthly injections of LHRH agonist are preferred and to be 
synchronized with Day 1 of each 28-day cycle. 
 
Locally advanced or metastatic adenocarcinoma of the breast, not amenable 
to treatment with curative intent  
 
Disease progression after treatment with one or two lines of systemic therapy 
in the locally advanced or metastatic setting 
One of the prior lines of systemic therapy may have included 
chemotherapy. 
Patients may not have received more than one prior targeted therapy 
regimen in the locally advanced or metastatic setting.  Targeted 
therapies may include, but are not limited to, CDK4/6 inhibitors, mTOR 
inhibitors, PI3K inhibitors or PARP inhibitors. 
One of the prior lines of systemic therapy must have included endocrine 
therapy, which must have been administered continuously for a minimum 
of 6 months in the locally advanced or metastatic setting prior to disease 
progression. 
Patients who were intolerant to their last systemic anti-cancer regimen 
may be considered eligible if all other eligibility criteria are met (including 
a minimum of 6 months continuous endocrine therapy). 
Intolerance is defined as any treatment-related Grade 4 adverse 
event, or any treatment-related Grade 2 or 3 adverse event that is 
unacceptable to the patient and persists despite standard 
countermeasures.  The reason for intolerance must be fully 
documented. 
 
Documented ER-positive tumor according to American Society of Clinical 
Oncology/College of American Pathologists (ASCO/CAP) or ESMO 
guidelines, assessed locally and defined as  1% of tumor cells stained 
positive based on the most recent tumor biopsy (or archived tumor sample) 
Patient must be considered appropriate for endocrine therapy. 
 
Documented HER2-negative tumor assessed locally and defined as meeting 
criteria according to ASCO/CAP guidelines (Wolff et al. 2018). 

 
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 
Confirmed availability of the most recently collected and representative tumor 
tissue specimen suitable for biomarker testing with de-identified associated 
pathology report is required (i.e., archived formalin-fixed, paraffin-embedded 
[FFPE] tissue block [preferred] or 1520 slides containing unstained, freshly 
cut, serial sections).  Whenever possible, tumor tissue from a metastatic site 
of disease is preferred, but archival tumor tissue from the primary tumor is 
acceptable if it is the most recently collected or most suitable for testing 
(see Section 4.5.7 and the laboratory manual)  
If tumor tissue is not available, a newly collected, pre-treatment biopsy 
will be required for patient participation.  In general, a minimum of three 
cores per block is preferred. 
If the aforementioned minimum tissue requirements cannot be met 
because of local regulatory requirements, patient may still be eligible for 
the study and study team is available for advice. 
 
Measurable disease as defined per RECIST v.1.1 or bone only disease 
which must have at least one predominantly lytic bone lesion confirmed by 
CT or MRI which can be followed.  
Tumor lesions previously irradiated or subjected to other locoregional 
therapy will be deemed measurable only if disease progression at the 
treated site after completion of therapy is clearly documented. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status 01 
 
Life expectancy of  6 months 
 
Adequate organ function as defined by the following criteria: 
– 
ANC  1.5  109/L (1500/L)  
– 
Platelet count  100  109/L (100,000/L) 
– 
AST and serum ALT  3  upper limit of normal (ULN)  
For patients with documented liver metastasis:  AST and ALT 
 5  ULN 
– 
Hemoglobin  90 g/L (9 g/dL) 
The blood counts are to meet the specified criteria without transfusion or 
growth factor support, unless it is clear that the bone marrow function is 
adequate and that any aberration has a clear and correctable cause, and 
the correction undertaken. 
– 
Serum bilirubin  1.5  ULN, with the following exception: 
Patients with known Gilbert syndrome:   3  ULN 
– 
Serum creatinine  1.5  ULN or estimated creatinine clearance  60 
mL/min as calculated per institutional guidelines 
 
INR (or PT)  1.5  ULN and PTT (or aPTT)  1.5  ULN (except for patients 
receiving anticoagulation therapy) 
For patients receiving warfarin, a stable INR between 2 and 3 is required. 

 
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For patients receiving heparin, PTT (or aPTT) between 1.5 and 2.5  ULN 
(or patient's value before starting heparin treatment) is required. 
If anticoagulation therapy is required for a prosthetic heart valve, stable 
INR between 2.5 and 3.5 is permitted. 
 
Resolution of all acute toxic effects of prior anti-cancer therapy or surgical 
procedures to NCI CTCAE v5.0 Grade  1 (except alopecia, Grade  2 
peripheral neuropathy, or other toxicities not considered a safety risk for the 
patient per investigator's judgment) 
 
For women of childbearing potential:  agreement to take precautions as 
outlined below for each treatment arm 
– 
If assigned to the control arm (physician's choice of endocrine 
monotherapy), agreement to comply with local prescribing guidelines 
regarding contraception for the chosen endocrine monotherapy 
– 
If assigned to the GDC-9545 arm:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraception, and 
agreement to refrain from donating eggs, as defined below: 
Women must remain abstinent or use non-hormonal contraceptive 
methods with a failure rate of  1% per year during the treatment 
period and for 10 days after the final dose of GDC-9545 or for the 
time period according to local prescribing guidelines.  Women must 
refrain from donating eggs during this same period.  
A woman is considered to be of childbearing potential if she is 
postmenarchal, has not reached a postmenopausal state 
( 12 continuous months of amenorrhea with no identified cause 
other than menopause), and is not permanently infertile due to 
surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or 
another cause as determined by the investigator (e.g., Müllerian 
agenesis).  The definition of childbearing potential may be adapted 
for alignment with local guidelines or regulations. 
Examples of non-hormonal contraceptive methods with a failure rate 
of  1% per year include bilateral tubal ligation, male sterilization, and 
copper intrauterine devices. 
For women of childbearing potential, hormonal contraceptive 
methods are not allowed in this study. 

 
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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 postovulation methods) and withdrawal are not 
adequate methods of contraception.  LHRH agonists are not 
adequate contraception.  If required per local guidelines or 
regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in 
the local Informed Consent Form. 
 
For men:  agreement to take precautions as outlined below for each 
treatment arm: 
– 
If assigned to the control arm (physician's choice of endocrine 
monotherapy), agreement to comply with local prescribing guidelines 
regarding contraception for the chosen endocrine monotherapy  
– 
If assigned to the GDC-9545 arm:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraceptive methods, 
and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential who is not pregnant, 
men must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of 1% per 
year during the treatment period and for 10 days after the final dose 
of GDC-9545 or for the time period according to local prescribing 
guidelines.  Men must refrain from donating sperm during this same 
period. 
With a pregnant female partner, men must remain abstinent or use a 
condom during the treatment period and for 10 days after the final 
dose of GDC-9545 or for the time period according to local 
prescribing guidelines 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 postovulation methods) and withdrawal are not 
adequate methods of contraception.  If required per local guidelines 
or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in 
the local Informed Consent Form. 
For female partners of male patients, hormonal contraceptive 
methods supplemented by a barrier method are permitted. 
 
Ability to comply with the study protocol, in the investigator's judgment 
 
Willing and able to use an electronic device for PRO data collection 

 
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 
For patients enrolled in an extended China enrollment phase:  current 
resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Prior treatment with a SERD, with the exception of fulvestrant, if fulvestrant 
treatment was terminated at least 28 days prior to randomization  
 
Treatment with any investigational therapy within 28 days prior to 
randomization  
 
Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy 
within 14 days prior to randomization 
Patient must have recovered from any resulting acute toxicity (to Grade 1 
or better) prior to randomization. 
Anticipation of need for a major surgical procedure during the course of 
the study is exclusionary. 
 
History of any other malignancy other than breast cancer within 5 years prior 
to screening, except for appropriately treated carcinoma in situ of the cervix, 
non-melanoma skin carcinoma, or Stage I endometrial cancer 
For participants with a history of other non-breast cancers within 5 years 
from the date of randomization and considered of very low risk of 
recurrence per investigator’s judgment (e.g., papillary thyroid cancer 
treated with surgery), eligibility is to be discussed with the Sponsor. 
 
Advanced, symptomatic, visceral spread that is at risk of life-threatening 
complications in the short term (including massive uncontrolled effusions 
[pleural, pericardial, peritoneal] or pulmonary lymphangitis) 
 
Known active uncontrolled or symptomatic CNS metastases, carcinomatous 
meningitis, or leptomeningeal disease 
Patients with a history of CNS metastases or cord compression are 
eligible if have been definitively treated with local therapy 
(e.g., radiotherapy, surgery), are clinically stable, and have not been 
treated with anticonvulsants or corticosteroids within 2 weeks prior to 
randomization. 
 
Active cardiac disease or history of cardiac dysfunction, including any of the 
following: 
– 
History (within 2 years of screening) or presence of idiopathic 
symptomatic bradycardia or resting heart rate  50 bpm at screening 
Patients on stable dose of a -blocker or calcium channel antagonist 
for preexisting baseline conditions (e.g., hypertension) may be 
eligible if resting heart rate is at least 50 bpm. 

 
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– 
History of angina pectoris or symptomatic congestive heart disease 
within 12 months prior to study entry 
– 
History of documented congestive heart failure (New York Heart 
Association Class IIIV) or cardiomyopathy  
– 
QT interval corrected through use of Fridericia's formula (QTcF) 
 470 ms for women, >450 ms for men, history of long or short QT 
syndrome, Brugada syndrome or known history of corrected QT interval 
prolongation, or torsades de pointes  
– 
Presence of an abnormal ECG that is clinically significant in the 
investigator's opinion, including complete left bundle branch block, 
second- or third-degree heart block, sick sinus syndrome. 
o Participants with first-degree heart block may be considered for 
inclusion following consultation with a cardiologist and 
determination that no additional cardiac risks are present. 
o Patients with history of well-controlled atrial fibrillation are eligible. 
– 
History (within 12 months) or presence of ventricular dysrhythmias or 
risk factors for ventricular dysrhythmias such as significant structural 
heart disease (e.g., severe left ventricular systolic dysfunction,) 
restrictive cardiomyopathy, hypertrophic cardiomyopathy, infiltrative 
cardiomyopathy, moderate to severe valve disease) or family history of 
long QT syndrome 
o Clinically significant electrolyte abnormalities (e.g., hypokalemia, 
hypomagnesemia, hypocalcemia) should be corrected prior to 
enrollment, 
 
Known clinically significant history of liver disease consistent with Child-Pugh 
Class B or C, including active viral or other hepatitis virus (e.g., hepatitis B or 
hepatitis C), current alcohol abuse, or cirrhosis 
Active viral infection is clinically defined as requiring treatment with antiviral 
therapy or the 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.  Patients are not required to have HBV, or HCV assessments 
at screening if these assessments have not been previously performed. 
Patients that have tested positive for anti-HBc would be eligible if tests for 
HBsAg and polymerase chain reaction (PCR) are HBV DNA are negative. 
Patients who have been cured of their HCV infection (must have an 
undetectable viral load i.e., a sustained virologic response for 3 months after 
completing treatment) are eligible to enroll.  Patients that have tested positive 
for the HCV antibody would be eligible if tests for HCV RNA are negative.  If 
the patient is a carrier of HCV and tests positive for HCV RNA, they would 
not be considered eligible. 
For patients who have been successfully treated for viral hepatitis, the 
possibility of re-activation of the virus or reinfection with viral hepatitis should 

 
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be considered by the Investigator and the overall potential benefits 
associated with study treatment for the patient should be deemed to exceed 
the overall risks. 
 
Known HIV infection 
 
Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, 
or major upper gastrointestinal (GI) surgery, including gastric resection, 
potentially affecting enteral absorption 
 
Serious infection requiring oral or IV antibiotics, or other clinically significant 
infection, within 14 days prior to randomization.  Patients who fully recovered 
from serious and clinically significant infections within 14 days prior to 
randomization are eligible. 
 
Any serious medical condition or abnormality in clinical laboratory tests that, 
in the investigator's judgment, precludes the patient's safe participation in 
and completion of the study 
 
Known allergy or hypersensitivity to any of the study drugs or any of their 
excipients 
 
For premenopausal/perimenopausal patients or male patients:  known 
hypersensitivity to LHRH agonists 
 
Pregnant or breastfeeding, or intending to become pregnant during the study 
or within 10 days after the final dose of GDC-9545, or within the time period 
specified per local prescribing guidelines after the final dose of physician's 
choice of endocrine monotherapy 
Women of childbearing potential must have a negative serum pregnancy 
test result within 7 days prior to initiation of study treatment. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
This is a randomized, open-label study.  After initial written informed consent has 
been obtained, all screening procedures and assessments have been completed, 
and eligibility has been established for a patient, the study site will obtain the 
patient's identification number and treatment assignment from an interactive 
voice or web-based response system (IxRS). 
Patients will be randomly assigned to one of two treatment arms to receive either 
GDC-9545 or physician's choice of endocrine monotherapy.  Randomization will 
occur in a 1:1 ratio through use of a permuted-block randomization method to 
ensure a balanced assignment to each treatment arm.  Randomization will be 
stratified according to the following factors: 
 
Site of disease (visceral vs. non-visceral), locally assessed 
Visceral is defined as any lung and/or liver involvement.  
Non-visceral is defined as absence of any lung and/or liver involvement. 

 
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 
Prior treatment with a CDK4/6 inhibitor (yes vs. no) 
 
Prior treatment with fulvestrant (yes vs. no) 
 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal products (IMPs) for this study are GDC-9545 and 
physician's choice of endocrine monotherapy.  LHRH agonists are considered 
non-IMPs. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
GDC-9545 
GDC-9545 will be supplied by the Sponsor as an immediate-release capsule.  
Each GDC-9545 capsule contains 30 mg of GDC-9545 (free base equivalent), 
packaged in high-density polyethylene bottles with a plastic child-resistant cap 
with induction seal and desiccant.  For information on the formulation of 
GDC-9545, see the pharmacy manual and the GDC-9545 Investigator's 
Brochure. 
4.3.1.2 
Physician's Choice of Endocrine Monotherapy 
The physician's choice of endocrine monotherapy will be limited to fulvestrant or 
an AI and will be either provided by the Sponsor where required by local health 
authority regulations or sourced locally by the site with reimbursement by the 
Sponsor.  The options are fulvestrant, letrozole, anastrozole, exemestane, 
formestane, aminoglutethimide, and testolactone.  For information on the 
formulation and packaging, see the local prescribing information for the 
respective product. 
4.3.1.3 
Luteinizing HormoneReleasing Hormone Agonist 
For premenopausal/perimenopausal patients (as defined in Section 4.1.1) and 
male patients in both treatment arms, the investigator will determine and supply 
the appropriate LHRH agonist locally approved for use in breast cancer.  
Acceptable agents include, but are not limited to, leuprolide acetate, goserelin 
acetate, or triptorelin pamoate.  The investigator will determine and supply the 
appropriate LHRH agonist locally approved for use in breast cancer.  If the 
patient becomes intolerant to current LHRH agonist, the patient may switch to 
another approved LHRH agonist during the study.  
To minimize the potential of exposure to the medication decreasing to sub-
therapeutic levels towards the end of the treatment cycle, monthly injections of 
LHRH agonist are preferred and to be synchronized with Day 1 of each 28-day 
cycle. 
For information on the formulation and packaging of the LHRH agonist, see the 
local prescribing information for the respective product. 

 
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4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1.1.  Patients should 
receive the first dose of study drug on the day of randomization, if possible.  If 
this is not possible, the first dose should occur no later than 3 days after 
randomization. 
Refer to the pharmacy manual for detailed instructions on drug preparation, 
storage, and administration. 
Details on treatment administration (e.g., dose and timing) 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. 
At the beginning of each patient's study participation, site study staff will provide 
the patient with detailed instructions and training for the handling and 
administration of study drugs.  Patients will receive and should be instructed to 
complete a medication diary.  For GDC-9545 and any other study drug 
administered at home, the medication diary, unused study drug, and study drug 
containers (used or unused) should be collected and reviewed for drug 
accountability at the beginning of each cycle. 
Capsules (or tablets, as applicable) that are not returned will be considered to 
have been taken, unless otherwise specified in the patient's diary/eCRF.  Note 
that dosing eCRFs should be completed using the following prioritization (in the 
event of discrepancies):  1) site pharmacy drug accountability logs (IMP 
disbursed minus IMP returned); 2) patient daily dosing diary; and 3) clinic visit 
patient interview notes. 
Guidelines for treatment interruption or discontinuation for patients who 
experience adverse events are provided in Section 5.1.3. 
4.3.2.1 
GDC-9545 
GDC-9545 should be taken orally at approximately the same time each day.  
Starting with Day 1 of Cycle 1, and on Day 1 of each 28-day cycle thereafter, 
GDC-9545 will be administered in the clinic, as indicated in the schedule of 
activities (see Appendix 1).  Date and time of GDC-9545 dosing in the clinic 
should be accurately recorded for all cycles and, in particular, on days when PK 
sampling is performed.  All other doses will be taken at home on all non-clinic 
visit days.  GDC-9545 may be taken with or without a meal.  GDC-9545 should 
be swallowed whole with a glass of water and should not be chewed, cut, or 
crushed.  If a dose is missed it should be made up unless the next dose is due 
within 6 hours.  If the patient vomits at any time after taking a dose, an additional 

 
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dose should not be taken that day.  Treatment may resume the next day as 
prescribed. 
4.3.2.2 
Physician's Choice of Endocrine Monotherapy 
Dose administration of physician's choice of endocrine monotherapy should 
be performed in accordance with the local prescribing information for the 
respective product. 
4.3.2.3 
Luteinizing HormoneReleasing Hormone Agonist 
Starting with Cycle 1, LHRH agonist will be administered by site staff to male 
patients and premenopausal/perimenopausal patients on Day 1 of each 28-day 
cycle (or according to clinical practice for the selected agent).  To minimize the 
potential of exposure to the medication decreasing to sub-therapeutic levels 
towards the end of the treatment cycle, and to minimize the number of 
clinic visits, monthly injections of LHRH agonist are preferred and to be 
synchronized with Day 1 of each 28-day cycle.  In the event of dose delay of 
study drug, LHRH agonists should continue to be administered monthly. 
4.3.3 
Investigational Medicinal Product Handling and Accountability 
GDC-9545 will be provided by the Sponsor.  As the choice of endocrine 
monotherapy is left to the physician's discretion, these IMPs will be either 
provided by the Sponsor where required by local health authority regulations or 
sourced locally by the site with reimbursement by the Sponsor.  The study site 
(i.e., investigator or other authorized personnel [e.g., pharmacist]) 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 supplied by the Sponsor 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 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. 

 
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IMPs will either be disposed of at the study site according to the study site's 
institutional standard operating procedure or 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 Sponsor-supplied 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 pharmacy manual and/or the GDC-9545 Investigator's Brochure 
and/or the local prescribing information for physician's choice of endocrine 
monotherapy for information on IMP handling, including preparation and storage, 
and accountability.  
4.3.4 
Continued Access to GDC-9545 
Currently, the Sponsor does not have any plans to provide Roche IMP (GDC-
9545) or any other study treatments to patients who have completed the study.  
The Sponsor may evaluate whether to continue providing GDC-9545 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.pd
f  
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-
the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF. 
Preliminary data from the Study GP44001 showed that itraconazole, a strong 
CYP3A inhibitor, increased giredestrant exposure to approximately 3.98-fold.  
Carbamazepine, a strong CYP3A inducer, decreased giredestrant exposure by 
approximately 75%. The results suggest giredestrant is a moderately sensitive 
CYP3A substrate.  

 
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The prescribing information/labels of any concomitant medication must be 
reviewed and the overall benefits and risks to the patient associated with the 
concomitant medications judged before the concomitant medications are used. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
 
Approved COVID-19 vaccines and treatments (including those with 
emergency use authorizations), according to prescribing information/label. 
 
Symptomatic anti-emetics, anti-diarrheal therapy, and other palliative and 
supportive care for disease-related symptoms may be administered at the 
investigator’s discretion.  All concomitant medication and/or therapies should 
be documented in the patient's eCRF. 
 
Pain medications administered per standard clinical practice are acceptable 
while the patient is enrolled in the study and are to be recorded on the 
Concomitant Medications eCRF. 
 
Bone-sparing agents (e.g., bisphosphonates, denosumab) for the treatment 
of osteoporosis/osteopenia or for palliation of bone metastases are allowed 
during the study.  It is preferred that patients are on stable doses prior to 
Day 1 of Cycle 1 to reduce the possibility of bone flare. 
 
In certain instances, focal radiation therapy for palliation of bone disease-related 
symptoms might be allowed after discussion with the Sponsor (see 
Section 4.4.3); however, the need for radiation therapy will generally be 
considered indicative of progressive disease. 
4.4.2 
Cautionary Therapy for Patients Receiving GDC-9545 
The following guidelines on cautionary therapy apply only to patients receiving 
GDC-9545.  For guidelines on cautionary therapy for patients receiving 
physician's choice of endocrine monotherapy (control arm), refer to the local 
prescribing information for the respective product.  
4.4.2.1 
Medications Associated with Bradycardia 
Investigators should use medical judgment and exercise caution when 
considering initiation of concomitant medication known to cause decreases in 
heart rate including, but not limited to, -blockers and calcium channel 
antagonists.  An alternative therapy should be used when possible.  Patients on 
stable dose of a -blocker or calcium channel antagonist for preexisting baseline 
conditions (e.g., hypertension) should be monitored closely in case dose 
modification is warranted. 
4.4.2.2 
Surgery 
Patients who require surgery as part of medical treatment in the absence of 
disease progression must exercise caution, and GDC-9545 should be 

 
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temporarily held for at least 7 days prior to major elective surgery.  After the 
temporary treatment hold is complete, GDC-9545 may be re-initiated based upon 
a clinical assessment of satisfactory wound healing and recovery from surgery. 
4.4.2.3 
Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions (DDIs) 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. 
4.4.2.4 
Moderate CYP3A Inducers 
Where possible and feasible, investigators should consider alternatives to the 
concomitant administration of moderate CYP3A inducers with giredestrant.  If 
this is not possible or there are no suitable alternatives, co-administration with 
moderate CYP3A inducers should be generally limited to short term use 
(approximately 30 days). 
 
4.4.3 
Prohibited Therapy 
Use of the following concomitant therapies is prohibited as described below: 
 
Investigational therapy (other than protocol-mandated study treatment) is 
prohibited within 28 days prior to initiation of study treatment and during 
study treatment. 
 
Any concomitant therapy intended for the treatment of cancer (other than 
protocol-mandated study treatment) including, but not limited to, 
chemotherapy, immunotherapy, biologic therapy, radiotherapy, or herbal 
therapy is prohibited for various time periods prior to starting study treatment, 
depending on the agent (see Section 4.1.2), and during study treatment, until 
disease progression is documented and the patient has discontinued study 
treatment. 
 
Hormone replacement therapy, topical estrogens (including any intra-vaginal 
preparations), megestrol acetate, and selective ER modulators 
(e.g., raloxifene) are prohibited unless required to treat adverse events. 
For female trial participants hormonal contraceptives are prohibited.  For 
female partners of male participants refer to Section 4.1.1. 
 
Radiotherapy for unequivocal progressive disease is prohibited, with the 
exception of new brain metastases in the setting of systemic response as 
follows:  
Patients who have demonstrated control of their systemic disease 
(defined as having received clinical benefit [i.e., a PR, CR, or SD for 
 24 weeks]), but who have developed isolated brain metastases that are 
treatable with radiation, will be allowed to continue to receive study 
treatment until systemic progression of disease and/or further 
progression in the brain (based on investigator assessments). 

 
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Endocrine therapy (i.e., GDC-9545 or physician's choice) may be 
administered concomitantly with radiotherapy.  Patients should not miss 
more than one cycle of study treatment due to radiotherapy and must 
meet eligibility requirements to continue study treatment (see 
Section 4.1.1). 
 
Other local radiotherapy is not permitted with the following exception.  It is 
understood that there may be circumstances requiring local radiotherapy in 
which the investigator does not believe that the symptoms are a result of 
disease progression (e.g., impending fracture) and the radiation field does 
not encompass a target/non-target lesion.  In such cases, the investigator 
should consult with the Medical Monitor, and such patients should have a 
tumor assessment of the lesion(s) before they receive radiotherapy.  If a 
patient received radiation therapy and a target or non-target lesion is 
included in the field of radiation, the lesion(s) will become un-evaluable for 
tumor response.   
Further reasons for avoiding local radiotherapy include the difficulty in 
distinguishing new symptomatic pain or worsening of lytic bone lesions 
from disease progression.  TTD in pain is a secondary endpoint of this 
study and palliative radiotherapy may alter these results.  As such, 
advice from Medical Monitor for palliative radiotherapy to bone in the 
absence of disease progression may be considered. 
Endocrine therapy (i.e., GDC-9545 or physician's choice) may be 
administered concomitantly with radiotherapy.  Patients should not miss 
more than one cycle of study treatment due to radiotherapy and must 
meet eligibility requirements to continue study treatment (see 
Section 4.1.1).   
Previous clinical experience also suggests that new bone pain is 
frequently a symptom of disease progression.  Bone pain can be treated 
with pain medications, nonsteroidal anti-inflammatory drugs, or 
corticosteroids. 
 
Primary prophylactic use of hematopoietic growth factors (e.g., 
erythropoietins, granulocyte colony-stimulating factor, and granulocyte-
macrophage colony-stimulating factor) is not permitted, however, they may 
be used to treat treatment-emergent neutropenia or anemia as indicated by 
the current ASCO guidelines or as secondary prophylaxis if dose reduction or 
delay is not considered a reasonable alternative and Medical Monitor can be 
consulted. 
 
Enrolled patients who subsequently require the use of any prohibited therapies 
must be discontinued from study treatment as outlined in Section 4.6.1.  
Co-administration of giredestrant with the following concomitant therapies 
should be avoided: 

 
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– 
Strong CYP3A inhibitors, including, but not limited to, the following: 
atazanavir, ritonavir, lopinavir, telaprevir, telithomycin, indinavir, 
nelfinavir, saquinavir, clarithromycin, troleandomycin, itraconazole, 
ketoconazole, voriconazole, posaconazole, nefazodone, mibefradil 
– 
Strong CYP3A inducers, including, but not limited to, the following: 
apalutamide rifampin, carbamazepine, phenytoin, enzalutamide, lumacaftor, 
and hyperforin (St. John's Wort). 
The above lists of CYP3A concomitant medications are not necessarily 
comprehensive.  Thus, the investigator should consult local prescribing 
information for any concomitant medication as well as the internet reference 
provided below when determining whether a certain medication strongly inhibits 
or induces CYP3A.  If the benefit from the use of a strong CYP3A inhibitor or 
strong CYP3A inducer outweighs the risk and no suitable alternative is 
available, a strong CYP3A inhibitor or strong CYP3A inducer may be used for a 
short period of up to 2 weeks.  Giredestrant should be withheld during the use of 
a strong CYP3A inhibitor (e.g., before initiating and during the 5-day COVID-
19 treatment with PAXLOVIDtm [containing the strong CYP3A inhibitor 
ritonavir]).  
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-
drug-interactions-table-substrates-inhibitors-and-inducers  
4.4.4 
Prohibited Food 
Consumption of grapefruit, grapefruit juice, grapefruit supplements, or Seville 
oranges (potent CYP3A inhibitors) is prohibited for at least 3 days prior to 
initiation of study treatment and during study treatment. 
 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in 
Appendix 1.  All activities should be performed and documented for each patient.   
Patients will be closely monitored for safety and tolerability throughout the study.  
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations) and 
may be obtained up to 6 weeks before initiation of study treatment.  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 

 
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eligibility or record reasons for screening failure, as applicable.  If a patient does 
not meet all eligibility criteria, the patient may qualify for one re-screening 
opportunity at the investigator's discretion. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and reproductive status will be 
recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 7 days prior to initiation of study 
treatment will be recorded.  At the time of each follow-up physical examination, 
an interval medical history should be obtained and any changes in medications 
and allergies should be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified 
visits, should include an evaluation of the head, eyes, ears, nose, and throat, and 
the cardiovascular, dermatologic, musculoskeletal, respiratory, GI, genitourinary, 
and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at 
specified postbaseline visits and as clinically indicated.  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 rate, and systolic 
and diastolic blood pressure while the patient is in a seated position, and 
temperature.  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. 
4.5.5 
ECOG Performance Status 
Performance status will be completed at screening and as specified in the 
schedule of activities (see Appendix 1) using the ECOG Performance Status 
Scale (see Appendix 11) and recorded on the eCRF. 

 
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4.5.6 
Tumor and Response Evaluations 
All known sites of disease must be documented at screening and re-assessed at 
each subsequent tumor evaluation.  Response will be assessed by the 
investigator on the basis of physical examinations, CT scans, MRI scans, and 
bone scans, according to RECIST v1.1 (see Appendix 4). 
CT scans should include chest, abdomen, and pelvic scans; CT scans of any 
other sites of disease should be included if clinically indicated.  At the 
investigator's discretion, CT scans may be repeated at any time if progressive 
disease is suspected. 
The CT scans, including brain CT scan (when clinically indicated), should be 
performed with contrast agents unless contraindicated for medical reasons.  If IV 
contrast is medically contraindicated, the imaging modality to be used to follow 
the disease (either CT without contrast or MRI) should be the modality which 
best evaluates the disease, and the choice should be determined by the 
investigator in conjunction with the local radiologist.  MRI of the abdomen and 
pelvis can be substituted for CT if MRI adequately depicts the disease. 
Clinical assessment of superficial disease must coincide with the imaging studies 
and will include photographs of all superficial metastatic lesions.  All lesion 
measurements must be recorded in the eCRF. 
Bone scan, 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.  Abnormalities identified 
on bone scans must be confirmed by X-ray, CT scan with bone windows, or MRI 
scan.  Special considerations regarding the measurability of bone lesions are 
outlined in RECIST v1.1 (see Appendix 4). 
To ensure a valid comparison of tumor data and uniformity in the assessment of 
tumor response during the study, the following procedures should be 
implemented at the study site: 
 
All lesions identified at baseline (target and non-target) will be reassessed 
using the same imaging method throughout the course of the study.  The 
same radiographic procedure used to assess disease sites at screening 
should be used throughout the study (e.g., the same contrast protocol for CT 
scans).  Assessments should be performed by the same evaluator to ensure 
internal consistency across visits. 
 
All CT scans and other relevant imaging such as MRIs obtained for all 
patients enrolled at the study site should be reviewed by the local radiologist 
who, together with the investigator, will determine the local assessment of 
response and progression.  All bone scans obtained from patients with bone 
metastases should also be reviewed similarly. 

 
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 
Images for all tumor assessments will be prospectively collected to enable a 
retrospective, blinded, independent central review. 
 
Recent literature indicates that vaccination-related adenopathy (enlarged lymph 
nodes) on radiologic imaging (e.g., CT, MRI) and transient uptake on PET scan 
are frequent findings (up to 16% in vaccine trials) after administration of COVID-
19 vaccines (Polack et al. 2020; CDC 2021; Grimm et al. 2021, McIntosh et al. 
2021; Becker et al. 2021).  These findings may appear similar to malignant nodal 
involvement and hence impact image interpretation.  
Concerns or confusion regarding vaccine-induced lymphadenopathy should not 
delay COVID-19 vaccination, particularly as the mortality related to COVID-19 is 
higher in cancer patients than the general population. 
If possible, and when it does not unduly delay care, screening tumor 
assessments should be performed prior to the first dose of a COVID-19 
vaccination or 46 weeks following the second dose of a COVID-19 vaccination.  
On-study tumor assessment schedule should be followed as closely as possible. 
After COVID-19 vaccination, performing additional follow-up tumor assessments 
should be considered, to ensure resolution of any possible confounding findings. 
4.5.6.1 
Baseline Tumor Assessments 
Baseline tumor assessment should be performed at screening within 28 days 
prior to randomization (unless otherwise specified) and will include the following 
assessments: 
 
CT or MRI scan of the chest, abdomen, and pelvis 
 
CT or MRI scan of brain, in patients with previously treated brain lesions 
The scan must be within the screening window and  4 weeks after the 
completion of radiotherapy.  For all other patients, brain scans should be 
acquired if clinically indicated. 
 
CT or MRI scan of any other sites of disease as clinically indicated 
 
Clinical assessment of superficial disease, including photographs of all 
superficial metastatic lesions 
 
Bone scans or other institutional standard bone imaging 
 
Radiographic tumor assessments and bone scans performed as routine 
procedures before the signing of the Informed Consent Form may be accepted 
as baseline assessments provided the following criteria are met: 
 
The tests were performed per the method requirements outlined above 
 
Appropriate documentation indicating that these radiographic tumor 
assessments were performed as standard of care is available in the patient's 
source notes 
 
For bone scans:  performed within 6 weeks prior to randomization  
 

 
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4.5.6.2 
Postbaseline Tumor Assessments 
Postbaseline tumor assessments will be performed according to the schedule 
below, from randomization, regardless of dose delay, until radiographically and/or 
clinically (i.e., for photographed or palpable lesions) disease progression as 
assessed by the investigator according to RECIST v1.1 (see Appendix 4), except 
in the case of isolated brain metastases as described in Section 4.4.3.  Thus, 
tumor assessments are to continue according to schedule in patients who 
discontinue treatment for reasons other than disease progression, even if they 
start new anti-cancer therapy.  For patients with symptomatic deterioration, every 
effort should be made to provide documented progression via radiographic 
modality.  Tumor assessments should be scheduled relative to the date of 
randomization rather than the date of the previous tumor assessment. 
The following postbaseline tumor assessments will be performed every 8 weeks 
( 7 days) from randomization for the first 18 months, then every 12 weeks 
( 7 days) thereafter: 
 
CT or MRI scan of the chest, abdomen, and pelvis 
 
CT or MRI scan of brain if clinically indicated 
 
CT or MRI scan of any other sites of disease identified at baseline 
 
Clinical assessment of sites of superficial disease identified at baseline  
 
For patients with bone lesions at baseline:  X-ray, CT scan, or MRI scan of 
selected evaluable bone lesions, ensuring consistent use of the same 
modality for all evaluations 
Bone scans are required to confirm CR; however, areas that have 
received palliative radiotherapy during the study cannot be used to 
assess response to study treatment. 
 
Postbaseline bone scans will be performed every 24 weeks ( 7 days) or as 
clinically indicated. 
At the investigator's discretion, tumor assessments may be repeated at any time 
if progressive disease is suspected.   
4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
Laboratory samples should be drawn according to the schedules of activities 
(see Appendix 1, Appendix 2, and Appendix 3).  For patients receiving 
GDC-9545, laboratory samples should be drawn within 72 hours prior to study 
drug administration and results of the following assessments should be available 
for review at each clinic visit prior to dosing to inform dosing decisions:  complete 
blood count, total bilirubin, ALP, AST, ALT, creatinine, BUN, and pregnancy test. 

 
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Samples for the following laboratory tests will be sent to the study site's local 
laboratory for analysis: 
 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet 
count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells) 
 
Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide (if 
considered standard of care for the region), sodium, potassium, chloride, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, 
total and direct bilirubin, ALP, ALT, AST, urate, and LDH 
 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test at 
screening, within 7 days prior to initiation of study treatment.  Urine 
pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test. 
 
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, 
blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) 
 
Coagulation:  INR (or PT), PTT (or aPTT) 
 
FSH and estradiol (for premenopausal/perimenopausal patients and female 
patients aged  60 years) 
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Plasma samples for PK analysis (GDC-9545 arm only) 
 
Plasma sample for determination of ESR1 mutation status 
 
Determination of ESR1 mutation status will be made using the 
FoundationOne Liquid CDx assay or an assay from an approved regional 
vendor.  
 
Blood and plasma samples for exploratory research on biomarkers and 
biomarker assay development 
 
Archival or newly collected tumor tissue sample obtained at baseline upon 
confirmation of enrollment onto the study for exploratory research on 
biomarkers 
Confirmed availability of the most recently collected and representative 
archived FFPE tumor tissue block (preferred) or approximately 
1520 slides (1115 slides in China) containing unstained, freshly cut, 
serial sections along with an associated de-identified pathology report is 
required prior to study enrollment.  Whenever possible, tumor tissue for a 
metastatic site of disease is preferred, but archival tumor tissue from the 

 
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primary tumor is acceptable if it is the most recently collected or most 
suitable for testing.  
Tumor tissue should be of good quality based on total and viable tumor 
content.  Samples should contain a minimum of 500 viable tumor cells 
that preserve cellular context and tissue architecture regardless of 
needle gauge or retrieval method.  Samples collected via resection, core-
needle biopsy (three cores preferred, embedded in a single paraffin 
block), or excisional, incisional, punch, or forceps biopsy are acceptable.  
Fine-needle aspiration (defined as samples that do not preserve tissue 
architecture and yield cell suspension and/or smears), brushing, cell 
pellets from pleural effusion, and lavage samples are not acceptable.  
Tumor tissue from bone metastases is not acceptable. 
If archival tumor tissue is unavailable or is determined to be unsuitable 
for required testing, a newly collected pretreatment tumor biopsy is 
required.  A tumor biopsy of the growing lesion is preferred.  A detailed 
description of tissue quality requirements and procedures for collection, 
handling and shipping of tumor tissue samples will be provided in a 
separate laboratory manual. 
Exploratory biomarker research may include, but will not be limited to, analysis of 
circulating tumor DNA, analysis of expression of ESR1 and ER target genes, 
signatures associated with breast cancer subtypes, immune-related genes, and 
PI3K signaling genes.  Research may involve extraction of DNA, cell-free DNA, 
or RNA; analysis of gene and/or protein expression; analysis of mutations, copy 
number, single nucleotide polymorphisms, and other genomic variants; and 
genomic profiling through use of NGS of a comprehensive panel of genes.  DNA 
extracted from blood and plasma may be compared with DNA extracted from 
tissue to identify somatic variants by distinguishing germline variants from 
somatic variants.  NGS methods may include WGS or WES of blood, plasma, 
and tissue samples, but WGS or WES of blood samples will be performed only at 
participating sites (see Section 4.5.10).  Tumor tissue, plasma, and blood 
samples may be used for future research and/or development of disease-related 
tests or tools. 
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), biological samples 
will be destroyed no later than the time of completion of the final Clinical Study 
Report, with the following exceptions: 
 
Plasma samples collected for PK analysis may be needed for drug 
metabolism research; therefore, these samples will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed. 

 
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 
Blood, plasma, and tumor tissue samples collected for biomarker research 
and biomarker assay development will be destroyed no later than 5 years 
after the final Clinical Study Report has been completed or earlier depending 
on local regulations 
 
For enrolled patients, remaining archival tissue blocks will be returned to the 
site upon request or no later than the date of final closure of the clinical 
database, whichever occurs first. 
 
When a patient withdraws from the study, samples collected prior to 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, including data on genomic variants, will be 
subject to the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, 
data derived from these analyses will generally not be provided to study 
investigators or patients unless required by law (with the exception of the report 
from Foundation Medicine).  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
4.5.8 
Electrocardiograms 
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled 
timepoints as indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity 
digital electrocardiograph machine equipped with computer-based interval 
measurements.  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.  All ECGs are to be obtained prior to other 
medical procedures scheduled at that same time (e.g., vital sign measurements, 
blood draws).  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording. 
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.  Digital recordings will be stored at the site.  The 
following should be recorded in the appropriate eCRF:  heart rate, RR interval, 
QRS interval, PR duration, uncorrected QT interval, and QTcF based on the 

 
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machine readings of the individual ECG tracings.  Any morphologic waveform 
changes or other ECG abnormalities must be documented on the eCRF.  If 
considered appropriate by the Sponsor, ECGs may be analyzed retrospectively 
at a central laboratory. 
If at a particular postdose timepoint the mean QTcF is  500 ms and/or  60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the 
next 5 minutes, and ECG monitoring should continue until QTcF has stabilized 
on two successive ECGs.  The Medical Monitor should be notified.  Standard-of-
care treatment may be instituted per the discretion of the investigator.  If a PK 
sample is not scheduled for that timepoint, an unscheduled PK sample should be 
obtained.  A decision on study drug discontinuation should be made, as 
described in Section 5.1.3.4.  The investigator should also evaluate the patient 
for potential concurrent risk factors (e.g., electrolyte abnormalities, 
co-medications known to prolong the QT interval, severe bradycardia). 
4.5.9 
Clinical Outcome Assessments 
PRO data will be collected to more fully characterize the clinical profile of GDC-
9545 in patients enrolled in the study.  PRO data will be collected via electronic 
questionnaires at the clinic sites using the following instruments:  QLQ-C30, 
QLQ-BR23, "worst pain" item from the BPI-SF, select items of the PRO-CTCAE, 
the FACT-G single-item GP5 for overall treatment burden, and the EQ-5D-5L.  
The questionnaires, translated into the local language as appropriate, will be 
distributed by the site staff and completed in their entirety by the patient at 
baseline (Day 1 of Cycle 1) and as noted in the schedule of activities (see 
Appendix 1). 
4.5.9.1 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at the clinic at the timepoints specified 
in the schedule of activities (see Appendix 1): 
At the clinic, instruments will be administered before the patient receives any 
information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment, unless otherwise 
specified. 
PRO instruments, translated into the local language as appropriate, will be 
completed through use of an electronic device provided by the Sponsor.  The 
device will be pre-programmed to enable the appropriate instruments to be 
administered in the correct order at each specified timepoint.  The electronic 
device and instructions for completing the instruments electronically will be 
provided by the site staff.  The data will be transmitted to a centralized database 
maintained by the electronic device vendor.  In case the PRO device is not 
available at site or not functioning, a web-based or paper backup process may be 

 
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used instead.  Under this process, web-based or printed questionnaires will be 
self-administered (i.e., completed by patients themselves in the same order and 
with the same content [including language versions] as when the device is used).  
Site staff should review the completed questionnaires to ask patients to rectify 
unclear responses and/or to confirm if an item is intentionally left blank.  Site staff 
will enter PRO data collected via paper into the same centralized database 
maintained by the electronic device vendor.  The data will be available for access 
by appropriate study personnel. 
If a PRO questionnaire is not available in a patient’s native language, the patient 
will be exempt from completing that specific assessment. 
During clinic visits, PRO instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by 
the Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments, 
estimated to be 1015 minutes at each specified visit. 
 
Sites should administer the instruments in a quiet area with minimal 
distractions and disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; 
there are no right or wrong answers. 
 
Site staff should not interpret or explain questions, but may read questions 
verbatim upon request. 
 
Patients should not obtain advice or help from others (e.g., family members 
or friends) when completing the instruments. 
 
4.5.9.2 
Description of Clinical Outcome Assessment Instruments 
EORTC QLQ C30 
The QLQ-C30 (see Appendix 5) is a validated and reliable self-report measure 
(Aaronson et al. 1993; Fitzsimmons et al. 1999) that 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), global 
health and quality of life, and six single items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties) with a recall period of the 
previous week.  Scale scores can be obtained for the multi-item scales.  The 
functioning and symptoms items are scored on a 4-point scale that ranges from 
"not at all" to "very much," and the GHS and QoL items are scored on a 7-point 
scale that ranges from "very poor" to "excellent."  The QLQ-C30 module takes 
approximately 10 minutes to complete. 

 
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EORTC QLQ-BR23 
The QLQ-BR23 breast cancer module (see Appendix 6) is meant for use among 
patients diagnosed with breast cancer (Sprangers et al. 1996).  The breast 
cancer module incorporates five multiple-item scales to assess systemic therapy 
side effects, arm symptoms, breast symptoms, body image, and sexual 
functioning.  In addition, single items assess sexual enjoyment, hair loss, and 
future perspective.  Male patients may be exempt from some of the questions 
included in the QLQ-BR23 breast cancer module. 
BPI-SF “Worst Pain” Item 
Cancer-related pain severity will be assessed using the BPI-SF "worst pain" item 
(see Appendix 7), a patient-reported measure rated on a 10-point numeric rating 
scale, with 0 meaning "no pain" and 10 indicating "worst pain you can imagine."  
This assessment approach follows consensus recommendations for measuring 
pain in clinical trials and is commonly used as a standalone item across diseases 
(including breast cancer), therapies, and languages (Dworkin et al. 2005; 
Harrington et al. 2014).  Patients will complete the pain severity assessment at 
each monthly visit using a 24-hour recall assessment window.  A threshold of 
 2 points, used to indicate clinically meaningful deterioration on the pain severity 
numeric rating scale, has been well-documented in patients with breast cancer 
and will be applied in this study (Cleeland et al. 2009; Mathias et al. 2010). 
EQ-5D-5L 
The EQ-5D-5L (see Appendix 9), 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.  The EQ-5D-5L is designed to capture the patient's current health status.  
Published weighting systems allow for creation of a single composite score of the 
patient's health status.  The EQ-5D-5L takes approximately 3 minutes to 
complete.  It will be used in this study for informing pharmacoeconomic modeling 
and will be included only descriptively in the Clinical Study Report. 
PRO-CTCAE 
The PRO-CTCAE (see Appendix 8) is a validated item bank that is used to 
characterize the presence, frequency of occurrence, severity, and/or degree of 
interference with daily function of 78 patient-reportable symptomatic treatment 
toxicities (Basch et al. 2014; Dueck et al. 2015).  The PRO-CTCAE contains 124 
questions that are rated either dichotomously (for determination of presence vs. 
absence) or on a 5-point Likert scale (for determination of frequency of 
occurrence, severity, and interference with daily function).  Treatment toxicities 

 
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can occur with observable signs (e.g., vomiting) or non-observable symptoms 
(e.g., nausea).  The standard PRO-CTCAE recall period is the previous 7 days.  
The PRO-CTCAE item bank was designed and validated as a repository of 
standalone items.  A subset of seven symptoms deemed most applicable to the 
current treatments has been selected for this study, i.e., diarrhea, nausea, 
vomiting, decreased appetite, fatigue, mouth sores, and rash.  Symptoms have 
been selected on the basis of being self-reportable, having a symptomatic 
equivalent in the PRO-CTCAE item library, and being associated with GDC-9545 
based on preliminary safety or published studies. 
FACT-G Single-Item GP5 
The FACT-G instrument, Version 4 (see Appendix 10), is a validated and reliable 
27-item questionnaire comprised of 4 subscales that measure physical (7 items), 
social and family (7 items), emotional (6 items), and functional well-being (7 
items), and is considered appropriate for use with patients with any form of 
cancer (Cella et al. 1993; Webster et al. 1999).  In this study, the single-item GP5 
(“I am bothered by side effects of treatment”) from the Physical Well-Being 
subscale of the FACT-G has been selected for individual item analysis to 
document the level of bother of symptoms on patient’s lives.  Patients will assess 
how true the statement "I am bothered by side effects of treatment" has been for 
them in the previous 7 days on a 5-point scale (0, not at all; 1, a little bit; 2, 
somewhat; 3, quite a bit; 4, very much).  The single-item GP5 from the FACT-G 
takes less than 1 minute to complete. 
4.5.9.3 
Optional Patient Interviews 
Patient interviews will be conducted among a subset of study participants (up to 
30 patients in GDC-9545 arm) following Cycle 2 (this can potentially include the 
post-treatment period).  The semi-structured interviews will be moderated by an 
external vendor and conducted by telephone (lasting up to an hour in duration).  
The interviews will explore participants’ experience of study treatment, 
therapeutic context, and disease journey.  Recording from the interviews will be 
transcribed and de-identified to maintain confidentiality.  Additional consent for 
this optional study component will be included in the relevant Informed Consent 
Form. 
4.5.10 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) 
At participating sites, blood samples will be collected for DNA extraction to 
enable WGS or WES to identify variants that are predictive of response to study 
drug, are associated with progression to a more severe disease state, are 
associated with acquired resistance to study drug, are associated with 
susceptibility to developing adverse events, can lead to improved adverse event 
monitoring or investigation, or can increase the knowledge and understanding of 

 
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disease biology and drug safety.  Research will be aimed at exploring inherited 
characteristics.  WES and WGS are not applicable in China. 
DNA extracted from blood and plasma may be compared with DNA extracted 
from tissue to identify somatic variants by distinguishing germline variants from 
somatic variants.  The samples may be sent to one or more laboratories for 
analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon 
the review and approval of the exploratory research by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for WGS or WES, this 
section of the protocol (Section 4.5.10) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease 
pathobiology.  WGS and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this 
study, may increase the opportunity for developing new therapeutic approaches 
or new methods for monitoring efficacy and safety or predicting which patients 
are more likely to respond to a drug or develop adverse events.  Data will be 
analyzed in the context of this study but may also be explored in aggregate with 
data from other studies.  The availability of a larger dataset will assist in 
identification and characterization of important biomarkers and pathways to 
support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS or WES are to be stored until they are no 
longer needed or until they are exhausted.  However, the storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable 
laws (e.g., health authority requirements). 
Refer to Section 4.5.7 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker 
analyses. 

 
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4.5.11 
Optional Tumor Biopsy (Patients at Participating Sites) 
At participating sites, consenting patients will undergo an optional tumor biopsy 
at time of disease progression (see Appendix 3).  Tumor biopsies of the growing 
lesion are preferred.  Patients may undergo additional on-treatment biopsies at 
any other time at the investigator's discretion (if deemed clinically feasible by the 
investigator).  Samples collected via resection, core-needle biopsy (at least three 
cores preferred), or excisional, incisional, punch, or forceps biopsy are preferred.  
Optional tumor biopsy at time of disease progression is not applicable in China. 
The Informed Consent Form will contain a separate section that addresses 
optional biopsies.  A separate, specific signature will be required to document a 
patient's agreement to undergo optional biopsies.  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 Optional Biopsy Sample 
Informed Consent eCRF. 
Samples may be used for exploratory biomarker research as described in 
Section 4.5.7.  For sampling procedures, storage conditions, and shipment 
instructions, see the laboratory manual.  Refer to Section 4.5.7 for details on 
duration of sample storage, use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker 
analyses.  
Tumor specimen may be used for centralized retrospective assessment to 
evaluate correlation between genes, proteins, DNA, and RNA relevant to the 
signaling pathways and sensitivity/resistance to the investigational agents. 
NGS may be performed by Foundation Medicine or an alternative, approved 
central laboratory for that region on tumor biopsies collected at time of disease 
progression.  If performed by Foundation Medicine, the investigator may obtain 
an NGS report through Foundation Medicine's web portal for results from testing 
performed on tissue submitted at the time of disease progression.  If allowed by 
local laws, the investigator may share and discuss the results with the patient, 
unless the patient chooses otherwise.  The NGS report is generated for research 
purposes and is not provided for the purpose of guiding future treatment 
decisions.  Results will not be available for samples that do not meet criteria for 
testing. 
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 biological specimens, including 
body fluids, solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, 
peptides).  The collection, storage, and analysis of RBR samples will facilitate the 

 
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rational design of new pharmaceutical agents and the development of diagnostic 
tests, which may allow for individualized drug therapy for patients in the future.  
RBR is not applicable in China. 
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve 
one or more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to 
developing adverse events or can lead to improved adverse event monitoring 
or investigation 
 
To increase knowledge and understanding of disease biology and drug 
safety 
 
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 
 
4.5.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples 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 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to GDC-9545, 
diseases, or drug safety: 
 
Leftover blood, plasma, and tumor tissue samples (with the exception of 
remaining archival tissue blocks, which will be returned to sites) and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides)  
 
The above samples may be sent to one or more laboratories for analysis of 
germline or somatic variants via WGS, WES, or other genomic analysis methods.  
Genomics is increasingly informing researcher's understanding of disease 
pathobiology.  WGS and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this 
study, may increase the opportunity for developing new therapeutic approaches 
or new methods for monitoring efficacy and safety or predicting which patients 
are more likely to respond to a drug or develop adverse events. 

 
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Data generated from RBR samples will be analyzed in the context of this study 
but may also be explored in aggregate with data from other studies.  The 
availability of a larger dataset will assist in identification and characterization of 
important biomarkers and pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples 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 
RBR samples and associated data will be labeled with a unique patient 
identification number. 
Patient medical information associated with RBR samples 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 of RBR samples, 
data derived from these analyses 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. 
Data generated from RBR samples 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 consent 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 samples.  Patients who decline to participate will not 
provide a separate signature. 

 
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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 samples and data will continue to be used as part of the RBR 
research. 
4.5.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples 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 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 this study 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 this study. 
4.5.12.7 
Monitoring and Oversight 
RBR samples 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 samples 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. 

 
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4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of 
the following: 
 
Any medical condition that the investigator or Sponsor determines may 
jeopardize the patient's safety if he or she continues to receive study 
treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the 
best interest of the patient 
 
Intolerable toxicity related to study treatment determined by the investigator 
to be unacceptable in light of the potential for treatment benefit and the 
severity of the event 
 
Disease progression per investigator assessment according to RECIST 1.1, 
with the exception of isolated brain metastases (see Section 4.4.3) 
 
Symptomatic deterioration attributed to disease progression, as assessed by 
the investigator 
 
Non-compliance with protocol-specified drug administration and follow-up 
tests 
 
Concomitant use of any other (non-protocol) systemic anti-cancer therapy  
 
Pregnancy 
 
The primary reason for study treatment discontinuation should be documented 
on the appropriate eCRF.  Patients who discontinue study treatment will not be 
replaced. 
Patients will return to the clinic for a treatment discontinuation visit 30 
( 3) days after the final dose of study treatment (unless final dose resulted in a 
dose delay prior to decision to discontinue).  For the control arm, the upper limit 
of the visit window will be dependent upon maximum dosing delay as permitted 
per local guidelines.  The visit at which response assessment shows progressive 
disease may be used as the treatment discontinuation visit if it falls within 28 ( 3) 
days after the patient's final dose of study treatment.  After treatment 
discontinuation, adverse events will continue to be recorded as outlined in the 
schedule of activities (see Appendix 1). 
Patients who discontinue study treatment for any reason other than unequivocal 
disease progression or death will continue to undergo tumor response 
assessments and PRO assessments as outlined in the schedule of activities (see 
Appendix 1). 
After treatment discontinuation (regardless of the reason), information on survival 
follow-up and new anti-cancer therapy will be collected via telephone calls, 

 
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patient medical records, and/or clinic visits approximately every 6 months or 
more frequently until death (unless the patient withdraws consent or the Sponsor 
terminates the study). 
Refer to the schedule of activities (see Appendix 1) for details on follow-up 
assessments to be performed for patients who discontinue study treatment.  
Patients who are unwilling to return to the clinic after treatment discontinuation 
will no longer undergo adverse event and tumor response assessments at clinic 
visits but can undergo follow-up for adverse events, survival, and new 
anti-cancer therapy via telephone calls.   
4.6.2 
Patient Discontinuation from the Study 
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 patient discontinuation from the study may include, but are not 
limited to, the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol 
requirements as determined by the investigator or Sponsor 
 
Every effort should be made to obtain a reason for patient discontinuation from 
the study.  The primary reason for discontinuation from the study should be 
documented on the appropriate eCRF.  If a patient requests to be withdrawn from 
the study, this request must be documented in the source documents and signed 
by the investigator, and must also be documented in the eCRF.  Patients who 
withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information 
source (e.g., county records) to obtain information about survival status. 
4.6.3 
Study 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. 
 

 
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The Sponsor will notify the investigator if the Sponsor decides to discontinue the 
study.   
4.6.4 
Site Discontinuation 
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 
GDC-9545 is not currently approved for any indication, and clinical development 
is ongoing.  The safety plan for patients in this study is based on clinical 
experience with GDC-9545 in ongoing studies.  The known (identified) and 
potential safety risks for GDC-9545 are outlined below. 
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, 
with severity graded according to NCI CTCAE v5.0.  An IMC will review safety 
data regularly throughout the study (see Section 3.1.3).  Furthermore, guidelines 
for managing adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided below. 
5.1.1 
Identified Risks of GDC-9545  
The identified risks are based on the data contained in GDC-9545 Investigator 
Brochure Version 5. 
5.1.1.1 
Arthralgia 
Arthralgia was very common (10%) in patients treated with GDC-9545.  The 
cases were generally mild to moderate, with the majority of cases being Grade 1 
in maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Management of arthralgia should be according to local 
standard of care and institutional guidelines. 

 
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5.1.1.2 
Bradycardia  
Bradycardia was commonly reported in patients treated with giredestrant. All 
cases were non-serious and mild to moderate, with most cases being Grade 1 in 
maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Please refer to Table 1 for management guidelines.  
 
5.1.1.3 
Diarrhea 
Diarrhea was very common (10%) in patients treated with GDC-9545.  The 
cases were generally mild to moderate, with the majority of cases being Grade 1 
in maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Please refer to Table 1 for management guidelines. 
5.1.1.4 
Dizziness 
Dizziness was common (10%) in patients treated with GDC-9545.  The cases 
were generally mild to moderate, with the majority of cases being Grade 1 in 
maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Dizziness should be managed according to 
institutional guidelines. 
5.1.1.5 
Headache  
Headache was commonly reported in patients treated with giredestrant. Cases 
were non-serious and Grade 1 or Grade 2 in severity. Most headache events 
resolved without treatment. 
 
5.1.1.6 
Hepatotoxicity  
Events of aspartate aminotransferase (AST) increased and/or alanine 
aminotransferase increased (ALT), were very commonly reported in patients 
treated with giredestrant.  Events of blood bilirubin increased were commonly 
reported.  The majority of events were Grade 1 or Grade 2, with few Grade 3 
events.  Overall, most events were non-serious and managed with either drug 
interruption or discontinuation of giredestrant, with treatment, or without any 
intervention.  Please refer to Table 1  for management guidelines. 
 
5.1.1.7 
Hot flush 
Hot flush was common (1% to 10%) in patients treated with GDC-9545.  The 
cases were generally mild to moderate, with the majority of cases being Grade 1 
in maximum intensity.  Hot flush should be managed according to institutional 
guidelines. 
5.1.1.8 
Fatigue 
Fatigue was very common (10%) in patients treated with GDC-9545.  The cases 
were generally mild to moderate, with the majority of cases being Grade 1 in 
maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Fatigue should be managed according to institutional 
guidelines. 

 
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5.1.1.9 
Musculoskeletal pain 
Musculoskeletal pain was very common (10%) in patients treated with GDC-
9545.  The cases were generally mild to moderate, with the majority of cases 
being Grade 1 in maximum intensity.  The vast majority of cases resolved without 
intervention or interruption of study drug.  Management of musculoskeletal pain 
should be according to institutional guidelines. 
5.1.1.10 
Nausea 
Nausea was very common (10%) in patients treated with GDC-9545.  The 
cases were generally mild to moderate, with the majority of cases being Grade 1 
in maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Please refer to Table 1 for management guidelines. 
5.1.1.11 
Vomiting 
Vomiting was common (1% to 10%) in patients treated with GDC-9545.  The 
cases were generally mild to moderate, with the majority of cases being Grade 1 
in maximum intensity.  The vast majority of cases resolved without intervention or 
interruption of study drug.  Please refer to Table 1 for management guidelines. 
5.1.2 
Potential Risks Associated with GDC-9545 
The potential risks associated with GDC-9545 are based on data from the GDC-
9545 Investigator’s Brochure Version 5.  Please refer to the GDC-9545 
Investigator's Brochure for further details.  
Guidelines for management of patients who develop signs of the potential risks 
described below are provided in Section 5.1.3. 
5.1.2.1 
Venous Thromboembolic Events (Including Pulmonary 
Embolism) 
No thromboembolic events related to GDC-9545 have been reported.  
Thromboembolic events occur in patients with malignancies, and the risk may be 
increased by suppression of ER signaling.  Patients should be closely monitored 
for signs and symptoms of thrombosis and instructed to immediately seek 
medical attention if thrombosis is suspected.   
In Study GO39932, as of the CCOD, in the single-agent cohorts at doses ranging 
from 10250 mg (N111), Grade 3 pulmonary embolism was reported in 1 patient 
(1.8%) treated at 100 mg and was considered unrelated to GDC-9545 by the 
investigator.  There were no cases of VTEs reported in the 30 mg single-agent 
cohort. 
5.1.2.2 
Renal Toxicity or Increased Creatinine 
In Study GO39932, no cases of acute kidney injury or adverse events of 
creatinine increase have been reported with single-agent GDC-9545 in doses up 

 
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to 250 mg (N111).  The following potentially relevant adverse events were 
reported: proteinuria and glomerular filtration rate decreased (1 patient each, 
0.9%). 
No trends of increase in serum creatinine levels were seen in laboratory results 
to date. 
5.1.2.3 
Changes in Female Reproductive Organs and Menopausal 
Symptoms  
Based on the anti-estrogenic pharmacologic activity of GDC-9545, the following 
effects are anticipated to occur:  loss of muscle and bone, hot flashes, vaginal 
dryness or discharge, irritation, mood swings, and decreased libido.  These 
symptoms could potentially be more severe than those experienced by typical 
menopausal patients. 
The following adverse events classified as “reproductive system and breast 
disorders” have been reported in patients in Study GO39932 who received 
single-agent GDC-9545 at doses of 10 to 250 mg (N111):  vulvovaginal 
dryness, vaginal discharge, breast pain, and vulvovaginal pruritus (all 1 patient 
each, with the exception of vaginal discharge which occurred in 2 patients 
[1.8%]); all were Grade 1.   
5.1.2.4 
Female and Male Fertility  
In nonclinical studies, perturbation and arrest of the estrus cycle was observed 
microscopically in early development.  There was evidence of a return to estrus 
cycling following a 16-week recovery period.  While this finding remains 
incompletely explained, any patients with concerns for future fertility should be 
made aware of this potential issue prior to joining this study.  Their concerns, 
including fertility preservation, should be discussed prior to enrolling in any study 
with GDC-9545. 
No microscopic effects on male reproductive organs were attributed to 
administration of GDC-9545 in a 13-week study in male rats. 
The effects of GDC-9545 on fertility in humans have not been studied. 
5.1.2.5 
Embryofetal Toxicity 
On the basis of the anti-estrogenic pharmacological activity of GDC-9545, 
administration of GDC-9545 during pregnancy is expected to have an adverse 
effect and poses a risk to the human fetus, including birth defects and 
miscarriage. 

 
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5.1.3 
Management of Patients Who Experience Adverse Events 
5.1.3.1 
Dose Modifications 
There is no dose modification permitted for GDC-9545 and GDC-9545 should be 
administered on each day during the 28-day cycle.  See Section 5.1.3.3 for 
further details on management of adverse events associated with GDC-9545. 
5.1.3.2 
Treatment Interruption 
GDC-9545 may be temporarily suspended or delayed for up to 28 days in 
patients who experience toxicity considered to be related to study drug.  In the 
event that GDC-9545 cannot be resumed after being withheld for 28 days, the 
patient should be discontinued from GDC-9545 as per Section 4.6.1. 
5.1.3.3 
Management Guidelines 
Guidelines for management of specific adverse events associated with GDC-
9545 are outlined in Table 1 .  Additional guidelines are provided in the 
subsections below. 
Table 1 
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with GDC-9545 
Event 
Action to Be Taken 
Elevation of Hepatic Transaminases: 
General guidance 
 
If patient presents with jaundice, coagulopathy, abdominal pain, or 
other symptoms suggestive of hepatic toxicity, perform liver function 
tests with additional evaluation per institutional guidelines. 
 
If hepatic enzymes are elevated with no obvious malignant cause 
found, consult with hepatologist.  
 
Treat patient with hepatic enzyme elevation according to local 
standard of care. 
Grade 1 or 2 
 
Continue GDC-9545. 
 
Rule out alternative etiologies (e.g., liver metastases, concomitant 
medications, or biliary obstruction). 
 
Treat patient according to local standard of care. 
 
Initiate close monitoring of LFTs until any abnormalities resolve or 
are assessed as stable. 
Grade 3 
 
Withhold GDC-9545.  
 
Consider consultation with hepatologist.  If event resolves to 
Grade  1 within 28 days, resume GDC-9545 at full dose, 
continuing close monitoring of LFTs until any abnormalities 
resolve or are assessed as stable. 
 
If event does not resolve to Grade  1 within 28 days, permanently 
discontinue GDC-9545. 
Grade 4 or meets 
criteria as defined by 
Hy's Law 
(see Section 5.3.5.7) 
 
Permanently discontinue GDC-9545. 
 
Consult with hepatologist. 

 
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Event 
Action to Be Taken 
Gastrointestinal Events (Nausea, Vomiting, Diarrhea)  
General guidance 
 
Monitor closely for GI symptoms.  If patient presents with nausea, 
vomiting, or diarrhea, manage according to local standard of 
care, including use of anti-diarrheal agents and supportive care 
such as hydration and dietary modification as appropriate. 
 
Infectious or alternate etiologies should be ruled out. 
Grade 1 
 
Continue GDC-9545. 
Grade 2 
 
Manage and treat according to local standard of care  
 
If persistent despite appropriate medical therapy, withhold 
GDC-9545 until resolution to Grade 1 or better. 
Grade  3 
 
Withhold GDC-9545 until event resolves to Grade 1 or better. 
 
Manage and treat patient according to local standard of care. 
 
Consider consulting with gastroenterologist.  
 
Resume GDC-9545 at regular dose once the event resolves to 
Grade 1 or better. 
 
If event is recurring and patient cannot tolerate treatment, 
permanently discontinue GDC-9545. 
GI  gastrointestinal; LFT  liver function test; ULN  upper limit of normal. 
 
 

 
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Table 1  
Guidelines for Management of Patients Who Experience Adverse 
Events Associated with GDC-9545 (cont.)  
Event 
Action to Be Taken 
Venous Thromboembolic Events (Including Pulmonary Embolism) 
General guidance 
 
Advise patients to seek immediate medical attention if they 
become aware of any symptoms of PE or DVT such as acute 
onset of chest pain, shortness of breath, or swelling in extremities.  
Grade 1 
 
Continue GDC-9545. 
Grade  2 
 
Withhold GDC-9545 until patient is stable (any thrombolytic 
therapy and in-patient anticoagulation has been completed). 
 
Manage and treat patient according to local standard of care.  
 
Resume GDC-9545 at full dose once the patient is stable.  
 
Permanently discontinue GDC-9545 for recurrent thromboembolic 
events. 
Bradycardia 
General guidance 
 
Monitor patient closely for symptomatic bradycardia  
Grade 1 
 
Continue GDC-9545. 
 
Continue to monitor patient per schedule of activities (Appendix 1).  
 
If heart rate falls below 40 bpm, withhold GDC-9545 until heart 
rate returns to  40 bpm and patient remains asymptomatic. 
Grade 2 
 
Withhold GDC-9545 and consult with cardiologist.   
 
Resume GDC-9545 at full dose once the event improves to 
Grade 1 or better and heart rate returns to  40 bpm. 
 
For recurrent Grade 2 bradycardia, permanently discontinue 
GDC-9545. 
Grade 3 
 
Permanently discontinue GDC-9545 and consult with cardiologist. 
Renal Toxicity or Increased Creatinine 
Grade 1 or 2 
 
Continue GDC-9545. 
 
Manage patient according to local standard of care. 
Grade 3 
 
Permanently discontinue GDC-9545. 
 
Manage patient according to local standard of care.  
 
Consult with nephrologist. 
Non-Hematologic Toxicity 
Grade 1 or 2 
 
Continue GDC-9545. 
 
Rule out alternative etiologies. 
Grade 3  
 
Withhold GDC-9545 until symptoms resolve to Grade 1 or better, 
and then resume GDC-9545 at full dose. 
Grade 4 
 
Permanently discontinue GDC-9545. 
DVT  deep vein thrombosis; PE  pulmonary embolism. 
 
 

 
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5.1.3.4 
Management of Increases in QT Interval 
GDC-9545 should be discontinued in patients who develop any of the following, 
unless there is a clear alternative cause for the changes: 
 
Sustained (at least two ECG measurements  30 minutes apart) QTcF that is 
 500 ms and  60 ms longer than the baseline value 
 
Sustained absolute QTcF that is  515 ms 
 
An episode of torsades de pointes or a new ECG finding of clinical concern 
 
Of note, if there is a new intraventricular conduction block, the increase in QRS 
complex duration should be subtracted from the QTcF change, because this 
represents an increase in QTcF unrelated to alterations in repolarization.  Also of 
note, it is not uncommon to record arrhythmias such as non-sustained ventricular 
tachycardia, supraventricular tachycardia, pauses, or atrial fibrillation in healthy 
volunteers receiving placebo during periods of extended ECG monitoring.  
Therefore, it is critical that expert cardiology advice be sought to confirm any 
ECG changes and to ascertain the likelihood of a drug-induced arrhythmia 
versus the background occurrence of this arrhythmia.  In such a situation, saving 
all available ECG data is highly suggested. 
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and 
possible discontinuation of other concomitant medications that are known to 
prolong the QT interval.  Consultation with a cardiologist or electrophysiologist is 
recommended, to help in the management of such patients. 
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 

 
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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) (see Sections 5.3.5.9 
and Section 5.3.5.10 for more information) 
 
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 5.3.5.11) 
 
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; see Section 5.3.3); the event itself may be of relatively 
minor medical significance (such as severe headache without any further 
findings). 

 
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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; see Section 5.4.2 for reporting instructions).  Adverse events of special 
interest for this study are as follows: 
 
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 5.3.5.7) 
 
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 hepatitis or elevations in AST or ALT 
 
Grade  3 acute kidney injury, creatinine increase, or renal toxicity 
 
Grade  2 bradycardia 
 
Grade  2 thromboembolism 
 
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 
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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 prior to 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 30 days after 
the final dose of study drug. 
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 (v5.0) will be used 
for assessing adverse event severity.  Table 2 will be used for assessing severity 
for adverse events that are not specifically listed in the NCI CTCAE. 

 
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Table 2 
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 (v5.0), 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  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. 
 
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 3): 
 
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 
 

 
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Table 3 
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 eCRF. 
5.3.5.1 
Injection Reactions (for Patients Receiving Fulvestrant or 
Formestane) 
Adverse events that occur during or within 24 hours after study drug 
administration for injectable anti-cancer therapy and are judged to be related to 
study drug injection should be captured as a diagnosis (e.g., "injection-site 
reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If possible, 
avoid ambiguous terms such as "systemic reaction."  If the adverse event is 
serious, associated signs and symptoms should be recorded on the dedicated 
"Additional case details and event narrative" section within the Adverse Event 
eCRF.  If a patient experiences both a local and systemic reaction to the same 
dose of study drug, each reaction should be recorded separately on the Adverse 
Event eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
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 

 
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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. 
5.3.5.3 
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 GI 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. 
5.3.5.4 
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 events. 
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. 

 
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5.3.5.5 
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  
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events. 
 
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., ALP 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 potassium," as opposed to "abnormal potassium").  
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 5.3.5.4 for details on recording persistent adverse events). 
5.3.5.6 
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 5.3.5.4 for details on recording persistent adverse events). 
5.3.5.7 
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 5.3.5.2) 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). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are 
attributed by the investigator solely to progression of underlying breast cancer 
should be recorded on the Death Attributed to Progressive Disease eCRF.  All 
other deaths that occur during the adverse event reporting period, 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).  An IMC 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 

 
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ascertained at the time of reporting, "unexplained death" should be recorded on 
the Adverse Event eCRF.  If the 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"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
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"). 
5.3.5.10 
Lack of Efficacy or Worsening of Breast Cancer 
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.  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. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
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. 

 
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The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
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 
 
5.3.5.12 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug 
misuse (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, 
including omission of dosing by patient in error 
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 event; see Section 5.4.2).  For GDC-9545, 
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. 

 
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 
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 GDC-9545, 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., patient forgot to take 
drug, 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. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO-CTCAE or other PRO data 
by the Sponsor.  In addition, the Sponsor will make no attempt to reconcile 
patient reports of treatment-related symptoms (via PRO-CTCAE) with 
investigator reports of adverse events.  Sites are not expected to review the 
PRO-CTCAE or other PRO data for adverse events. 
5.3.5.14 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the 
Sponsor, and safety biomarker data will not be included in the formal safety 
analyses for this study.  In addition, safety biomarker data will not inform 
decisions on patient management. 
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) 

 
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 
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 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 
 
Investigators must also comply with local requirements for reporting serious 
adverse events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
The Medical Monitor is available to the Principal Investigator to advise and 
answer any questions related to study inclusion or exclusion criteria and may 
share risk information pertinent to the patient.  The Medical Monitor must refrain 
from providing clinical advice.  The decision to enroll the patient in the study is 
the responsibility of the investigator. All eligibility decisions are made by the 
investigator and the Medical Monitor is available to advise as needed. 
To ensure the safety of study participants, access to the Medical Monitors is 
available 24 hours per day, 7 days per week.  Details are provided separately. 
To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts 
cannot be reached.  The Emergency Medical Call Center will connect the 
investigator with an Emergency Medical Contact, provide medical translation 
service if necessary, and track all calls.  Contact information, including toll-free 
numbers for the Emergency Medical Call Center, will be distributed to 
investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to 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 paper Clinical Trial Adverse Event/Special Situations Form 

 
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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, all serious adverse events and adverse events of 
special interest will be reported until 30 days after the final 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 paper 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  30 days after the 
final dose of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant 
while on the study, within 10 days after the final dose of GDC-9545, or within the 
time period specified per local prescribing guidelines after the final dose of 
physician's choice of endocrine monotherapy.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit it to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form 
using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother 
during or after the pregnancy, or a congenital anomaly/birth defect in the child) 
should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on 
the course and outcome of the pregnancy becomes available.   

 
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5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to 
immediately inform the investigator about the estimated date of conception if their 
partner becomes pregnant during the study, within 10 days after the final dose of 
GDC-9545, or within the time period specified per local prescribing guidelines 
after the final dose of physician's choice of endocrine monotherapy.  The 
investigator should report the pregnancy on the paper Clinical Trial Pregnancy 
Reporting Form, which should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax 
number 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 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. 
5.4.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers abortions to be medically significant), 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). 
If a therapeutic or elective abortion was performed because of an underlying 
maternal or embryofetal toxicity, the toxicity 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).  A therapeutic or elective abortion performed for reasons other 
than an underlying maternal or embryofetal toxicity is not considered an adverse 
event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical 
Trial Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed 
to study drug or the female partner of a male patient exposed to study drug 
should be classified as a serious adverse event, recorded on the Adverse Event 

 
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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 and adverse events of special interest 
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, email, 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 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period 
(defined as 30 days after the final dose of study drug), if the event is believed to 
be related to prior study drug treatment.  These events should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not 
available, the investigator should report these events directly to the Sponsor or 
its designee, either by faxing or by scanning and emailing the paper Clinical Trial 
Adverse Event/Special Situations Form using the fax number or email address 
provided to investigators. 
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 

 
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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 through use of the reference safety 
information in the document listed below: 
Drug 
Document 
GDC-9545 
GDC-9545 Investigator's Brochure  
Physician's choice of endocrine monotherapy: 
Fulvestrant 
E.U. SmPC 
Letrozole 
E.U. SmPC 
Anastrozole 
E.U. SmPC 
Exemestane 
E.U. SmPC 
Testolactone 
USPI 
Aminoglutethimide 
USPI 
Formestane 
Chinese Package Insert 
SmPC  Summary of Product Characteristics; USPI  U.S. Package Insert. 
 
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. 

 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The primary efficacy objective for this study is to evaluate the efficacy of 
GDC-9545 compared with physician's choice of endocrine monotherapy in 
patients with ER-positive, HER2-negative locally advanced or metastatic breast 
cancer.  Statistical analyses will be performed using two analysis populations as 
described below: 
 
Intent-to-treat (ITT) population:  The ITT population will consist of all patients 
assigned to treatment groups as randomized by the IxRS.  All efficacy 
analyses will be performed using the ITT population, unless otherwise 
specified. 
 
Safety-evaluable population:  The safety population will consist of all patients 
who receive at least one dose of study drug (GDC-9545 or physician's choice 
of endocrine monotherapy) and will be analyzed based on the treatment 
received.  Thus, all patients who received at least one dose of GDC-9545 are 
included in the GDC-9545 safety-evaluable group and all patients who 
received at least one dose of endocrine monotherapy per physician's choice 
are included in the control group.  All safety analyses will be performed using 
the safety-evaluable population. 
 
The global population will include all patients enrolled during the global 
enrollment phase (including patients enrolled in mainland China, Hong Kong, 
and/or Taiwan during that phase), and the China subpopulation will include all 
patients enrolled in mainland China, Hong Kong, and/or Taiwan (i.e., during both 
the global enrollment phase and the extended China enrollment phase).  
Separate analyses will be performed for the global population and the China 
subpopulation; the analyses described in Sections 6.16.8 apply to the global 
population, see Section 6.9 for information on the China subpopulation analyses. 
The primary efficacy analysis of PFS and the details and timing of the primary 
efficacy analysis are outlined in Sections 6.1 and 6.4. 
Details of analyses will be provided in the Statistical Analysis Plan (SAP). 
6.1 
DETERMINATION OF SAMPLE SIZE 
Approximately 300 patients will be enrolled and randomized in a 1:1 ratio to 
receive either GDC-9545 (experimental arm) or physician's choice of endocrine 
monotherapy (control arm).  The sample size is determined by the primary 
endpoint, investigator-assessed PFS, comparing the two treatment arms. 
The primary analysis of PFS will be conducted when approximately 166 PFS 
events from both arms are observed.  The 166 PFS events allow for 80% power 
to detect an improvement in median PFS from 5.5 months to approximately 8.5 
months (hazard ratio  0.647) at the 5% (two-sided) level of significance.  The 

 
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largest hazard ratio determined to be statistically significant at the 5% level will 
be approximately 0.738 (with median improvement in PFS from 5.5 to 7.5 
months). 
The enrollment duration is projected to be approximately 15 months after 
randomization of the first patient.  For both the GDC-9545 and control arms, an 
annual loss to follow-up rate of 10% is assumed.  On that basis, it is projected 
that the primary PFS analysis will occur approximately 18 months after the first 
patient is enrolled. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Study enrollment, duration, study drug discontinuation, and study discontinuation, 
as well as reasons for study drug discontinuation and study discontinuation, will 
be listed and summarized by treatment arm.  Major protocol deviations, including 
major deviations with regard to inclusion and exclusion criteria, will also be listed 
and summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
The evaluation of treatment group comparability between the treatment arms will 
include summaries of demographic and baseline characteristics, including 
stratification factors and patient treatment history.  
Continuous variables will be summarized using means, standard deviations, 
medians, and ranges.  Categorical variables will be summarized by counts and 
proportions. 
6.4 
EFFICACY ANALYSES 
Unless otherwise specified, the ITT population consisting of all randomized 
patients, with patients grouped according to their assigned treatment, will be 
used for efficacy analysis. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is investigator-assessed PFS as 
defined in Section 2.1.1.  Data for patients without the occurrence of disease 
progression or death as of the CCOD will be censored at the time of the last 
tumor assessment prior to the CCOD (or at the time of randomization plus 1 day 
if no tumor assessment was performed after the baseline visit).  PFS will be 
compared between treatment arms using the stratified log-rank test.  The hazard 
ratio will be estimated using a stratified Cox proportional hazards model.  The 
95% CI for the hazard ratio will be provided.  The stratification factors used will 
be the same as the randomization stratification factors (see Section 4.2.1).  
Results from an unstratified analysis will also be provided.  For each treatment 
arm, Kaplan-Meier methodology will be used to estimate the median PFS, and 

 
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the Brookmeyer-Crowley method will be used to construct the 95% CI for the 
median PFS.  Kaplan-Meier curves will also be produced. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study, OS, ORR, DOR, and PFS (in 
subgroups characterized by baseline ESR1 mutation status); and the PROs TTD 
in pain severity, PF, RF, GHS/QoL, and pain presence/interference and burden, 
are defined in Section 2.1.2.  ORR and DOR are determined by the investigator 
according to RECIST v1.1. 
6.4.2.1 
Overall Survival 
Data for patients who are alive at the time of the analysis data cutoff will be 
censored at the last date they were known to be alive.  Data from patients 
without postbaseline information will be censored at the date of randomization 
plus 1 day. 
The OS analyses will be conducted at the time of the primary analysis of PFS, at 
least 12 months after the primary analysis, and at the end of the study, which is 
expected to occur at least 25 months after the last patient is enrolled in the global 
study.  OS will be hierarchically tested if the primary endpoint, PFS, is statistically 
significant at the primary PFS analysis.  Analysis methodology for OS is the 
same as outlined for the primary endpoint, PFS.  
6.4.2.2 
Objective Response Rate 
The analysis population for ORR will be all randomized patients with measurable 
disease at baseline.  Patients not meeting the criteria for ORR, including patients 
without any postbaseline tumor assessment, will be considered non-responders. 
An estimate of ORR and its 95% CI will be calculated using the Clopper-Pearson 
method for each treatment arm.  ORR will be compared between treatment arms 
using the stratified Cochran-Mantel-Haenszel test.  The stratification factors to be 
used will be the same as those used for the analysis of the primary endpoint.  
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. 
6.4.2.3 
Duration of Response 
Analysis of DOR will include only patients who had an objective response.  Data 
for patients who have not progressed and who have not died at the time of 
analysis will be censored at date of the last tumor assessment. 
The Kaplan-Meier approach will be used to estimate the median DOR and the 
corresponding 95% CIs. 

 
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6.4.2.4 
Clinical Benefit Rate  
CBR, defined as the proportion of patients with stable disease for  24 weeks or a 
CR or PR, as determined by the investigator according to RECIST v1.1.  CBR 
will be analyzed using the same methods as those used for ORR. 
6.4.2.5 
PFS by ESR1 Mutation Status 
Investigator-assessed PFS will be analyzed in subgroups categorized by ESR1 
mutation status determined at baseline from plasma ctDNA. 
Similar to PFS analysis, 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).  PFS by ESR1 
positive- and negative- mutation status will be compared between treatment arms 
using the stratified log-rank test.  Hazard ratio estimates, confidence intervals 
and plots will follow the same methods as those used for primary endpoint PFS 
analysis. 
6.4.2.6 
Patient-Reported Outcomes 
The PRO-evaluable population consists of randomized patients with at least one 
postbaseline assessment.  Data for patients who do not have an observed 
deterioration at the time of the CCOD will be censored at the last non-missing 
assessment date.  Data for patients without a postbaseline assessment will be 
censored at the time of randomization plus 1 day. 
To evaluate TTD in pain severity, the "worst pain" item from the BPI-SF will be 
assessed.  A 2-point change in the worst pain rating is defined as clinically 
meaningful (Mathias et al. 2010). 
TTD in EORTC QLQ-C30 scale scores for pain presence and interference 
(Items 9 and 19), PF (Items 15), RF (Items 6 and 7), and GHS/ QoL (Items 29 
and 30) will be assessed.  A  10-point change in EORTC QLQ-C30 scale scores 
is defined as clinically meaningful (Osoba et al. 1998). 

 
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6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints for this study will be additional PROs as 
defined in Section 2.1.3. 
Summary statistics (mean, standard deviation, median, 25th and 75th 
percentiles, and range) of linear transformed scores will be reported for the 
"worst pain" item of the BPI-SF, as well as all scales (symptoms, functional 
domains, and GHS/QoL) of the QLQ-C30 and QLQ-BR23 questionnaires for 
each assessment timepoint.  The mean change of the linear transformed scores 
from baseline (and 95% CI using the normal approximation) will also be analyzed 
for each treatment arm.  Line charts depicting the mean and mean changes from 
the baseline assessment (and 95% CIs) of items and scales over time will be 
provided for each treatment arm.  In the event of incomplete data for all 
questionnaire scales, if more than 50% of the constituent items are completed, a 
prorated score will be computed consistent with the scoring manuals and 
validation papers.  For scales with less than 50% of the items completed, the 
scale will be considered as missing in accordance with the EORTC scoring 
manual guidelines (Fayers 2001). 
PRO completion, compliance rates, and reasons for missing data will be 
summarized at each timepoint by treatment arm for each measure in ITT 
population.  The compliance rate will be based on the total number of patients 
expected to complete the questionnaire at a particular timepoint.  
Note that data collected via patient interviews will be analyzed separately, on a 
qualitative/descriptive basis, and will not be included in the main study database 
or detailed in the SAP. 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all patients who received at least 
one dose of study drug (GDC-9545 or physician's choice of endocrine 
monotherapy), with patients grouped according to treatment received. 
6.5.1 
Analyses of Exposure, Adverse Event, Laboratory, and Vital 
Sign Data  
The frequency, nature, and severity of treatment-emergent adverse events, 
adverse events leading to death, adverse events leading to study drug 
discontinuation, serious adverse events, and adverse events of special interest 
will be summarized by treatment arm.  All deaths will be summarized.  Relevant 
vital signs will be presented using summary statistics by treatment received.  
Drug exposure will also be summarized, including duration of treatment, 
cumulative dose, and dose intensity. 

 
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Treatment-emergent adverse events are defined as adverse events that occur 
after the first dose of study treatment.  Adverse events will be mapped to 
MedDRA thesaurus terms and appropriate MedDRA hierarchy.  Adverse event 
severity will be graded according to NCI CTCAE v5.0.  Multiple occurrences of 
the same event will be counted once at the maximum severity. 
Selected laboratory and vital sign data will be summarized by treatment received, 
and grade compared with baseline and measurements outside of the normal 
range will be identified. 
6.5.2 
Exploratory Safety Analyses of PRO-CTCAE and GP5 Data 
PRO-CTCAE analyses will be descriptive, with a focus on characterizing the 
pattern of symptomatic treatment toxicities over the course of the study.  The 
number and percentage of patients reporting each symptom and the change from 
baseline by category (frequency of occurrence, severity, or interference) will be 
summarized at each assessment timepoint by treatment arm.  For items that are 
rated on a 5-point Likert scale, the maximum postbaseline score and change 
from baseline will be summarized by treatment arm. 
Results from these exploratory analyses will be presented separately from the 
safety analyses.  PRO-CTCAE data will be analyzed at the item level in line with 
current NCI recommendations for data handling (Basch et al. 2014).  Graphical 
representation of PRO-CTCAE data over time will also be provided.  PRO-
CTCAE data will be summarized over time.  These analyses will also apply to the 
GP5 overall treatment burden item.  The proportion of missing data at each 
assessment timepoint will also be summarized to facilitate interpretation of data. 
A descriptive analysis of absolute scores and the proportion of patients selecting 
each response option at each assessment timepoint by treatment arm will be 
reported for the FACT-G single-item GP5. 
6.6 
PHARMACOKINETIC ANALYSES 
The PK analysis population will consist of patients who received GDC-9545 and 
have at least one evaluable GDC-9545 concentration.  PK parameters (e.g., area 
under the concentrationtime curve, time to maximum concentration, maximum 
concentration observed, and half-life if appropriate) will be estimated from an 
intensive PK samplesubset patient population.  Summary statistics (e.g., 
geometric mean, standard deviation, coefficient of variation, median, minimum, 
and maximum) will be presented for PK data.  Plasma GDC-9545 concentration 
versus time data will be tabulated and plotted.  
GDC-9545 PK data may be pooled and analyzed using a population PK analysis 
approach as appropriate and reported in a standalone report. 

 
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6.7 
BIOMARKER ANALYSES 
Although no formal statistical analysis of exploratory biomarkers will be 
performed, data may be analyzed in the context of this study and in aggregate 
with data from other studies.  Results may be presented in a separate report. 
6.8 
HEALTH STATUS UTILITY ANALYSES 
Change from baseline in EQ-5D-5L health utility index-based and VAS scores 
will be calculated at specified timepoints. 
6.9 
CHINA SUBPOPULATION ANALYSES  
The China subpopulation will include all patients enrolled in mainland China, 
Hong Kong, and/or Taiwan (i.e., during both the global enrollment phase and the 
extended China enrollment phase).  Results from these analyses will be 
summarized in a separate Clinical Study Report.  
After global recruitment is closed, additional patients in China may subsequently 
be enrolled, following the same randomization procedures and 1:1 ratio.  The 
total number of patients in the China subpopulation should allow for sufficient 
demonstration of treatment benefit consistency between the global population 
and China subpopulation. 
The efficacy objective of the China subpopulation analyses is to evaluate 
whether the efficacy of GDC-9545 compared with physician's choice of endocrine 
monotherapy in the China subpopulation (enrolled during both the global 
enrollment phase and the extended China enrollment phase) is consistent with 
the efficacy observed in the global population enrolled during the global 
enrollment phase.  Therefore, no formal hypothesis testing will be performed for 
China subpopulation.  
The China subpopulation analyses will be conducted when sufficient PFS events 
have occurred to demonstrate an acceptable probability of maintaining  50% of 
risk reduction compared with that estimated from the global population.  The 
exact timing of analyses will be specified in the SAP.  
The analysis methods for China subpopulation will be the same as for the global 
population unless elsewhere noted.  The results of the China subpopulation 
analyses will be summarized in a separate report from the Clinical Study Report 
for the global population.  
GDC-9545 concentrationtime plots, concentration summaries, and PK 
parameters may be separately summarized for the intensively sampled patients 
from mainland China and the intensively sampled patients from the global 
population (not including mainland China).  All sparse PK samples as well as the 
intensive PK samples will be included in a population PK analysis, where race 

 
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may be tested as a covariate on PK parameters, if appropriate.  These analyses 
will be reported separately from the Clinical Study Report. 
Further details will be provided in the SAP. 
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 (see Section 7.3 for details).  In case the PRO device is not available at 
site or not functioning, a web-based or paper backup process may be used 
instead. 
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 that must be kept with the study records.  Acknowledgement 
of receipt of the data is required. 

 
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7.3 
ELECTRONIC PATIENT-REPORTED OUTCOME DATA 
An electronic device will be used to capture PRO data.  The device is designed 
for entry of data in a way that is attributable, secure, and accurate, in compliance 
with U.S. Food and Drug Administration (FDA) regulations for electronic records 
(21 CFR Part 11).  The data will be transmitted to a centralized database 
maintained by the electronic device vendor.  In case the PRO device is not 
available at site or not functioning, a web-based or paper backup process may be 
used instead.  Data collected in the printed version of the instrument will be 
transcribed by site staff into the same centralized database maintained by the 
electronic device vendor. 
The electronic data will be available for view access only, via a secure web 
server.  Only identified and trained users may view the data, and their actions will 
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. 
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 that must be kept with the 
study records as source data.  Acknowledgement of receipt of the data 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, patient-
reported outcomes, 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 

 
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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 and review, 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 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 IMP, 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. 

 
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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 
applicable 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 Trial Directive (2001/20/EC) 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 an Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) 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 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 (where allowed by local regulations) 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 

 
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Consent Forms must be provided to the Sponsor for health authority submission 
purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while 
a patient is participating in the study, the patient or a legally authorized 
representative (where allowed by local regulations) must re-consent by signing 
the most current version of the Consent Forms or the addendum, in accordance 
with applicable laws and IRB/EC policy.  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 (where allowed by local regulations).  
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. 
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 

 
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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 exploratory biomarker analyses, 
data derived from these analyses will generally not be provided to study 
investigators or patients unless required by law (with the exception of the report 
from Foundation Medicine).  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication (see Section 9.6). 
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). 

 
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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 (see definition of end of study in Section 3.2). 
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. 
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. 

 
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9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' 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 trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The 
Sponsor will provide clinical operations management, data management, and 
medical monitoring. 
Approximately 125 sites globally will participate to enroll approximately 300 
patients.  Enrollment will occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; 
local laboratory ranges will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the 
study.  An IRC will conduct a retrospective independent evaluation of disease 
response and progression (see Sections 3.1.2 and 3.1.3). 
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 will be made available 
upon request.  For more information, refer to the Roche Global Policy on Sharing 
of Clinical Study Information at the following website: 
 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 Clinical Study Report.  In addition, 

 
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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). 
10. 
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Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in 
hormone-resistant breast cancer. Nat Genet 2013;45:143945. 
Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for 
summarising adverse events of cancer treatment by the Radiation Therapy 
Oncology Group. Lancet Oncol 2007;8:61324. 
Van Tine BA, Crowder RJ, Ellis MJ. ER and PI3K independently modulate 
endocrine resistance in ER-positive breast cancer. Cancer Discov 
2011;1:2878. 
Webster K, Odom L, Peterman A, et al. The Functional Assessment of Chronic 
Illness Therapy (FACIT) measurement system: validation of version 4 of the 
core questionnaire. Quality Life Res 1999;8:604. 
Wolf AC, Hale Hammond ME, Allison KH, et al. Human epidermal growth factor 2 
testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists Clinical Practice Guideline Focused Update. Arch 
Pathol Lab Med 2018;142:1364-1382. 
Wood R, de Courcy J, Mitra D, et al. Patient reported pain severity and 
interference in HR+/HER2− advanced/metastatic breast cancer in real world 
settings. Ann Oncol 2016;27:6899.  
Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in 
postmenopausal patients with HR(+) breast cancer: BOLERO-2 final 
progression-free survival analysis. Adv Ther 2013;30:8704. 
 

 
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Appendix 1 Schedule of Activities 
Day 
(Window) 
Screening a 
Treatment Cycles (28-day cycles) 
Treatment 
Discontinuation 
Visit b 
PRO 
Follow-Up 
Follow-Up 
Cycles 12 
Cycles 3 and 
Beyond 
–28 to –1 
–7 to –1 
1c 
( 3 days) 
1 
( 3 days) 
30 Days after 
Final Dose 
( 3 days) 
90 Days 
after TD  
(7 days) 
Every 
6 months 
(7 days) d 
Informed consent 
x e 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
Medical history and baseline 
conditions 
x 
 
 
 
 
 
 
Vital signs f 
x 
 
x 
x 
x 
 
 
Weight 
x 
 
x 
x 
x 
 
 
Height 
x 
 
 
 
 
 
 
Complete physical examination g 
x 
 
 
 
 
 
 
Limited physical examination h 
 
 
x 
x 
x 
 
 
12-lead ECG i 
x 
 
x 
Day 1 of Cycle 4, 
then every four 
cycles thereafter 
x 
 
 
LVEF j 
x 
 
 
 
 
 
 
ECOG Performance Status 
x 
 
x 
x 
x 
 
 
Hematology k 
 
x  
x 
x 
x 
 
 
Chemistry l 
 
x  
x 
x 
x 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 1 Schedule of Activities (cont.)  
Day 
(Window) 
Screening a 
Treatment Cycles (28-day cycles) 
Treatment 
Discontinuation 
Visit b 
PRO 
Follow-Up 
Follow-Up 
Cycles 12 
Cycles 3 and 
Beyond 
–28 to –1 
–7 to –1 
1c 
( 3 days) 
1 
( 3 days) 
30 Days after 
Final Dose 
( 3 days) 
90 Days 
after TD  
(7 days) 
Every 
6 months 
(7 days) d 
Coagulation (INR [or PT], PTT [or 
aPTT]) 
 
x 
 
 
 
 
 
FSH and estradiol (for 
premenopausal/perimenopausal 
patients, and female patients aged 
 60 years only) m 
 
x  
Day 1 of each cycle for three cycles 
and then every three cycles thereafter, 
if receiving LHRH agonist 
 
 
 
Pregnancy test n 
 
x  
x n 
x 
x 
 
 
Urinalysis o 
x 
 
Perform as clinically indicated 
 
 
Confirmation of availability of 
tumor tissue specimen 
x 
 
 
 
 
GDC-9545 administration 
QD Days 128 of each cycle 
 
 
Administered at clinic visits 
(Day 1 of each cycle); otherwise 
administered at home p 
 
 
 
Physician's choice of endocrine 
monotherapy administration 
 
 
Administered as per local prescribing 
guidelines p 
 
 
 
LHRH agonist administration q 
(for premenopausal/perimenopausal 
patients and male patients only) 
 
 
Preferred option administered at 
clinic visit 
on Day 1 of each cycle (or according 
to clinical practice)  
 
 
 
 
 

 
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Appendix 1 Schedule of Activities (cont.)  
Day 
(Window) 
Screening a 
Treatment Cycles (28-day cycles) 
Treatment 
Discontinuation 
Visit b 
PRO 
Follow-Up 
Follow-Up 
Cycles 12 
Cycles 3 and 
Beyond 
–28 to –1 
–7 to –1 
1c 
( 3 days) 
1 
( 3 days) 
30 Days after 
Final Dose 
( 3 days) 
90 Days 
after TD  
(7 days) 
Every 
6 months 
(7 days)d 
Medication diary r 
 
 
Complete when medication is taken 
at home or at clinic visit 
 
 
 
Tumor assessment:  
CT, MRI, clinical s 
x 
 
Every 8 weeks ( 7 days) from randomization for the 
first 18 months,  
then every 12 weeks ( 7 days) thereafter until PD 
 
 
Bone scan  t 
x 
 
Every 24 weeks ( 7 days) from randomization until PD 
 
 
PK samples  
 
 
See Appendix 2 
 
 
Biomarker samples 
See Appendix 3 
 
 
PRO-CTCAE, GP5, EORTC QLQ-
C30, QLQ-BR23, BPI-SF "worst 
pain" item, EQ-5D-5L u 
 
 
x 
Cycle 3 and every 
other cycle 
thereafter u 
x 
x v 
 
Patient interviews (optional)w 
 
 
 
Once following 
Cycle 2 
 
 
 
Concomitant medications x 
 
x x 
x 
x 
x 
 
 
Adverse events y, z 
x 
x 
x 
x 
x 
 
 
Survival and new anti-cancer 
therapy follow-up  
 
 
 
 
 
 
x z, aa 

 
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BPI-SF  Brief Pain InventoryShort Form; CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; EORTC   European 
Organisation for Research and Treatment of Cancer; FACT-G  Functional Assessment of Cancer TherapyGeneral; FSH  follicle-stimulating 
hormone; GP5  General Population, Question 5; LHRH  luteinizing hormone-releasing hormone; LVEF  left ventricular ejection fraction; PD= 
progressive disease; PK  pharmacokinetic; PRO  patient-reported outcome; PRO-CTCAE  Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events; QD  once a day; RECIST  Response Evaluation Criteria in Solid Tumors; TD  treatment discontinuation. 
Notes:  On treatment days that coincide with clinic visits, all assessments should be performed prior to dosing, unless otherwise specified.  
For patients receiving GDC-9545, laboratory samples should be drawn within 72 hours prior to study drug administration. 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 of Cycle 1 may 
be used; such tests do not need to be repeated for screening, unless otherwise indicated. 
b Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit 30 ( 3) days after their final dose of study 
treatment (unless final dose resulted in a dose delay prior to decision to discontinue).  For the control arm, the upper limit of the visit window will 
be dependent upon maximum dosing delay as permitted per local guidelines.  The visit at which response assessment shows progressive 
disease may be used as the treatment discontinuation visit if it falls within 28 ( 3) days after the patient's final dose of study treatment. 
c Patients should receive their first dose of study treatment on the day of randomization, if possible, but no later than 3 business days after 
randomization. 
d Patients who experience disease progression will discontinue treatment (except in the case of isolated brain metastases as outlined in 
Section 4.4.3) and enter a follow-up period during which survival and new anti-cancer therapy information will be collected every 6 months or 
more frequently until death (unless the patient withdraws consent or the Sponsor terminates the study). 
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 6 weeks before 
initiation of study treatment.  Patients who do not meet the criteria for participation in this study (screen failure) must re-sign the consent form 
prior to re-screening. 
f Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
g Complete physical examination includes evaluation of the head eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. 
h Perform a limited, symptom-directed examination at specified postbaseline timepoints and as clinically indicated at other timepoints. 
i 12-lead ECG recordings will be obtained during screening; on Day 1 of Cycles 1, 2, and 4; on Day 1 of every four cycles thereafter (i.e., Cycles 8, 
12, 16, etc.); at the treatment discontinuation visit; and as clinically indicated at other timepoints.  Patients should be resting in a supine position 
for at least 10 minutes prior to ECG recording (see Section 4.5.8). 
j LVEF to be measured using multiple-gated acquisition scan or echocardiogram. 
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells).  Complete blood count should be available for review prior to dosing to inform dosing decisions (see 
Section 4.5.7).  

 
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l Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphate, calcium, total and direct bilirubin, ALP, ALT, AST, urate, 
and LDH.  BUN, creatinine, total bilirubin, ALP, ALT, and AST counts should be available for review prior to dosing to inform dosing decisions 
(see Section 4.5.7). 
m FSH and estradiol should be tested on Day 1 of Cycles 13 and on Day 1 of every three cycles thereafter, for the duration of study treatment. 
n All women of childbearing potential will have a serum pregnancy test at screening, within 7 days prior to initiation of study treatment.  
Urine pregnancy tests will be performed at specified subsequent visits, starting on Day 1 of Cycle 2.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.  Pregnancy test should be available for review prior to dosing to inform dosing decisions 
(see Section 4.5.7). 
o Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood) and microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria).  Urinalysis should be performed as clinically indicated during study treatment. 
p If the next cycle's Day 1 visit occurs with delay, patients should continue taking the medication at home until they use all medication dispensed. 
q LHRH-agonist administration for premenopausal/perimenopausal patients and male patients only.  To minimize the potential of exposure to the 
medication decreasing to sub-therapeutic levels towards the end of the treatment cycle, monthly injections of LHRH agonist are preferred and to 
be synchronized with Day 1 of each 28-day cycle (or according to clinical practice for the selected agent). 
r Patients will receive and should be instructed to complete a medication diary.  The medication diary, unused study drug, and study drug 
containers (used or unused) should be collected and reviewed on Day 1 of each cycle for drug accountability (see Section 4.3.2). 
s Tumor assessments should be performed as per instructions in Section 4.5.6.  All screening tumor assessments (unless otherwise specified) 
should be completed within 28 days prior to randomization.  Brain CT/MRI is required at screening only if clinical indicated or when a patient had 
previously treated brain lesions.  At subsequent tumor assessment time points, brain scans should be acquired if disease was present at baseline 
or if clinically indicated.  Response must be assessed by the investigator according to RECIST v1.1 (see Appendix 4).  Patients who discontinue 
study treatment for any reason other than disease progression or death should continue to undergo tumor assessments every 8 weeks ( 7 days) 
from randomization for the first 18 months, then every 12 weeks ( 7 days) thereafter, as per instructions.  
t Bone scan to be performed at screening.  Evaluable bone lesions should be assessed as per RECIST v1.1 (see Appendix 4) every 8 weeks 
( 7 days) from randomization for the first 18 months, then every 12 weeks ( 7 days) thereafter.  Bone scans are to be repeated every 24 weeks 
(7 days) or as clinically indicated, as per instructions in Section 4.5.6. 

 
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u PRO assessments (PRO-CTCAE [Appendix 8], GP5 [Appendix 10], EORTC QLQ-C30 [Appendix 5], BPI-SF "worst pain" item [Appendix 7], 
EQ-5D-5L [Appendix 9], and EORTC QLQ-BR23 [Appendix 6]) will be completed before the patient receives any information on disease status, 
prior to the performance of non-PRO assessments, and prior to the administration of study treatment.  Questionnaires are to be administered on 
Day 1 of Cycles 1, 2, and 3, Day 1 of every other cycle thereafter (i.e., Cycles 5, 7, 9, etc.), and at the treatment discontinuation visit.  The 
QLQ-BR23 is to be given immediately after the QLQ-C30; male patients may be exempt from some of the questions included in the QLQ-BR23 
module.  For patients who discontinue study treatment for reasons other than disease progression, PRO assessments will continue to be 
administered according to the schedule of tumor assessments (i.e., every 8 weeks [ 7 days] from randomization for the first 18 months, then 
every 12 weeks [ 7 days] thereafter).   
v The following PROs are to be completed 90 ( 7) days after treatment discontinuation at a PRO follow-up visit (or via web-based system as 
required):  BPI-SF "worst pain" item, EQ-5D-5L, and select scales of the QLQ-C30 (global health status/quality of life [Items 29 and 30], Physical 
Functioning [Items 1-5], Role Functioning [Items 6 and 7], pain [Items 9 and 19], fatigue [Items 10, 12, and 18], and dyspnea [Item 8]).  This PRO 
follow-up visit is not applicable for patients who discontinue study treatment for reasons other than disease progression and who continue to be 
administered PROs according to the schedule of tumor assessments. 
 w Optional telephone interviews will be conducted with a subset of participants in the GDC-9545 arm at one timepoint following Cycle 2 (this can 
include the post-treatment period). 
x Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 7 days prior to initiation of study treatment until the treatment discontinuation visit. 
y 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.  After initiation of study drug, all adverse events will be reported until 30 days after the final dose of study drug.  
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 exposure to study drug. 
z Patients who are unwilling to return to the clinic for assessments after treatment discontinuation will no longer undergo adverse event and tumor 
response assessments at clinic visits but can undergo follow-up for adverse events, survival, and new anti-cancer therapy via telephone calls. 
aa After treatment discontinuation, information on survival follow-up and new anti-cancer therapy will be collected via telephone calls, patient medical 
records, and/or clinic visits approximately every 6 months or more frequently until death (unless the patient withdraws consent or the Sponsor 
terminates the study).  If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents 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. 
 

 
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Appendix 2  
Schedule of Pharmacokinetic Samples 
for Patients in GDC-9545 Arm 
Table 1 
Sparse PK Sample Collectiona  
Visita 
Timepoint 
Sample Type 
Day 1 of Cycles 1 and 2 
Predose b 
GDC-9545 PK (plasma)  
3 ( 1) hours postdose GDC-9545 PK (plasma) 
Day 1 of Cycle 3, and Day 1 of 
every two cycles thereafter 
(e.g., Cycles 5, 7, 9, etc.) 
through Cycle 15 
Predose b 
GDC-9545 PK (plasma) 
Treatment discontinuation visit 
At any time during visit GDC-9545 PK (plasma) 
PK  pharmacokinetic. 
Notes: 
 Sparse PK samples will be collected from all patients in GDC-9545 arm. 
 Actual dates and times must be recorded precisely for all doses and 
PK samples. 
 Except for Cycle 1, all other 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. 
 
a All patients in GDC-9545 arm except subset of intensive PK patients. 
b Same day as treatment administration (within 2 hours before dosing). 

Appendix 2: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples 
  
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Table 2 
Intensive PK Sample Collection a 
Visit 
Timepoint 
Sample Type 
Day 1 of Cycles 1 and 2 
Predose b 
GDC-9545 PK (plasma) 
1, 2, 3, 4, and 6 hours 
( 15 minutes) postdose GDC-9545 PK (plasma) 
Day 1 of Cycle 3, and Day 1 of 
every two cycles thereafter 
(e.g., Cycles 5, 7, 9, etc.) 
through Cycle 15 
Predose c 
GDC-9545 PK (plasma) 
Treatment discontinuation visit 
At any time during visit GDC-9545 PK (plasma) 
PK  pharmacokinetic. 
Notes: 
 Intensive PK samples will be collected from a subset of patients in 
GDC-9545 arm. 
 Actual dates and times must be recorded precisely for all doses and 
PK samples. 
 Except for Cycle 1, all other 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. 
 
a Subset of intensive PK patients in GDC-9545 arm only.  For intensive 
PK sample collection, approximately 40 patients (including 20 patients from 
mainland China during global enrollment phase and eventually extended China 
enrollment phase) will be enrolled in the GDC-9545 arm at selected sites to 
have approximately 1624 PK-evaluable patients for GDC-9545 (812 patients 
globally and 812 patients from mainland China).  Once this number has been 
obtained, sites will be informed that subsequently enrolled patients will not 
require intensive PK sampling. 
b Same day as treatment administration (within 30 minutes before dosing). 
c Same day as treatment administration (within 2 hours before dosing). 
 

 
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Appendix 3  
Schedule of Biomarker Samples 
Visit 
Timepoint 
Sample Type 
Screening 
Days –28 to –1 
Any 
Pretreatment archival or fresh 
tumor tissue sample a 
Day 1 of Cycle 1 
Predose 
Plasma (somatic tumor 
mutations) 
Plasma (exploratory 
biomarker) b 
Blood (WGS or WES) c 
Day 1 of Cycle 2 
At any time during 
visit 
Plasma (somatic tumor 
mutations)  
Plasma (exploratory 
biomarker) b 
Day 1 of Cycle 3 and Day 1 of 
every two cycles thereafter 
(e.g., Cycles 5, 7, 9, etc.) 
At any time during 
visit 
Plasma (somatic tumor 
mutations) b  
Treatment discontinuation 
visit  
At any time during 
visit 
Plasma (somatic tumor 
mutations)  
Plasma (exploratory 
biomarker) b  
At disease progression 
(optional) d 
Within 8 weeks of the 
progression 
assessment and prior 
to initiation of a new 
anti-cancer therapy 
Fresh progression tumor tissue 
sample (optional) d 
WGS  whole genome sequencing. 
Notes:  Except for Cycle 1, all other 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. 
a See Section 4.5.7 for details on tissue sample requirements. 
b Not applicable in China. 
c Not applicable for a site that has not been granted approval for WGS or WES.  Not 
applicable in China (see Section 4.5.10).  If missed for this time point, this blood 
sample for WGS or WES can be collected at any point in the study. 
d  Optional post-treatment tumor biopsy collected at time of disease progression for 
patients who have provided written informed consent and if collection of tumor 
biopsy sample is deemed clinically feasible (see Section 4.5.11).  If possible, 
optional fresh biopsies should be obtained within 48 hours of the patient's final dose 
of study treatment, but no later than 8 weeks from the progression assessment and 
prior to initiation of subsequent anti-cancer therapy.  Tumor biopsy of the growing 
lesion is preferred.  Samples collected via resection, core-needle biopsy (minimum 
of three cores preferred), or excisional, incisional, punch or forceps biopsy are 
preferred.  Not applicable in China. 

 
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Appendix 4  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with 
slight modifications from the original publication and the addition of explanatory 
text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable 
lesions should be assessed at screening and at subsequent protocol-specified 
tumor assessment timepoints.  Additional assessments may be performed as 
clinically indicated for suspicion of progression. 
DEFINITION OF MEASURABLE 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 as 
follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) 
scan (CT/MRI scan slice thickness/interval  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  5 mm).  At baseline and follow-up, only the short axis will 
be measured and followed.  Additional information on lymph node measurement 
is provided below (see "Identification of Target and Non-Target Lesions" and 
"Calculation of Sum of Diameters"). 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 

Appendix 4:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 
mm or pathological lymph nodes with short axis  10 mm but  15 mm) 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 mass/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: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography 
scans, and plain films are not considered adequate imaging techniques for 
measuring 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) because 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 non-cystic 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 (e.g., brain 
metastases) or in an area subjected to other locoregional therapy are usually 
not considered measurable unless there has been demonstrated progression 
in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if 
clinically assessed.  All baseline evaluations should be performed as close as 

Appendix 4:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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possible to the treatment start and never more than 4 weeks before the 
beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the 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 AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  In this guideline, the definition of 
measurability of lesions on CT scan is based on the assumption that CT slice 
thickness is  5 mm.  When CT scans have slice thickness of  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 because of 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 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 and interpretation of non-target disease or new 
lesions on a different modality, because the same lesion may appear to have a 
different size using a new modality. 

Appendix 4:  Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
  
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ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology 
cannot be utilized for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate 
the overall tumor burden at baseline and use this as a comparator for 
subsequent measurements. 
IDENTIFICATION 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 that, for instances in 
which 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 considered non-target 
lesions.   
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, but in addition 
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 because 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.  Lymph node size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT, 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 

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lesions.  Nodes that have a short axis of  10 mm are considered non-
pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are 
not required.  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"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis 
for lymph node lesions) will be calculated for all target lesions at baseline and at 
each subsequent tumor assessment as a measure of tumor burden. 
Measuring 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 node regresses to  10 mm during the study.  
Thus, when lymph nodes are included as target lesions, the sum of diameters 
may not be zero even if complete response criteria are met, because a normal 
lymph node is defined as having a short axis of  10 mm. 
Recent literature indicates that vaccination-related adenopathy (enlarged lymph 
nodes) on radiologic imaging (e.g., CT, MRI) and transient uptake on PET scan 
are frequent findings (up to 16% in vaccine trials) after administration of COVID-
19 vaccines.  These findings may appear similar to malignant nodal involvement 
and hence impact image interpretation.  
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded 
at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or 
lymph nodes that are recorded as target lesions at baseline become so faint on 
CT scan that the radiologist may not feel comfortable assigning an exact 
measurement 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 "too small to 
measure" should be ticked.  (Note:  It is less likely that this rule will be used 

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for lymph nodes because 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 "too small to measure" should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, 
that should be recorded, even if it is  5 mm, and in that case "too small to 
measure" should not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the 
fragmented portions should be added together to calculate the sum of diameters.  
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 maximum longest 
diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant 
lymph node non-target lesions should be monitored for reduction to  10 mm in 
short axis.  Non-target lesions should be noted at baseline and should be 
identified as "present" or "absent" and (in rare cases) may be noted as "indicative 
of progression" at subsequent evaluations.  In addition, if a lymph node lesion 
shrinks to a non-malignant size (short axis  10 mm), this should be captured on 
the CRF as part of the assessment of non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target 
lesions are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to 
 10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of 
all target lesions, taking as reference the baseline sum of diameters, in the 
absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum of diameters on study 
(including baseline)  

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In addition to the relative increase of 20%, the sum of diameters must 
also demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  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 schedule of 
activities. 
 
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 lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve 
unequivocal progression on the basis of the non-target lesions, there must be an 
overall level of substantial worsening in non-target lesions in a magnitude that, 
even in the presence of SD or PR in target lesions, 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 lesions in the face of SD or PR in target lesions 
will therefore be extremely rare. 
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 PR or CR.  For example, 

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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 if it represents truly new disease.  If 
repeat scans confirm there is definitely a new lesion, progression should be 
declared using the date of the initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each 
response assessment timepoint for patients who have measurable disease at 
baseline. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  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 all 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 
Criteria for Overall Response at a Single Timepoint:  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 

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Non-Target Lesions 
New Lesions 
Overall Response 
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. 
 
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 measurements are made on only a subset of 
target lesions at a timepoint, 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 lesions 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.  
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be reported as having "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 lesions as 
shown in Table 2. 
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. 
REFERENCES 
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.

 
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Appendix 5  
European Organisation for Research and Treatment of Cancer 
QLQ-C30 Questionnaire (EORTC QLQ-C30) 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study 
 

Appendix 5: European Organisation for Research and Treatment of Cancer QLQ-C30 
Questionnaire (EORTC QLQ C30) 
  
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Appendix 6  
European Organisation for Research and Treatment of Cancer 
QLQ-BR23 Questionnaire 
(EORTC QLQ-BR23) 
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study 
 
 

Appendix 6: European Organisation for Research and Treatment of Cancer 
QLQ-BR23 Questionnaire (EORTC QLQ-BR23) 
  
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Appendix 7  
Brief Pain InventoryShort Form (BPI-SF) "Worst Pain" Item 
 

 
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Appendix 8  
National Cancer Institute Patient-Reported Outcomes Common 
Terminology Criteria for Adverse Events 
(NCI PRO-CTCAE) Items  
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study 
 

Appendix 8: National Cancer Institute Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events (NCI PRO-CTCAE) Items 
  
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Appendix 9  
EQ-5D-5L  
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study 
 
 
 
 
 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 

Appendix 9: EQ-5D-5L 
  
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Appendix 9: EQ-5D-5L 
  
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Appendix 10  
FACT-G Single-Item GP5, Overall Treatment Burden  
Do not reproduce or distribute.  The Sponsor will provide sites with all 
instruments to be completed in this study 
 
 

 
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Appendix 11  
Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restrictions 
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% 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 
 

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