A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER TRIAL OF ARV-471 (PF-07850327) VS FULVESTRANT IN PARTICIPANTS WITH ESTROGEN RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE BASED TREATMENT FOR ADVANCED DISEASE (VERITAC-2)
Phase: PHASE3
Conditions: Advanced Breast Cancer
Sponsor: Pfizer

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 1
                                                 
Title Page
A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER TRIAL OF ARV-471 
(PF-07850327) VS FULVESTRANT IN PARTICIPANTS WITH ESTROGEN
RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER 
WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE BASED 
TREATMENT FOR ADVANCED DISEASE (VERITAC-2)
Study Intervention Number:
PF-07850327
Study Intervention Name:
ARV-471 (vepdegestrant)
US IND Number:
140264
EU CT Number:
2022-500544-38-00
ClinicalTrials.gov ID:  
NCT05654623
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4891001
Phase:
3
Sponsor Legal Address (Outside US):
Pfizer Inc. 
66 Hudson Boulevard East
New York, NY 10001
United States
Sponsor Legal Address (In US):
Arvinas Estrogen Receptor, Inc. 
5 Science Park, 395 Winchester Ave.
New Haven, CT 06511
United States
Brief Title: Phase 3, Open-label Study of ARV-471 (PF-07850327) vs Fulvestrant in 
Participants With ER(+)/ HER2(-) Advanced Breast Cancer (VERITAC-2)
This document and accompanying materials contain confidential information belonging to Pfizer. Except 
as otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) 
or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 2
Document History
Document 
Version Date
Amendment 3
6 November 2024
Amendment 2
24 May 2023
Amendment 1
25 October 2022
Original protocol
15 June 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 3 (6 November 2024)
Overall Rationale for the Amendment: The protocol is amended to address health 
authority feedback on statistical analyses due to emerging evidence of differential efficacy of 
SERDs in ESR1 mutation positive versus ESR1 mutation negative patients.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Change statistical 
hypothesis testing strategy 
from truncated Hochberg 
procedure to graphical 
multiple testing strategy. 
Statistical hypothesis 
testing strategy was 
amended upon FDA 
recommendation based on 
emerging evidence of 
differential efficacy of 
SERDs in ESR1 mutation 
positive vs ESR1 mutation 
negative patients. The new 
hypothesis testing strategy 
incorporates a testing order 
based on clinical 
importance and logical 
relevance per FDA 
comments.  
Section 1.1 Synopsis
Section 4.1 Overall design 
Section 9.1 Statistical 
hypotheses
Section 9.1.2 Multiplicity
Adjustment
Section 9.4 Interim analysis 
Section 9.5 Sample size 
determination
Pre-specify a minimum 
efficacy effect in PFS for 
ESR1 mutation negative 
To address FDA request 
and to pre-specify a 
minimum efficacy effect in 
Section 9.1 Statistical 
hypotheses 
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 3
Description of Change
Brief Rationale
Section # and Name
subgroup according to 
Rothmann criteria.
ESR1 mutation negative 
patients for benefit/risk 
evaluation.
Non-substantial Modification(s)
Potential for pausing 
enrollment of one 
population (either ESR1
mutation or wild type 
participant) has been 
removed.
An enrollment pause was 
never implemented as no 
meaningful imbalance was 
observed. Thus, text 
regarding a potential pause 
was removed.
Section 1.3 Schedule of 
Activities Table 1 and Section 
4.1 Overall Design
Enrollment will continue 
until approximately 280 
participants with the ESR1 
mutation have been 
enrolled.
The number of ESR1 
mutant participants is
needed to ensure number 
of events for planned 
statistical analysis
Section 1.1 Synopsis and 
Section 4.1 Overall Design
Updated regulatory 
information in Section 
2.2.4 based on the 
elacestrant approval in 
2023.
Elacestrant has been 
registered in 2023 and 
fulvestrant is no longer the 
only approved SERD.
Section 2.2.4 SERD
Development and 
reproductive toxicity have 
been added as an 
additional potential risk of 
clinical significance 
Section revised in 
alignment with the IB 
dated Oct 2024.
The change is considered 
non-substantial since risk 
mitigation already in place 
based on ARV-471 
mechanism of action. 
Section 2.3.1 Risk Assessment
Text updated to include 
the 3 months formulation 
to the already specified 28 
days formulation.
In addition to the LHRH 
formulation given every 28 
days, the use of the 3 
months formulation is 
acceptable. This 
Section 6.9.1. Luteinizing 
Hormone-Releasing Hormone 
Agonist and 
Section 1.3. Schedule of 
Activities Table 2
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 4
Description of Change
Brief Rationale
Section # and Name
This change incorporates 
the Protocol 
Administrative Change 
Letter (PACL) dated 06-
Jul-2023.
formulation will reduce 
participants’ burden 
without compromising the 
LHRH efficacy.
Following text added in 
the SOA notes: PROs 
mandatory unless the 
electronic devices will 
never be available due to 
local restrictions. In this 
case completion of any 
PRO version including the 
paper version is not 
required.
This change incorporates 
the PACL dated 06-Jul-
2023.
Clarified that the PRO 
questionnaires (EuroQol 
EQ5D-5L, EORTC QLQ-
C30; EORTC QLQ-BR23, 
BPI-SF, Evening Daily 
Diary, Patient Preference 
Questionnaire) are required 
assessments unless the 
electronic devices cannot 
be imported into the 
country. In these cases, the 
collection of the PRO data 
is not required.
Importation of the 
electronic PRO (ePRO) 
devices in certain countries 
(eg, Turkey) are impacted 
due to recent updates to 
local/government 
regulations. In addition, the 
ePRO vendor does not 
currently have local 
resources for in-country 
device provisioning. 
Despite availability of 
paper PROs, the 
completion of only this 
paper version for the 
duration of study 
participation is not a valid 
option due to the high 
probability of missing data, 
which will impact the 
overall completion rate and 
may jeopardize data 
interpretation. Participants 
Section 1.3 Schedule of 
Activities Table 2
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 5
Description of Change
Brief Rationale
Section # and Name
who do not complete any 
PRO will be treated as 
non-participants rather 
than non-completers and 
therefore will not impact 
the study’s PRO 
completion.
Text updated to extend the 
collection time window 
for electrolyte testing.
This change incorporates 
the PACL dated 06-Jul-
2023.
The collection time 
window for the electrolyte 
testing has been extended 
until –2 days prior to 
dosing to be consistent 
with the other laboratory 
safety tests. This change 
does not impact patient’s 
safety. The ECG will be 
performed on Day 1 of the 
cycles (as per Table 3). If 
electrolyte testing is not 
performed on Day 1 of the 
cycle (i.e. performed up to 
-2 days), electrolytes test 
must be repeated on Day 1 
only in case of ECG 
abnormalities. 
This is consistent with 
Section 6.6.2.3. of the 
study protocol, that 
requires the evaluation and
correction of possible 
alternative reversible 
causes such as serum 
electrolytes abnormalities 
in the event of QTc 
prolongation.
Section 8.3.3 
Electrocardiograms and Section 
1.3 Schedule of Activities 
Table 2 & Table 3
The PK samples should be 
collected within 2.5 hours 
prior to dosing (not 2 
hours) for consistency 
Transcription error 
corrected. 
Section 1.3 Schedule of 
Activities Table 3
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 6
Description of Change
Brief Rationale
Section # and Name
with the same information 
reported in this Table 3.  
This change incorporates 
the PACL dated 06-Jul-
2023.
Instructions for ARV-471 
administration have been 
updated to clarify that the 
morning intake is not a 
mandatory requirement.  
This change incorporates 
the PACL dated 21-Sep-
2023.
ARV-471 drug intake is 
recommended at 
approximately the same 
time in the morning. 
However, no issues from a 
safety perspective have 
been identified in case the 
drug is taken later in the 
same day.
Section 1.3 Schedule of 
Activities Table 2, Section 
5.3.2. Meals and Dietary 
Restrictions and 
Section 6.1.1.1 ARV-471
Footnote added to allow 
up to 4 hours pre-dose 
time window for 
evaluation assessment 
reported in Table 3.
This change incorporates 
the PACL dated 21-Sep-
2023.
The time window of 2.5 
hours pre-dose may be 
extended up to 4 hours to 
accommodate site needs as 
long as all samples are 
collected on each 
evaluation day as per 
Schedule of Activities.
Section 1.3 Schedule of 
Activities Table 3
Inclusion criterion 3b 
updated to clarify that 
HER-2 status for inclusion 
should be assessed on the 
same tumor sample used 
for characterizing the ER 
status (on the most recent 
tumor biopsy).
This change incorporates 
the PACL dated 21-Sep-
2023.
Text added for clarification 
purposes.
Section 1.1 Synopsis and 
Section 5.1 Inclusion Criteria
Faslodex® included.
Text was added to clarify 
that Faslodex® may also 
Section 6.1 Study 
Intervention(s) Administered
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 7
Description of Change
Brief Rationale
Section # and Name
This change incorporates 
the PACL dated 21-Sep-
2023.
be used in addition to 
generic Fulvestrant.
Text updated to include 
the instruction to consult 
the respective local 
product label of the P-gp 
substrate before use and to 
allow the use of H2 
receptor antagonists or 
antacids when ARV-471 is 
taken with a moderate-fat 
meal (400-800 calories, 
approximately 35% fat).
This change incorporates 
the PACL dated 21-Sep-
2023.
The updates to the text 
provide additional 
clarification on 
administration of P-gp 
substrates and H2 receptor 
antagonists and antacids 
that were included in the 
IB dated August 2023 to 
ensure consistency across 
documents. For P-gp 
substrates, details were 
added to refer to the 
respective product labels. 
Administration 
requirements around H2 
receptor antagonists or 
antacids were loosened due 
to emerging data.
Section 6.9.4 Concomitant 
Treatments to be used with 
caution or not recommended
Text updated in Inclusion 
Criteria 3a, 3d to clarify 
that for those study 
participants where a de 
novo biopsy is clinically 
contraindicated an 
archival tumor tissue at 
initial diagnosis is 
acceptable. 
This change incorporates 
the PACL dated 25-Jan-
2024.
The collection of a de novo 
biopsy may impact the 
participant’s safety if 
clinically contraindicated.
Section 1.1 Synopsis, Section 
5.1 Inclusion Criteria & Section 
8.7.1 Tumor Biopsies
Text added to clarify that 
results of cholesterol and 
triglycerides are not 
needed for retreatment.
This change does not 
impact participant’s safety 
and allows more flexibility 
for sites.
Section 1.3 Schedule of 
Activities Table 2
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 8
Description of Change
Brief Rationale
Section # and Name
This change incorporates 
the PACL dated 25-Jan-
2024.
The “Medical Device 
Constituent Supplemental 
Form” has been removed.
This change incorporates 
the PACL dated 25-Jan-
2024.
If an SAE occurs in the 
setting of a medical device 
deficiency, the SAE must 
be recorded using the 
Clinical Trial (CT) SAE 
Report Form or Pfizer SAE 
Submission Assistant 
(PSSA) tool. The Medical 
Device Constituent 
Supplemental Form is no 
longer a valid option to 
report a medical device 
deficiency and should not 
be chosen.
Section 8.4.9.3. Prompt 
Reporting of Device 
Deficiencies
The process for contacting 
a medically qualified 
individual has been 
changed.
This change incorporates 
the PACL dated 25-Jan-
2024.
The process for contacting 
a medically qualified 
individual has changed 
from a medical escalation 
process via a Pfizer Call 
Center to direct clinical 
team contact using a Study 
Team Contact List. The 
Emergency Contact Card is 
being replaced by a study 
information card and will 
no longer be referenced.
Section 10.1.12 Appendix 1 
Sponsor's Medically Qualified 
Individual and Section 10.16. 
Appendix 16: Abbreviations
Text added to clarify that 
if participants will be 
contacted for survival 
information the 
investigators may ask also 
information on poststudy 
anticancer therapies, as 
already specify in the 
sentence above.
Typo. Text added to align 
with previous sentence in 
the same paragraph
Section 7.1.1.2 Survival 
Follow-up
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 9
Description of Change
Brief Rationale
Section # and Name
Text added for the latest
EU-CTR. 
Text added to comply with 
latest EU-CTR 
requirements. 
Section 10.11 Appendix 11 
Country Specific Requirements
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 10
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................17
LIST OF FIGURES .................................................................................................................17
1. PROTOCOL SUMMARY...................................................................................................18
1.1. Synopsis ..................................................................................................................18
1.2. Schema ....................................................................................................................28
1.3. Schedule of Activities .............................................................................................29
2. INTRODUCTION ...............................................................................................................48
2.1. Study Rationale .......................................................................................................48
2.2. Background .............................................................................................................48
2.2.3. ARV-471.....................................................................................................49
2.2.3.1. Non-clinical Pharmacokinetics and Metabolism.......................50
2.2.3.2. Potential Drug-Drug Interactions..............................................50
2.2.3.3. ARV-471 Preliminary Safety, Efficacy and PK in Humans .....51
2.2.3.4. QTc Evaluation Data.................................................................54
2.2.4. SERD..........................................................................................................55
2.3. Benefit/Risk Assessment.........................................................................................56
2.3.1. Risk Assessment.........................................................................................57
2.3.2. Benefit Assessment.....................................................................................62
2.3.3. Overall Benefit/Risk Conclusion................................................................62
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................63
4. STUDY DESIGN.................................................................................................................64
4.1. Overall Design.........................................................................................................64
4.2. Scientific Rationale for Study Design.....................................................................67
4.2.1. Patient Input Into Design............................................................................67
4.2.2. Diversity of Study Population ....................................................................67
4.2.3. Choice of Contraception/Barrier Requirements .........................................68
4.2.4. Collection of Retained Research Samples..................................................68
4.3. Justification for Dose ..............................................................................................68
4.3.1. ARV-471.....................................................................................................68
4.3.2. Fulvestrant ..................................................................................................69
4.4. End of Study Definition ..........................................................................................69
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
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5. STUDY POPULATION......................................................................................................69
5.1. Inclusion Criteria.....................................................................................................70
5.2. Exclusion Criteria....................................................................................................72
5.3. Lifestyle Considerations..........................................................................................74
5.3.1. Contraception..............................................................................................74
5.3.2. Meals and Dietary Restrictions...................................................................75
5.4. Screen Failures ........................................................................................................75
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................75
6.1. Study Intervention(s) Administered........................................................................75
6.1.1. Administration............................................................................................76
6.1.1.1. ARV-471 ...................................................................................76
6.1.1.2. Fulvestrant.................................................................................77
6.1.2. Medical Devices .........................................................................................77
6.2. Preparation, Handling, Storage, and Accountability...............................................77
6.2.1. Preparation and Dispensing........................................................................79
6.3. Assignment to Study Intervention...........................................................................79
6.4. Blinding...................................................................................................................80
6.5. Study Intervention Compliance...............................................................................80
6.6. Dose Modification...................................................................................................80
6.6.1. Fulvestrant ..................................................................................................81
6.6.2. ARV-471.....................................................................................................81
6.6.2.1. ARV-471 Dose Reductions.......................................................81
6.6.2.2. Recommended ARV-471 Dose Modifications .........................82
6.6.2.3. ARV-471/QTc prolongation management................................83
6.6.2.4. ARV-471 Dosing Interruptions.................................................85
6.6.2.5. ARV-471 Dose Delays..............................................................85
6.7. Continued Access to Study Intervention After the End of the Study......................86
6.8. Treatment of Overdose............................................................................................86
6.9. Prior and Concomitant Therapy..............................................................................87
6.9.1. Luteinizing Hormone-Releasing Hormone Agonist...................................87
6.9.2. Prohibited Inhibitors/Inducers ....................................................................88
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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6.9.3. Other Prohibited and/or Anti-Cancer or Experimental Drugs, or 
Procedures........................................................................................................88
6.9.4. Concomitant Treatments to be used with caution or not 
recommended...................................................................................................89
6.9.5. Supportive Care ..........................................................................................89
6.9.6. Hematopoietic Growth Factors...................................................................90
6.9.7. Antidiarrheal, Antiemetic Therapy.............................................................91
6.9.8. Corticosteroids............................................................................................91
6.9.9. Anti-Inflammatory Therapy........................................................................91
6.9.10. Concurrent Surgery and Radiotherapy .....................................................91
6.9.11. Rescue Medicine.......................................................................................92
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................92
7.1. Discontinuation of Study Intervention ....................................................................92
7.1.1. Post-treatment Follow-up ...........................................................................93
7.1.1.1. Safety Follow-up.......................................................................93
7.1.1.2. Survival Follow-up....................................................................93
7.1.2. COVID-19 ..................................................................................................93
7.2. Participant Discontinuation/Withdrawal From the Study.......................................94
7.2.1. Withdrawal of Consent...............................................................................94
7.3. Lost to Follow-Up ...................................................................................................95
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................95
8.1. Administrative and Baseline Procedures.................................................................95
8.1.1. Pre-screening ..............................................................................................96
8.1.2. Baseline Procedures....................................................................................97
8.1.3. Telehealth Visits.........................................................................................97
8.1.4. Home Health Visits.....................................................................................98
8.1.5. Alternative Facilities...................................................................................99
8.2. Efficacy Assessments..............................................................................................99
8.2.1. Imaging Tumor Response Assessments .....................................................99
8.2.1.1. Treatment Beyond Progression in Both Arms ........................102
8.2.1.2. Independent Review of Disease Assessments.........................103
8.2.1.3. Management of Incidental Findings........................................103
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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8.2.1.4. Alternative Facilities for Tumor Assessment..........................103
8.2.2. Survival Follow-up Analysis ....................................................................104
8.3. Safety Assessments ...............................................................................................104
8.3.1. Physical Examinations..............................................................................104
8.3.2. Vital Signs ................................................................................................104
8.3.3. Electrocardiograms...................................................................................105
8.3.3.1. Alternative Facilities for Electrocardiograms .........................107
8.3.4. Clinical Safety Laboratory Assessments ..................................................107
8.3.4.1. Alternative Facilities for Clinical Safety Laboratory 
Assessment ......................................................................................108
8.3.5. Pregnancy Testing ....................................................................................108
8.3.5.1. At-Home Pregnancy Testing...................................................108
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting ...............108
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.....109
8.4.1.1. Reporting SAEs to Pfizer Safety.............................................110
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF.................110
8.4.2. Method of Detecting AEs and SAEs ........................................................110
8.4.3. Follow-Up of AEs and SAEs....................................................................110
8.4.4. Regulatory Reporting Requirements for SAEs.........................................111
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................111
8.4.5.1. Exposure During Pregnancy....................................................111
8.4.5.2. Exposure During Breastfeeding ..............................................113
8.4.5.3. Occupational Exposure ...........................................................113
8.4.6. Cardiovascular and Death Events.............................................................114
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs............................................................................114
8.4.8. Adverse Events of Special Interest...........................................................114
8.4.8.1. Lack of Efficacy......................................................................114
8.4.9. Medical Device Deficiencies....................................................................114
8.4.9.1. Time Period for Detecting Medical Device Deficiencies .......115
8.4.9.2. Follow-up of Medical Device Deficiencies.............................115
8.4.9.3. Prompt Reporting of Device Deficiencies ..............................115
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8.4.9.4. Regulatory Reporting Requirements.......................................116
8.4.10. Medication Errors...................................................................................116
8.5. Pharmacokinetics ..................................................................................................117
8.6. Genetics.................................................................................................................118
8.6.1. Specified Genetics ....................................................................................118
8.6.2. Retained Research Samples for Genetics .................................................118
8.7. Biomarkers ............................................................................................................119
8.7.1. Tumor Biopsies.........................................................................................119
8.7.2. Blood Samples..........................................................................................120
8.8. Immunogenicity Assessments...............................................................................120
8.9. Health Economics .................................................................................................120
9. STATISTICAL CONSIDERATIONS ..............................................................................121
9.1. Statistical Hypotheses ...........................................................................................121
9.1.1. Estimands..................................................................................................122
9.1.1.1. Primary Estimand/Coprimary Estimands................................122
9.1.1.2. Secondary Estimands ..............................................................122
9.1.2. Multiplicity Adjustment............................................................................123
9.2. Analysis Sets .........................................................................................................124
9.3. Statistical Analyses ...............................................................................................125
9.3.1. General Considerations.............................................................................125
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ..............................................125
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis..........................................126
9.3.3.1. Key Secondary Efficacy Endpoint ..........................................126
9.3.3.2. Other Secondary Endpoints.....................................................127
9.3.4. Other Analysis ..........................................................................................130
9.3.5. Exploratory Analysis ................................................................................130
9.3.5.1. Biomarker Analyses ................................................................130
9.4. Interim Analysis ....................................................................................................131
9.5. Sample Size Determination...................................................................................131
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................133
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............133
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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10.1.1. Regulatory and Ethical Considerations ..................................................133
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................133
10.1.2. Financial Disclosure ...............................................................................134
10.1.3. Informed Consent Process ......................................................................134
10.1.4. Data Protection .......................................................................................135
10.1.5. Committees Structure .............................................................................136
10.1.5.1. Data Monitoring Committee .................................................136
10.1.5.2. Steering Committee...............................................................136
10.1.6. Dissemination of Clinical Study Data ....................................................136
10.1.7. Data Quality Assurance ..........................................................................137
10.1.8. Source Documents..................................................................................138
10.1.9. Use of Medical Records..........................................................................139
10.1.10. Study and Site Start and Closure ..........................................................139
10.1.11. Publication Policy.................................................................................140
10.1.12. Sponsor’s Medically Qualified Individual............................................141
10.1.13. Transfer of Obligations Statement........................................................141
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................142
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................144
10.3.1. Definition of AE .....................................................................................144
10.3.2. Definition of an SAE ..............................................................................145
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................147
10.3.4. Reporting of SAEs..................................................................................150
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................151
10.4.1. Male Participant Reproductive Inclusion Criteria..................................151
10.4.2. Female Participant Reproductive Inclusion Criteria...............................151
10.4.3. Woman of Childbearing Potential ..........................................................152
10.4.4. Contraception Methods...........................................................................153
10.5. Appendix 5: Genetics..........................................................................................154
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines .....................................................155
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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10.7. Appendix 7: Kidney Safety Monitoring Guidelines ...........................................157
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................157
10.7.2. Age-Specific Kidney Function Calculation Recommendations.............157
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations  eGFR  (mL/min/1.73m²)................................................157
10.7.3. Kidney Function Calculation Tool .........................................................157
10.7.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................158
10.8. Appendix 8: ECG Findings of Potential Clinical Concern .................................159
10.9. Appendix 9: AEs, ADEs, SAEs, SADEs, USADEs, and Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting in Medical Device Studies.........................................................161
10.9.1. Definition of AE and ADE .....................................................................161
10.9.2. Definition of SAE, SADE, and USADE ................................................161
10.9.3. Definition of Device Deficiency.............................................................162
10.9.4. Recording/Reporting and Follow-up of and Medical Device 
Deficiencies....................................................................................................162
10.9.5. Reporting of SAEs..................................................................................164
10.9.6. Reporting of SADES ..............................................................................164
10.10. Appendix 10: Concomitant Medications That May Result in DDI ..................165
10.10.1. CYP3A inhibitors/inducers...................................................................165
10.10.2. Drugs Known to Predispose to Torsade de Pointes or QT interval 
prolongation...................................................................................................166
10.10.3. P-gp Sensitive Substrates......................................................................168
10.10.4. PPI.........................................................................................................168
10.11. Appendix 11: Country Specific Requirements..................................................169
10.11.1. European Union....................................................................................169
10.11.2. France ...................................................................................................170
10.12. Appendix 12: Bone Marrow Reserve in Adults................................................171
10.13. Appendix 13: RECIST (Response Evaluation Criteria in Solid Tumors) 
version 1.1 Guidelines.............................................................................................173
10.14. Appendix 14: Additional Study Assessments, Inventories, and 
Questionnaires .........................................................................................................179
10.14.1. Patient-reported Outcomes Assessments..............................................179
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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10.14.2. Eastern Cooperative Oncology Group (ECOG) Performance..............181
10.15. Appendix 15: Protocol Amendment History.....................................................182
10.16. Appendix 16: Abbreviations .............................................................................200
11. REFERENCES ................................................................................................................207
LIST OF TABLES
Table 1.
SoA: Prescreening ....................................................................................29
Table 2.
Study SoA.................................................................................................31
Table 3.
Pharmacokinetic and ECGs, Schedule of Activities.................................45
Table 4.
Study Interventions Administered............................................................75
Table 5.
ARV-471 Dose Modification Levels for Adverse Reactions...................82
Table 6.
Recommended Dose Modifications for ARV-471 -Related Toxicity......82
Table 7.
Recommended ARV-471 Dose Modification in the event of QTc 
Prolongation..............................................................................................84
Table 8.
Objective Response Status at Each Assessment for Participants with 
Measurable Disease at Baseline..............................................................177
Table 9.
Objective Response Status at Each Assessment for Participants with 
Non-Target Disease Only .......................................................................178
LIST OF FIGURES
Figure 1.
Statistical hypothesis testing strategy.....................................................124
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 18
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 3, Randomized, Open-Label, Multicenter Trial of ARV-471 (PF-
07850327) vs Fulvestrant in Participants with Estrogen Receptor-Positive, HER2-Negative 
Advanced Breast Cancer Whose Disease Progressed After Prior Endocrine Based Treatment 
for Advanced Disease (VERITAC-2)
Brief Title: Phase 3, Open-label Study of ARV-471 (PF-07850327) vs Fulvestrant in 
Participants With ER(+)/ HER2(-) Advanced Breast Cancer (VERITAC-2)
Regulatory Agency Identification Number(s):
US IND Number:
140264
EU CT Number:
2022-500544-38-00
ClinicalTrials.gov ID:  
NCT05654623
Pediatric Investigational Plan Number:
N/A
Protocol Number:
C4891001
Phase:
3
Rationale:
In nonclinical studies, ARV-471 has demonstrated robust estrogen receptor (ER)
degradation, superior activity against clinically relevant ER mutated forms (eg, Y537S and 
D538G), and improved tumor growth inhibition (TGI) as single agent compared to 
fulvestrant in ER wild type and estrogen receptor 1 (ESR1) mutant patient-derived xenograft 
models. In the first in human (FIH) study, ARV-471 administered orally once daily (QD) as a 
single agent appears to be safe and well tolerated across total daily doses of 30 mg to 700 mg 
with preliminary evidence of efficacy in participants pretreated with cyclin dependent kinase 
4/6 (CDK4/6) inhibitor plus endocrine therapy.  These results support the hypothesis that 
ARV-471 may represent an important therapeutic approach in patients with ER(+)/human 
epidermal growth factor receptor 2 negative [HER2(-)] advanced breast disease.
Objectives, Endpoints, and Estimands:
Objectives
Endpoints
Estimands
Primary: 
Primary: 
Primary:
To demonstrate that ARV-471 
is superior to fulvestrant in 
prolonging progression-free 
survival (PFS) by blinded 
independent central review 
(BICR) assessment in 
PFS, defined as the time from the 
date of randomization to the date 
of first documented disease 
progression, as determined by 
BICR assessment per Response 
Evaluation Criteria in Solid 
The primary estimand is to compare the 
treatment effect (as measured by hazard 
ratio [HR]) of ARV-471 versus 
fulvestrant on PFS in participants with 
ER(+)/HER2(-) aBC (all participants and 
participants with ESR1 mutation-
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
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Objectives
Endpoints
Estimands
participants with 
ER(+)/HER2(-) advanced 
breast cancer (aBC) (all 
participants and participants 
with ESR1 mutation-positive 
breast cancer [BC]) who have 
received prior endocrine-based 
treatment for their advanced 
disease
Tumors Version 1.1(RECIST 
v1.1), or death due to any cause, 
whichever occurs first
positive BC) who have received prior 
endocrine-based treatment for their 
advanced disease. PFS will be analyzed 
using the stratified log-rank test and 
Kaplan-Meier method. PFS data will be 
censored for those who did not have a 
PFS event, discontinued the study 
treatment due to withdrawal of consent 
prior to an event, started a new anti-
cancer therapy prior to an event, had an 
event after an unacceptably long interval, 
or lost to follow-up.
Key Secondary: 
Key Secondary: 
Key Secondary:
To demonstrate that ARV-471 
is superior to fulvestrant in 
prolonging overall survival 
(all participants and 
participants with ESR1 
mutation-positive BC)
Overall Survival (OS), defined as 
the time from the date of 
randomization to the date of death 
due to any cause
The estimand for OS is to compare the 
treatment effect (as measured by HR) of 
ARV-471 versus fulvestrant in 
participants with ER(+)/HER2(-) aBC 
(all participants and participants with 
ESR1 mutation-positive BC) who have 
received prior endocrine-based treatment 
for their advanced disease. OS will be 
analyzed using the stratified log-rank test 
and Kaplan-Meier method. OS data will 
be censored for those who did not have 
an OS event.
Secondary:
Secondary: 
Secondary:
To compare measures of 
tumor control between 
treatment arms and to evaluate 
the duration of response 
(DOR) by BICR assessment 
within each treatment arm
Objective Response (OR): 
confirmed complete response (CR)
or partial response (PR) by BICR 
assessment
Clinical benefit response (CBR)
defined as confirmed CR or PR at 
any time or stable disease (SD) or 
non-CR/non-progressive disease 
(PD) ≥24 weeks by BICR 
assessment
DOR by BICR assessment
Not applicable.
To evaluate safety and 
tolerability between the 
treatment arms
Type, incidence, severity (as graded 
by National Cancer Institute 
Common Terminology Criteria for 
Adverse Events [NCI CTCAE]
v5.0), seriousness and relationship 
to study medications of adverse 
events (AEs) and any laboratory and 
electrocardiogram (ECG)
abnormalities
Not applicable. 
To characterize the effects of 
ARV-471 on corrected QT 
interval (QTc)
QTc
Not applicable. 
To evaluate patient reported 
outcomes between two 
treatment arms
European Organization for the 
Research and Treatment of Cancer 
and Quality of Life Questionnaire 
(EORTC QLQ-C30)
Not applicable. 
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
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Objectives
Endpoints
Estimands
European Organization for the 
Research and Treatment of Cancer 
and Quality of Life Questionnaire-
Breast Cancer specific (EORTC 
QLQ-BR23)
European quality of life five-
dimension five-level scale
(EuroQol; EQ-5D-5L)
Brief pain inventory short form 
(BPI-SF)
To determine plasma 
concentrations of ARV-471 
and ARV-473 after repeated 
dosing of ARV-471
Plasma concentrations of ARV-471 
and its epimer ARV-473 
Not applicable.
To assess changes from 
baseline levels in plasma 
circulating tumor DNA 
(ctDNA)
ctDNA plasma quantitative changes 
from baseline to evaluate their 
associations with clinical outcomes
Not applicable.
Overall Design:
This is an international Phase 3 multicenter, randomized, open-label, parallel-group study 
aimed to demonstrate that ARV-471 is superior to fulvestrant in prolonging the PFS (by 
BICR assessment) in participants with ER(+)/HER2(-) aBC who have progressed after prior 
endocrine treatment-based regimen(s) for advanced disease.
Approximately 560 participants (of which approximately 280 are participants with ESR1 
mutation) will be randomly assigned to Arm A (ARV-471, PF-07850327) or Arm B 
(fulvestrant). Enrollment will continue until approximately 280 participants with the ESR1 
mutation have been enrolled.
Participants will be randomly assigned on a 1:1 basis to: 

Arm A: (Investigational Arm; n ≈280). Participants will receive ARV-471 200 mg 
orally, once daily on a 28-day continuous dosing schedule. 

Arm B: (Comparator Arm; n ≈280). Participants will receive fulvestrant 500 mg, 
intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting 
from C2D1 (28-day cycle).
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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Participants will be stratified by ESR1 mutational status (Mutant, Yes/No) and visceral 
disease (Yes/No).
Visceral refers to lung, liver, brain, pleural, and peritoneal involvement.
Pre- and peri-menopausal female and male participants must receive therapy with an LHRH 
agonist starting on Cycle 1 Day 1 (if not already on treatment) and continued during the 
study. 
Crossover between treatment arms will NOT be allowed.
The study includes a QTc sub-study in approximately 80 participants in Arm A enrolled at 
selected sites which will evaluate the effect of ARV-471 on QTc interval via triplicate ECGs 
(central reading) time-matched with PK draws.
Evaluation of ESR1 status (wild-type versus ESR1 mutated) will be performed using ctDNA 
blood samples. ctDNA blood samples may be used for development of companion 
diagnostics.
Safety will be monitored at regular intervals (once per cycle) throughout the study by 
laboratory tests, triplicate ECGs (first 3 cycles and at the end of treatment [EOT]) and 
clinical visits. Blood samples for pharmacokinetics analysis of ARV-471 and its epimer, 
ARV-473 will be collected up to Cycle 7 in Arm A participants.
Participants will undergo regular efficacy assessments by computed tomography (CT)/
magnetic resonance imaging (MRI) scan (ie, every 8 weeks for the first 48 weeks from date 
of randomization and then every 12 weeks thereafter) and bone scan, if applicable (ie, every 
24 weeks from randomization date). Efficacy analyses will be performed using BICR tumor 
assessments as the primary data source. All radiographic images, as well as other information 
collected on-study will be verified by BICR to determine the protocol defined endpoints of 
disease response and progression.
PRO assessments will be administered by various questionnaires to evaluate the impact on 
quality of life, functioning, symptoms, general health status, and preference of route 
administration in both Arms. Worst pain severity, pain interference, pain medication usage 
(in both Arms) and injection site pain (only in Arm B) will be evaluated and captured in the 
evening daily diary. 
Serial ctDNA blood will be collected to assess ctDNA plasma quantitative change. 
Moreover, the association between breast tumor genomic alterations and tumor 
sensitivity/resistance to ARV-471 will be assessed in serial ctDNA blood and tumor samples. 
A blood sample for DNA extraction (ie, Retained Research Sample for Genetics) will be 
collected, unless prohibited by local regulations, or by Institutional Review Boards (IRBs)/
ethics committees (ECs) for research related to the study intervention(s) and advanced breast 
cancer.
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The screening period should occur within 28 days prior to randomization. Study intervention 
will be administered in 28-day cycles. Participants will continue to receive assigned study 
intervention until one of the following reasons occurs: 

Objective disease progression assessed by Investigator; however, participants with 
disease progression as per RECIST v1.1 who are continuing to derive clinical benefit 
from the study intervention (ie, positive benefit/risk assessment as assessed by 
investigator), will be eligible to continue study intervention;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Participant refused further treatment;

Study terminated by sponsor;

Death.
An external data monitoring committee (E-DMC) will be established to review aggregate 
safety data to monitor safety and tolerability by treatment arm.
A Global Steering Committee will be established at the program level for ARV-471. It will 
be responsible for providing scientific advice and medical input on the ongoing and future 
clinical development plans for ARV-471 in ER(+) breast cancer, including for this study.
It is anticipated that the final PFS analysis will occur at approximately 310 PFS events in all 
participants population and approximately 165 PFS events in the ESR1 mutant subgroup 
population. The final OS analysis will occur at approximately 396 OS events in all 
participants population and 194 OS events in ESR1 mutant subgroup population.
Number of Participants:
Approximately 560 participants will be randomized in the study. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent process and 
randomization to study intervention. 
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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Study Population: 
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:

Participants aged 18 years or older (or the minimum age of consent in accordance with 
local regulations) at screening.
a.
Female participants under 60 years of age, with cessation of regular menses for 12 
consecutive months and with no alternative medical cause, must have a 
follicle-stimulating hormone (FSH) level within the post-menopausal level, as per 
local laboratory reference range.
b. Pre/peri-menopausal female and male participants must agree to initiate or 
continue to use an luteinizing hormone-releasing hormone (LHRH) agonist.  
c.
Woman/women of childbearing potential (WOCBP) female and male participants 
must agree to use contraception.

Histological or cytological confirmation of breast cancer with evidence of locoregional
recurrent or metastatic disease which is not amenable to surgical resection or radiation 
therapy with curative intent.  
a.
Documented ER(+) tumor, defined as ER(+) ≥10% stained cells by an assay 
consistent with local standards, on the most recent tumor biopsy, ie, at diagnosis 
of recurrence or metastatic disease.  The sole exception is those participants with 
bone only disease and participants in whom the collection of a biopsy is clinically 
contraindicated, for whom ER(+) using archival tissue at initial diagnosis is 
acceptable.
b. Documented HER2(-) tumor by either immunohistochemistry (IHC) or in-situ
hybridization per American Society of Clinical Oncology/College of American 
Pathologists (ASCO/CAP) guidelines on the most recent tumor biopsy and as per 
above in inclusion criterion a.
c.
Participants who have bilateral breast cancers which are both ER(+)/HER2(-) are 
eligible.
d. Participants must provide a blood sample AND a tumor sample collected at the 
time of diagnosis of locoregional recurrent or metastatic disease. If not available, 
a de novo biopsy is required, unless the participant has bone only disease or in 
whom the collection of a biopsy is clinically contraindicated. In these cases, an 
archival tumor tissue at initial diagnosis is acceptable.
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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
Prior therapies for locoregional recurrent or metastatic disease must fulfill all the 
following criteria: 
Note: Progression during or within 12 months from the end of adjuvant therapy is 
counted as a line of therapy in advanced/metastatic setting. 
a.
One line of CDK4/6 inhibitor therapy in combination with endocrine therapy 
(ET). Only one line of CDK4/6 inhibitor is allowed in any setting. 
b. ≤ 1 endocrine therapy in addition to CDK4/6 inhibitor with ET. 
c.
Most recent endocrine treatment duration must have been given for ≥6 months 
prior to disease progression. This may be the endocrine treatment component of 
the CDK4/6 inhibitor line of therapy.
d. Radiological progression during or after the last line of therapy. 

At least one measurable lesion as defined by RECIST version 1.1. Bone only disease: 
participants with only non-measurable disease are eligible.  

ECOG PS ≤1
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:

History of any other solid tumor malignancies within the past three years, except for the 
following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) 
curatively treated in situ carcinoma of the cervix. For all other solid tumors, must have 
been curatively treated and with no evidence of disease for >3 years. Participants with 
inflammatory breast cancer are excluded.

Participants with newly diagnosed brain metastasis or symptomatic central nervous 
system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as
indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants 
with a history of CNS metastases or cord compression are eligible if they have been 
definitively treated (e.g., radiotherapy, stereotactic surgery) and clinically stable 
(including participants with residual CNS symptoms/deficits) off enzyme-inducing 
anticonvulsants and steroids for at least 14 days prior to randomization.

Participants in visceral crisis at risk of immediately life-threatening complications in the 
short term, including participants with massive uncontrolled effusions (pleural, 
pericardial, and peritoneal), pulmonary lymphangitis, or liver involvement >50%.

Impaired cardiovascular function or clinically significant cardiovascular diseases.
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
Prior treatment with:
a.
ARV-471, fulvestrant, elacestrant, mammalian target of rapamycin (mTOR), 
phosphoinositide-3-kinase (PI3K), protein kinase B (AKT) pathway inhibitors, 
poly adenosine diphosphate-ribose polymerase (PARP) inhibitor, other 
investigational agents (including novel endocrine therapy, any selective estrogen 
receptor degraders [SERDs], selective estrogen receptor covalent antagonists
[SERCAs], complete estrogen receptor antagonists [CERANs]) for any setting.
b. prior chemotherapy for advanced/metastatic disease.
Participation in other studies involving investigational drug(s) within 28 days prior to 
randomization. If in the follow-up (FU) Phase, the participant is eligible provided at least 
5 half-lives have elapsed from the last dose.

Inadequate liver, kidney and bone marrow function.
Study Arms and Duration:
Study Intervention
Intervention Name
ARV-471 (PF-07850327)
Fulvestrant
Arm Name
(group of participants receiving a 
specific treatment or no treatment)
A (Investigational)
B (Comparator)
Dose Formulation
Tablet
Solution for intramuscular (IM)
injection
Unit Dose Strength(s)
100 mg
250 mg/5 mL
Route of Administration
Oral
IM
Use
Experimental
Active comparator
Investigational medicinal product 
(IMP) or non-investigational 
medicinal product/auxiliary 
medicinal products (NIMP/AxMP)
IMP
IMP
Study Arm(s)
Arm Title
Arm A (ARV-471)
Arm B (Fulvestrant)
Arm Type
Experimental
Active comparator
Arm Description
Participants will receive two ARV-
471 100 mg tablets (200 mg QD) 
administered orally, once daily, on 
Days 1-28 of each 28-day cycle. 
Participants will receive fulvestrant as 
two 5 mL IM injections (250 mg/5 
mL) on Days 1 and 15 of Cycle 1 and 
then on Day 1 of each cycle starting 
from C2D1 (28-day cycle). 
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Statistical Methods:
The primary endpoint is PFS assessed by BICR, which is defined as the time from the date of 
randomization to the date of the first documentation of objective progression of disease (PD) 
per RECIST v1.1, or death due to any cause, whichever occurs first. 
The key secondary endpoint is OS, which is defined as the time from date of randomization 
to date of death due to any cause.  
The study will perform statistical hypotheses tests in each of the two populations: 1) all 
randomized participants, and 2) participants with ESR1 mutation. 
Primary endpoint family: 
H0 all participants: HRPFS ≥ 1 vs H1 all participants: HRPFS < 1 
H0 ESR1 mutant participants: HRPFS ≥ 1 vs H1 ESR1 mutant participants: HRPFS < 1 
where HRPFS is the hazard ratio (ARV-471 vs fulvestrant) of PFS.
And secondary endpoint family:
H0 all participants: HROS ≥ 1 vs H1 all participants: HROS < 1 
H0 ESR1 mutant participants: HROS ≥ 1 vs H1 ESR1 mutant participants: HROS < 1 
where HROS is the hazard ratio (ARV-471 vs fulvestrant) of OS.
A graphical multiple testing strategy will be used for PFS and OS testing to maintain the 
overall 1-sided type I error rate within 2.5% (α) at the whole study level. 
No interim analysis is planned for the primary endpoint PFS. 
Two interim analyses for efficacy are planned for the key secondary endpoint of OS. The 
first OS interim analysis will be performed at the time of the final PFS analysis. The second 
OS interim analysis will be performed at 130 OS events in participants with ESR1 mutation 
and 265 OS events in all participants population (approximately 67% of total OS events 
required for final analysis).
For PFS in the all participants population, based on a 1:1 randomization allocation ratio, a 
total of 310 PFS events will provide 92.5% power for a 1-sided log-rank test at a 0.01875 
significance level to detect a hazard ratio [HR] < 0.67. For PFS in participants with ESR1 
mutation, a total of 165 PFS events will provide 88% power for a 1-sided log-rank test at a 
0.01875 significance level to detect a hazard ratio [HR] < 0.60.  
It is estimated that approximately 560 participants will be needed to observe the 310 PFS 
events in all participants population, and out of which, approximately 280 participants with 
ESR1 mutation are required to observe 165 PFS events in the subgroup population. 
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All efficacy analyses will be performed using the full analysis set (FAS), defined as all 
participants who were randomized to the study treatment. Efficacy analyses (PFS, objective 
response rate [ORR], DOR, CBR) will be performed using a BICR assessment as the primary 
data source. 
All safety analyses will be performed on the safety analysis set (SAS), defined as all 
randomized participants who receive at least 1 dose of study intervention.  Severity of the 
AEs will be graded according to the NCI CTCAE v5.0. 
Ethical Considerations:
In non-clinical studies, ARV-471 as a single agent demonstrated in vitro potent and robust 
ER degradation even in the presence of clinically relevant, mutated forms of ESR1.
Initial safety data reported from participants treated with ARV-471 monotherapy across 
multiple doses in the ARV-471-mBC-101 FIH study (Part A dose escalation of ARV-471 of 
total daily doses of 30 to 700 mg QD and Part B dose expansion of ARV-471 at 200 mg QD 
and 500 mg QD, N=149) showed ARV-471 was well tolerated, without any dose limiting 
toxicities. Most treatment-related adverse events were Grade 1 or Grade 2 in severity. Data 
from the monotherapy dose escalation and dose expansion at ARV-471 200 mg QD and 500 
mg QD support the monotherapy dose selection of ARV-471 200 mg QD as RP3D, based on 
the lack of clear differences in efficacy (by CBR) and no meaningful differences in the 
overall safety between ARV-471 200 mg QD and 500 mg QD, except for an apparent higher 
risk of potential QTc prolongation and dose reductions observed at ARV-471 500 mg QD 
monotherapy dose.  Promising preliminary efficacy by CBR and ORR was observed for all 
ARV-471 doses.
Participants may experience improvements during the study and will benefit from more 
intense monitoring and assessments compared to usual standard of care. The number of visits 
or other tests/assessments will only slightly exceed what is usually required with routine 
standard of care and should not create a significant risk to participant health. The minimum 
number/volume of blood samples and of visits/all other tests requested are designed to reduce 
participant’s burden without compromising the safety/efficacy evaluations and 
investigational purposes.
Overall, preliminary data from the ongoing FIH ARV-471-mBC-101 study suggest that 
ARV-471 may represent an important therapeutic option in participants with ER(+)/HER2(-) 
aBC who have progressed after prior endocrine-based treatment(s) for their advanced 
disease.
Given current data the anticipated benefits that may be afforded to participants with 
ER(+)/HER2(-) advanced breast cancer outweigh the potential risks identified in association 
with ARV-471.
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1.2. Schema
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Table 1.
SoA: Prescreening 
The purpose of the prescreening visit is to obtain blood samples to evaluate the potential participant’s estrogen receptor gene (ESR1) status (wild-type or mutated).  
Screening activities may be performed while waiting for ESR1 test results/approval of prior ESR1 status, but ESR1 status must be available before randomization. The 
sponsor will monitor the frequency of the ESR1 status (wild-type or mutated) across the study population (see Section 9.5) to evaluate the proportion of wild-type or mutated 
ESR1 status (targeting approximately 280 participants with wild type ESR1/280 participants with mutated ESR1).  
General Activities
Prescreening
Comments
Timing from signing pre-screening consent to randomization should not exceed 6 weeks. 
If combining prescreening and screening, screening procedures should be completed within 28 days 
from main consent of the study to randomization unless otherwise specified.
Prescreening Informed Consent, SSID 
Number
X 
Prescreening ICD must be signed before any prescreening activity is performed as per below:
- blood sample collection for ESR1 status evaluation 
- ask for sponsor approval (with the exception of participants in China) for using a prior ESR1 status 
result. Sponsor approval may be obtained if the following criteria are met:
- The test result confirms ESR1 mutated status (will not be accepted for wild-type status 
results)
- Result is provided using an FDA approved test using ctDNA/tumor sample
- Participant’s ctDNA sample/tumor sample was collected within 6 months from 
randomization in the current study.
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Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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Table 1.
SoA: Prescreening 
ctDNA Blood Sample 
X
Mandatory: Three samples of 10 mL each of whole blood (only two samples of 10 mL blood sample for 
China) must be collected.
Samples to be collected:

For all participants with the exception of China: The collection of the 3 samples is mandatory and 
will be used either for ESR1 status evaluation or for retrospective ESR1 confirmation after 
participants’ randomization (only for the participants with an acceptable and approved prior ESR1 
status result) and may also be used for the development of companion diagnostics. One of the 3 
samples is to be processed into plasma at the study site as per Lab manual instructions.  The other 
two whole blood samples will be sent directly to the laboratory identified for analysis. See Section 
8.1.1 and Laboratory Manual.

For participants in China: Two samples are mandatory for ESR1 status evaluation: the remaining 
sample may be also used for development of companion diagnostics. The sample may be also used 
for tumor molecular profile/ctDNA level and ctDNA burden if the participants are randomized in 
the trial. See Section 8.1.1 and Laboratory Manual.
ESR1 test will be performed using a NGS test that evaluates other genes in addition to ESR1 gene. The 
results of the other genes will not be collected in the CRF. 
Demography 
X
Disease Characteristics
X
See Section 8.1.1
AE Collection/Review
X
Record study procedure-related AEs in the eCRF from the time blood sample collection is performed 
through and including 14 days or longer in case of serious complications (see Appendix 3 for AE/SAE). 
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Clinical Assessments
Registration and 
Informed Consent 
Process
X
ICD must be obtained within 28 days of randomization and prior 
to any protocol required assessments being performed unless 
otherwise specified eg, assessments by imaging
See Appendix 1 and Section 10.1.3
Screen for 
Inclusion/Exclusion 
Criteria
X
See Section 5.1 and Section 5.2
Physical Examination*
/Vital signs*
X
X
X
X
X
C1D1 PE not required if acceptable screening assessment is 
performed within 7 days from randomization
Height at screening only and weight at screening, at each cycle 
and at the EOT.
See Section 8.3.1 and Section 8.3.2
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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Page 32
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Medical/ Oncological 
History
X
See Section 8.1.2
ECOG PS
X
Participants must have an ECOG PS ≤1 as per IC Number 6. 
See Section 5.1, and Appendix 14
12-Lead ECG*
See Table 3
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
LHRH agonist*
X
(Every 28 days/3 months from Cycle 1 Day 1)
X (at PI 
discretion)

Pre/peri-menopausal female and male participants must start 
LHRH agonist on Cycle 1 Day 1 (if not already on treatment) 
and continue throughout the active treatment phase every 28 
days/3 months (depending on the LHRH formulation) 
irrespective of cycle duration and until 28 days after the last 
dose.

Participants already on treatment with a 28 days/3-month LHRH 
formulation can continue it.

LHRH agonist during the survival FU should be given at the 
PI’s discretion in both arms.

If LHRH agonist is administered at home, the administration 
details will be collected in a dosing diary. 

See Section 6.9.1.
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Contraception 
Compliance check (as 
applicable)*
X
X
X
X
X
X (up to 30 
days)
WOCBP and male participants: contraception is mandatory 
Regular checks are required at times noted in this table.
See Appendix 4 for details on contraception requirements and 
guidance.
Laboratory Studies-
Hematology*
X
X
X
X
X
X
(Only if 
laboratory 
abnormalities 
not resolved 
at EOT) 
C1D1 assessment not required if acceptable screening assessment 
is performed within 7 days prior to randomization. 
Refer to Section 8.3.4 and Appendix 2
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Blood Chemistry*
X
X
X
X
X
X
(Only if 
laboratory 
abnormalities 
not resolved 
at EOT) 

C1D1 assessment not required if acceptable screening 
assessment is performed within 7 days prior to randomization 
with the exception of electrolytes (sodium, potassium, 
magnesium, total calcium) that should be assessed on C1D1 
(with a time window of -2 days, see  Table 3.
Assessments must be performed at each visit with the exception of:

Glucose (fasting) and HbA1C (fasting) only required at 
screening, C1D1 and then every 3 cycles (eg, Cycles 4, 7, 10 
etc.) and during the first 2 years of study treatment (until Cycle 
25) from randomization and EOT 

Cholesterol and triglycerides required at screening, C4D1, C7D1 
and then every 6 cycles and at the EOT. Results of these tests 
are not needed for retreatment.

Total Calcium and magnesium are performed at screening, 
C1D1, C2D1, C3D1 and EOT.

  Refer to Section 8.3.4 and Appendix 2  
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
HBV, HCV and HIV 
Tests
[X]
Only if required by local regulations.
Coagulation
X
See Section 8.3.4 and Appendix 2
FSH (as applicable)
X
To confirm a postmenopausal status of female participants under 
60 years of age, cessation of regular menses for 12 consecutive 
months and with no alternative medical cause.
See Appendix 2 and Appendix 4 .
Pregnancy 
Test (as applicable)*
X
X
X
X
X
X
For WOCBP only. A serum pregnancy test is mandatory at 
screening. 
Post screening, pregnancy tests (urine or serum tests with a 
sensitivity of at least 25 mIU/mL) are required.
Additional pregnancy tests may be performed at any time as per 
Investigator judgment or if required by local regulations or 
IRBs/ECs. 
See Section 8.3.5, Appendix 2.
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Disease Assessments 
Tumor assessments (other 
than Bone scan)
X
◄--►
Every 8 weeks (±7 days) for 
the first 48 weeks from the 
date of randomization. Then 
every 12 weeks (± 7 days) 
thereafter from the date of 
randomization
X
Images, as well as all the other information as per Section 8.2.1.2
must be sent for central reading on an ongoing basis (as soon as 
they are available) and until PD is confirmed by BICR regardless 
of the initiation of a new anticancer therapy.
Tumor assessments should continue as per Section 8.2.1 and 
Section 8.2.1.2.
On active treatment phase bone scan should be performed only if 
needed as per Section 8.2.1 requirement.
See Section 8.2.1.1 for further details on treatment continuation 
beyond progression.
Please see Section 8.2.1 for CR/PR confirmation.
Post-Treatment oncologic assessments (including bone scan, if 
applicable) are required only for participants who discontinued the 
study treatment for reason other than PD.
See Section 8.2
Radionuclide Bone Scan, 
Whole Body
X
◄--►
Every 24 weeks (± 7 days) 
from the date of 
randomization 
X
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
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Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Randomization and Study Treatment
Randomization 
X
Randomization must occur after having carefully reviewed all 
eligibility criteria and confirmed they are satisfied.
At randomization, randomization number and treatment arm are 
assigned.
Study treatment must start within 3 days after randomization.
See Section 6.3
ARV-471 (Arm A)*
Once Daily ◄--►
ARV-471 is given orally, in continuous daily dosing, for a 28-day 
cycle, with food at approximately the same time preferably in the 
morning.
See Section 6.1.1 and Section 6.1.1.1 for details on drug intake.
Fulvestrant (Arm B)*
X (Days 
1 and 
15)
X
X
Fulvestrant should be administered intramuscularly on Days 1 and 
15 (±2) of Cycle 1. Then from Cycle ≥2, on Day 1 of each cycle.  
Refer to Section 6.1.1.2
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 39
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Other Clinical Assessments 
Drug Compliance*
◄--►
Any unused tablets of ARV-471 must be returned to the clinic for 
drug accountability. 
From Cycle 2 onward, compliance will be performed at each 
cycle, prior to dispensing drug for the following cycle.
A dosing diary for ARV-471 will be given to participants to record 
dosing compliance 
Refer to Section 6.2 and Section 6.5
Adverse Event 
Reporting*
X
X
X
X
X
X
See Section 8.4.1, Section 8.4.9, Appendix 3, and Appendix 9 for 
details on AE/SAE reporting requirements during the active 
reporting period and for SAE reporting requirements after the end 
of reporting period.
Concomitant 
Medications/ 
Treatments*
X
X
X
X
X
X
See Section 6.9 and Appendix 10
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 40
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
PRO Assessments*:
EuroQol; EQ-5D-5L; 
EORTC QLQ-C30;
EORTC QLQ-BR23
BPI-SF
X
X
X
X
(Cycles 3, 
4, 5, 6 and 
then every 
other 
Cycle, ie, 
cycles 8, 
10, 12, 
etc) 
X
X
All self-assessment questionnaires should be completed by the 
participants prior to any Day 1 procedure.
See Section 8.9, Appendix 14
Female and male versions of the EORTC QLQ-BR23 
questionnaire will be utilized depending on the participant’s 
gender. 
Questionnaire by paper or electronic. If both versions are 
available, electronic version must be completed. 

PROs mandatory unless the electronic devices are not available
due to local restrictions. In this case completion of any PRO 
version including the33 paper version is not required.
PRO/ Evening Daily 
Diary: 
mBPI-SF
pain medication
Daily

“Evening daily diary” to be filled in the evening and includes:

Arms A & B:
o
mBPI-SF assessments: includes the worst pain 
severity (item 3) and pain interference (item 9a) 
assessments. 
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 41
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
injection site pain 
o
Pain medication usage.

Arm B only:
o
Injection site pain.

Evening daily diary by paper or electronic handheld device. If 
both versions are available, electronic version must be 
completed. 

PROs mandatory unless the electronic devices are not available
due to local restrictions. In this case completion of any PRO
version including the paper version is not required.
See Section 8.9, Appendix 14
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 42
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
PRO Assessment*: 
Patient preference 
questionnaire 
X
X (only at 
Cycle 4)

The patient preference questionnaire will be completed by the 
participants prior to any Day 1 procedure at Cycle 2 and Cycle 
4.

Questionnaire by paper or electronic. If both versions are 
available, electronic version must be completed 

PROs mandatory unless the electronic devices are not available
due to local restrictions. In this case completion of any PRO 
version including the paper version is not required.

See Section 8.9, Appendix 14
Survival Follow-up
X
Survival status will also include all FU anticancer therapies.
Survival may be collected also by telephone contact, email, etc.
See Section 7.1.1.2
Pharmacokinetic assessments to be shipped to the central laboratories
Blood sample for PK 
(Arm A)*
See Table 3
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 43
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Special Laboratory Studies to be shipped to the central laboratories
ctDNA Blood Sample*
X
X
X
(Cycle 6 
only)
X
Two samples of 10 mL of whole blood (one 10 mL whole blood 
sample for China) at each timepoint will be collected. 
C1D1 samples may also be used for the development of 
companion diagnostics, if needed.
Refer to Section 8.7.2 and Laboratory Manual.
Retained Research Blood 
Sample for genetics
X
A single 4 mL whole blood sample for DNA extraction (Prep D1) 
will be collected, unless prohibited by local regulations, 
IRBs/ECs.
If not collected on the designated collection day, collect at the next 
available time point when biospecimens are being collected in 
conjunction with a participant visit.
See Section 8.6.2
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 44
Table 2.
Study SoA
Protocol Activity
Screeninga Active Treatment Phaseb
(1 Cycle = 28 days)
EOT / 
Withdrawalc
Post-Treatment FU
Notes
Cycle 1 Cycle 2 Cycles ≥3
Safety FUd
Survival FUe a. Screening: screening procedures should be completed within 
28 days from consent to randomization unless otherwise specified. 
b. Active Treatment Phase assessments should be performed, and 
safety assessments reviewed prior to dosing on the visit days, 
unless otherwise specified, using the following sequence (if 
performed on the same day): 1) PROs (with the exception of the 
evening daily diary); 2) ECGs; 3) blood drawn for PK; 4) blood 
drawn for lab tests/ctDNA/Retained Research Sample; 5) PE/Vital 
signs.
c. EOT assessments should be performed only if they have NOT 
been completed: 1) within the previous 4 weeks for safety 
assessments, unless needed for monitoring of safety findings; 2) 
within the previous timepoint for tumor assessments (8 or 12 
weeks as per frequency of tumor assessments) or 24 weeks for 
bone scan if bone scan is the preferred technique to follow bone 
lesion/s on treatment and unless PD has been confirmed 
elsewhere.
d. Safety FU is a minimum of 28 days from last dose OR prior to 
initiation of a new anticancer therapy, whichever comes first 
(Section 7.1.1.1).
e. Survival FU is every 3 months from EOT (Section 7.1.1.2).
Study Day
≤ 28 days
Day 1
Day 1
Day 1
28 days from 
last dose
Every 3 mos 
from the EOT
Visit Window
(days)
-2
±2
±2
+7
±14
Tumor Tissue for 
Biomarkers 
X 
(Mandatory
)
X (optional)
See Section 8.7.1
* Assessments may be performed during home health visits that will be allowed on a case-by-case basis. Confirmation from the sponsor will include which visits can be performed at 
home.
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 45
Table 3.
Pharmacokinetic and ECGs, Schedule of Activities
Protocol 
Activity
Active Treatment Phase
(1 Cycle = 28 days)
Notes
Study Day
Screening 
Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3, 5 & 7 Day 1
EoT/Withdra
wal
On the visit days, participant should be 
instructed not to take ARV-471 dosing 
and to withhold their daily dose of 
ARV-471 until the pre-dose assessments 
have been completed.
On the visit days assessments should be 
performed, unless otherwise specified, 
using the following sequence: ECGs, 
blood drawn for PK and blood drawn for 
lab tests. 
Visit Window
(days)
±2
±2
Hours post 
dosing
≤ 28 days
0 h
(within 2.5 h prior 
to dose**)
0 h
(within 2.5 h 
prior to 
dose**)
5-7 h 
0 h
(within 2.5 h 
prior to dose**)
5 -7 h

Arm A: Participants in the QTc-Substudy and all the remaining participants in Arm A
12 Lead ECG 
(triplicate)*
X
X 
X 
X
X 
(Cycle 3 only)
X
(Cycle 3 only)
X
For the participants in the QTc 
sub-study (approximately 80 
participants enrolled at selected 
sites):  at least 1-hour fasting needed 
at all timepoints with the exception of 
screening. Central reading is required 
for all ECG timepoints apart from 
screening. 
Triplicate ECG should be performed 
immediately before PK blood draws 
at respective time points.
ECG measurement required at any 
time between 5-7 hours after drug 
intake.

Blood sample for electrolytes 
(sodium, potassium, magnesium, 
total calcium) must be collected at 
Day 1 pre-dose (with a time 
window of -2 days) (see the note 
for sequence above if performed on 
the same day of ECG and PK). If 
not performed on Day 1, 
electrolytes must be repeated on 
Day 1 if ECG abnormalities are 
observed.   
Refer to Section 8.3.3
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 46
Table 3.
Pharmacokinetic and ECGs, Schedule of Activities
Protocol 
Activity
Active Treatment Phase
(1 Cycle = 28 days)
Notes
Study Day
Screening 
Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3, 5 & 7 Day 1
EoT/Withdra
wal
On the visit days, participant should be 
instructed not to take ARV-471 dosing 
and to withhold their daily dose of 
ARV-471 until the pre-dose assessments 
have been completed.
On the visit days assessments should be 
performed, unless otherwise specified, 
using the following sequence: ECGs, 
blood drawn for PK and blood drawn for 
lab tests. 
Visit Window
(days)
±2
±2
Hours post 
dosing
≤ 28 days
0 h
(within 2.5 h prior 
to dose**)
0 h
(within 2.5 h 
prior to 
dose**)
5-7 h 
0 h
(within 2.5 h 
prior to dose**)
5 -7 h
Blood sample 
for PK*  
X 
X
X 
X 
(Cycle 3 only)
A single 3 mL whole blood sample 
will be collected at each time point.
Pre-dose PK samples should be 
collected within 2.5 hours prior to 
dosing.
PK samples will be shipped to the 
central laboratory.
Refer to Section 8.5

Arm B  
12 Lead ECG 
(triplicate)*
X
X 
X 
X 
(Cycle 3 only)
X
Triplicate ECG is required at all time 
points.

Blood sample for electrolytes 
(sodium, potassium, magnesium, 
total calcium) must be collected at 
Day 1 pre-dose (with a time 
window of -2 days) (see the note 
for sequence above if performed on 
the same day of ECG and PK). If 
not performed on Day 1, 
electrolytes must be repeated on 
Day 1 if ECG abnormalities are 
observed).   
Refer to Section 8.3.3
* Assessments may be performed during home health visits that will be allowed on a case-by-case basis. Confirmation from the sponsor will include which visits can be performed
at home.
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 47
Table 3.
Pharmacokinetic and ECGs, Schedule of Activities
Protocol 
Activity
Active Treatment Phase
(1 Cycle = 28 days)
Notes
Study Day
Screening 
Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3, 5 & 7 Day 1
EoT/Withdra
wal
On the visit days, participant should be 
instructed not to take ARV-471 dosing 
and to withhold their daily dose of 
ARV-471 until the pre-dose assessments 
have been completed.
On the visit days assessments should be 
performed, unless otherwise specified, 
using the following sequence: ECGs, 
blood drawn for PK and blood drawn for 
lab tests. 
Visit Window
(days)
±2
±2
Hours post 
dosing
≤ 28 days
0 h
(within 2.5 h prior 
to dose**)
0 h
(within 2.5 h 
prior to 
dose**)
5-7 h 
0 h
(within 2.5 h 
prior to dose**)
5 -7 h
** The time window of 2.5 hours is strongly recommended; however, it may be extended up to 4 hours to accommodate site needs as long as all samples are collected on each 
evaluation day as per Table 3.
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ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 48
2. INTRODUCTION
ARV-471 (also known as PF-07850327 or vepdegestrant) is a potent, selective, orally 
bioavailable PROTAC, which is a small molecule that induces degradation of the ER. In this 
study (VERITAC-2) ARV-471 is being investigated in participants with ER(+), human 
epidermal growth factor receptor negative (HER2[-]) unresectable locoregional recurrent or 
mBC who have progressed after prior endocrine based treatment(s) for advanced disease. 
The investigational drugs ARV-471 (PF-07850327) and fulvestrant will be identified 
throughout the protocol as ARV-471 and fulvestrant. 
The study population, participants with unresectable locoregional recurrent or mBC, will be 
reported as participants with aBC throughout the protocol.
2.1. Study Rationale 
The purpose of this study is to demonstrate the superiority of ARV-471 in terms of 
progression free survival compared to fulvestrant in participants with ER(+)/HER2(-) aBC 
who have progressed after prior endocrine based treatment(s) for their advanced disease.
The past decade has seen significant improvements in the treatment options for patients with 
advanced ER(+)/HER2(-) breast cancer. However, there is still an unmet need to improve 
clinical outcomes after progression with existing ET, particularly for the second- and third-
line patients where the desire is to delay treatment with chemotherapy. ARV-471 may 
represent a potential alternative due to its unique mechanism of action that may have the 
advantage of achieving complete inhibition of the ER by essentially eliminating the entire 
protein. This may be particularly advantageous in the setting of constitutively active ESR1 
mutations.
2.2. Background 
2.2.1. Breast Cancer
Female breast cancer has now surpassed lung cancer as the leading cause of global cancer 
incidence in 2020, with an estimated 2.3 million new cases, representing 11.7% of all cancer 
cases. BC is the fifth leading cause of cancer mortality worldwide, with 685,000 deaths 
(Sung et al, 2021) and the second leading cause of cancer death in women, with over 43,250 
women expected to die from the disease in 2022 in the US (Siegel et al, 2022).  While BC is 
less common in men, men account for approximately 1% of all newly diagnosed cases, and 
almost 530 men are projected to die from their disease in 2022 (Siegel et al, 2022).    
Globally, the number of people living with mBC is increasing, primarily because of 
improvements in available treatment options.  In the US the estimated number of women 
living with mBC increased by 17% from 2000 to 2010 and was projected to increase by 31% 
from 2010 to 2020 (Mariotto et al, 2017).  In this country the vast majority (approximately 
73%) have HR+ and HER2(-) disease (Howlader et al, 2014). 
Although age adjusted mortality from BC has been decreasing during the last decades, the 
median survival time for patients with metastatic disease is still approximately 18-24 months 
090177e1a21d13b3\Approved\Approved On: 07-Nov-2024 07:38 (GMT)

ARV-471 (PF-07850327)
Protocol C4891001
Final Protocol, Amendment 3, 6 Nov 2024
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 49
and there remains urgent medical need for more active agents in this metastatic setting 
(Zheng et al, 2020). 
2.2.2. Treatment Options for ER-positive Breast Cancer
Treatment options for patients with aBC depend on many different factors, including whether 
the tumors express hormone receptors (ER and/or progesterone receptor [PR]) or HER2.  The 
standards of care for people with ER(+) aBC are ETs (ie, letrozole, anastrozole, exemestane, 
fulvestrant, tamoxifen), as a single agent or co-administered with targeted therapy (CDK4/6 
inhibitors, PI3K inhibitors, mTOR inhibitors, and PARP inhibitors), and/or chemotherapy. 
Targeting estrogen receptor signaling is a cornerstone of treatment for ER(+) breast cancer 
and has evolved over time from the use of selective ER modulators (tamoxifen) to aromatase 
inhibitors (letrozole, anastrozole, exemestane), and selective estrogen receptor degraders 
(SERDs, fulvestrant). More recently, combinations of endocrine therapy with molecularly 
targeted agents have further improved outcome of patients (McAndrew & Finn, 2021).
Despite the significant clinical benefit, patients still develop endocrine resistance after or 
during endocrine treatment. Endocrine resistance is a clinical challenge and can present at 
diagnosis (de novo/intrinsic resistance) or after treatment with endocrine therapy (acquired
resistance).  Intrinsic resistance is thought to be present in up to 30% of patients and due to 
lack of expression of ER (Belachew & Sewasew, 2021).  30-50% of patients will develop 
SERD/SERM/AI-resistant ER-positive metastatic lesions after an average of 5 years 
(Fanning & Greene, 2019; Rozeboom et al, 2019).
2.2.3. ARV-471
ARV-471 is a potent, selective, orally bioavailable PROTAC small molecule that induces 
degradation of the ER. ARV-471 is a hetero-bifunctional PROTAC molecule that 
simultaneously binds the ER and the cereblon E3 ligase complex, enabling protein-protein 
interactions between ER and the ligase complex. As a result, the ER becomes poly-
ubiquitinated on accessible lysine residues and subsequently undergoes targeted degradation 
by the proteasome leading to its elimination from cells.
In non-clinical studies, ARV-471 demonstrated in vitro potent (< 1 nM) and robust (> 90%) 
ER degradation even in the presence of clinically relevant, mutated (Y537S and D538G) 
forms of ER. Based on non-clinical studies, ARV-471 may have advantages over fulvestrant 
and other oral SERDs in clinical development such as RAD1901/elacestrant (Flanagan et al, 
2018). While SERDs destabilize ER and indirectly lead to ER degradation, ARV-471 
actively degrades ER, which may lead to less drug resistance. In vivo, ARV-471 inhibits 
tumor growth in multiple mouse xenograft models. Notably, ARV-471 demonstrates superior 
TGI compared to fulvestrant in a Y537S ESR1 mutant patient-derived xenograft model 
(ARV-471 IB). In the MCF7-xenograft mouse model, 3 to 30 mg/kg ARV-471, orally 
administered to mice once daily for 28 days, displayed dose-dependent efficacy with doses of 
3 and 10 mg/kg/day inhibiting tumor growth by 85% and 98%, respectively, and 30 
mg/kg/day leading to tumor shrinkage (124% TGI). At study termination, the tumor ER 
levels were reduced by ≥94% suggesting that higher doses are required for maximal efficacy 
than for maximal ER degradation.
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These nonclinical data suggest that ARV-471 has the potential to offer improved ER 
degradation as compared to fulvestrant.
2.2.3.1. Non-clinical Pharmacokinetics and Metabolism
ARV-471 is a BCS Class IV compound (low solubility/low permeability). The PK profile of 
ARV-471 in the nonclinical species (mouse, rat, dog, and monkey) was characterized by a 
low to moderate clearance (13.8% to 33.8% of hepatic blood flow), extensive tissue 
distribution (2.1 to 6.0 L/kg), short to moderate half-life of elimination (T1/2) (2.1 to 8.2 
hours), and moderate to good oral bioavailability (27% to 65%). ARV-471 can interconvert 
to its epimer, ARV-473 (ARV-471 IB).
A dose-dependent increase in ARV-471 exposure was observed when ARV-471 was 
administered as an oral solution in the mouse (10, 30, 100 mg/kg), rat (30, 100, 300 mg/kg), 
dog (15, 45, 90, 200, and 400 mg/kg), and monkey (1 and 3 mg/kg) (ARV-471 IB).
A 3-fold increase in AUC and reduced inter-animal variability was observed in fed dogs; as 
such, the data indicated that the tablets should be administered with food in clinical trials.
CYP3A4 is the main isoform contributing to ARV-471 CYP metabolism (accounting for 
85% of CYP metabolism).
2.2.3.2. Potential Drug-Drug Interactions
Drugs that are inhibitors of CYP3A4 may increase the exposure of ARV-471, whereas drugs 
that are inducers of CYP3A4 may reduce the exposure of ARV-471.
In vitro, ARV-471 is an inhibitor of CYP2B6 with an IC50 of 16.0 μM. However, subsequent 
mechanistic static modeling, using bupropion as the probe CYP2B6 substrate drug, indicated 
a low potential for DDI due to ARV-471-mediated reversible inhibition of CYP2B6 at 
human exposures associated with the 500 mg QD dose. Since bupropion is the only known 
sensitive CYP2B6 substrate, participants enrolled in clinical trials are allowed to receive 
CYP2B6 substrates or CYP2B6 substrates with narrow therapeutic indices.
ARV-471 showed weak inhibition of human BCRP and is considered an in vitro inhibitor of 
P-gp. Based on the lack of significant safety issues when a sensitive BCRP substrate, 
rosuvastatin, was administered together with ARV-471 in study ARV-471-mBC-101, 
participants enrolled in clinical trials will be allowed to receive sensitive BCRP substrates or 
BCRP substrates with narrow therapeutic indices. Clinical DDI studies with P-gp substrates 
have not yet been conducted (ARV-471 IB). 
Studies conducted in fasted dogs and rats showed a pH effect on absorption when 
administered with famotidine (lowered PK at neutral pH). Elevated gastric pH may reduce 
ARV-471 absorption. Effect of PPI on ARV-471 in healthy participants was evaluated in 
Study ARV‑471-CPhm-103. Preliminary results demonstrated that ARV-471 AUC values 
were similar when administered with PPI or without PPI, although PPI decreased median 
ARV-471 Cmax about 18% which is not considered clinically meaningful. This indicates that 
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there are no effects of PPI on exposure of ARV-471 when administered with a moderate fat 
meal. The concomitant use of PPIs with ARV-471 is not recommended. If PPI treatment is 
required, ARV-471 intake with a moderate-fat meal (400-800 calories, approximately 35% 
fat) is recommended. Administer ARV-471 ≥2 hours before or after antacids. Administer 
ARV 471 ≥2 hours before or 10-12 hours after H2 receptor antagonists (ARV-471 IB).
2.2.3.3. ARV-471 Preliminary Safety, Efficacy and PK in Humans
In the ongoing FIH Study [ARV-471-mBC-101], ARV-471 is being assessed as a 
monotherapy and in combination with palbociclib in participants with ER(+)/HER2(-) aBC 
who had previously received CDK4/6 inhibitors and/or endocrine therapy and/or 
chemotherapy in the locally advanced/metastatic setting.  The FIH study has 3 parts: Part A 
is a monotherapy dose escalation, Part B is a monotherapy dose expansion (200 mg or 500 
mg, oral daily dosing), and Part C is evaluating the combination of ARV-471 and palbociclib 
(ARV-471 at 180, 200, 400 and 500 mg oral daily dosing plus palbociclib at 125 mg oral 
daily for 3 consecutive weeks followed by 1 week off treatment). As of 06 June 2022, 176 
participants have been treated in the FIH study (Part A n=78; Part B n=71, Part C n=27) 
(ARV-471 IB). 
Based on the current safety data (data cutoff date of 06 June 2022), ARV-471 has been well-
tolerated across total daily doses of 30 mg to 700 mg in patients with mBC, with no DLTs 
observed and most TRAEs were Grade 1 or 2.  In addition, evaluation of preliminary safety 
data from participants treated with palbociclib in combination with ARV-471 shows TEAEs 
consistent with TEAEs observed after treatment with either ARV-471 or palbociclib alone 
(ARV-471 IB).
In Part A (monotherapy dose escalation), a total of 71 out of the 78 participants (91.0%) 
reported at least 1 TEAE. The most common TEAEs (regardless of attribution to study drug) 
observed in ≥10% of participants were: fatigue (33%), nausea (33%), constipation (31%), 
arthralgia (18%), vomiting (18%), back pain (17%), diarrhea (17%), headache (17%), 
decreased appetite (15%), AST increase (14%), hot flush (14%), hyperglycemia (13%), pain 
in extremity (13%), insomnia (11%), ALT increased (10%), and dizziness (10%). 
Most of the patients experienced Grade 1 or 2 TEAEs (74.3%), with Grade ≥3 occurred in 
16.6% of patients.
The Grade 3 TEAEs were hypertension (2 patients) and nausea, stomatitis, arthralgia, fatigue, 
aspartate aminotransferase increased, electrocardiogram QT prolonged, amylase increased, 
blood alkaline phosphatase increased, lipase increased, headache, presyncope, embolism, 
embolism venous, procedural pain, humerus fracture, acute kidney injury, and malignant 
pleural effusion (1 patient each). The Grade 4 TEAEs of hypoglycemia, neutrophil count 
decreased, and neutropenia occurred in 1 patient each. The Grade 5 TEAE of cardiac arrest 
occurred in 1 patient and was unrelated to ARV-471.
A total of 54 participants (69%) had at least 1 TEAE considered potentially related to ARV-
471. The most frequently (≥10% participants) reported treatment-related AEs (all grades) 
were nausea (26%), fatigue (22%), constipation (13%), arthralgia (10%), decreased appetite 
(10%), hot flush (10%), and vomiting (10%). Most participants experienced Grade 1 or 2 
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TRAEs (64.1%). Grade 3 TRAEs (5.1%) were headache, asymptomatic amylase and lipase 
increased, nausea and asymptomatic electrocardiogram QT prolonged, and venous embolism. 
There were no Grade 4 or Grade 5 TRAEs.
Safety profile from Part B (monotherapy dose expansion) is consistent with what has been 
observed in Part A (monotherapy dose escalation).
In Part B, a total of 62 of the 71 participants (87.3%) reported at least 1 TEAE. The most 
commonly reported TEAEs observed in ≥10% of participants include fatigue (39%), nausea 
(21%), constipation (17%), arthralgia (17%), AST increased (13%), back pain (11%), 
decreased appetite (11%), and headache (11%). 
Most participants experienced Grade 1 or 2 TEAEs (64.8%) with Grade ≥3 occurred in 
22.5% of patients. The Grade 3 TEAEs were anemia (2 patients) and intestinal obstruction, 
muscular weakness, aspartate aminotransferase increased, alanine aminotransferase 
increased, blood alkaline phosphatase increased, electrocardiogram QT prolonged, brain 
oedema, seizure, syncope, thrombocytopenia, cholangitis, neutropenia, spinal cord 
compression, upper gastrointestinal haemorrhage, fatigue, pyrexia, back pain, and decreased 
appetite (1 patient each). The Grade 4 TEAEs of hyperbilirubinaemia, hypercalcaemia and 
hepatic haemorrhage were reported in 1 patient each. A Grade 5 TEAE of acute respiratory 
failure was reported in 1 patient, after that patient presented with progressive malignant 
pleural effusion. 
A total of 51 participants (71.8%) experienced at least 1 TRAE. The most common TRAEs, 
observed in ≥10% of participants include fatigue (34%), nausea (17%), and arthralgia (13%). 
Most participants experienced Grade 1 or 2 TRAEs (64.8%). Grade 3 events (7.0%) of 
electrocardiogram QT prolonged, thrombocytopenia, neutropenia, decreased appetite, and 
fatigue were experienced by 1 patient each. There was one Grade 4 TRAE of 
hyperbilirubinaemia. There were no Grade 5 TRAEs reported.
Based on preliminary safety data from patients treated with ARV-471 in combination with 
palbociclib (Part C), the combination appears tolerable. Part C is ongoing and as of 06 June 
2022 a total of 24 of 27 participants (88.9%) reported at least 1 TEAE. The most common 
TEAEs observed in ≥20% of participants included neutrophil count decreased (51.9%), 
fatigue (44.4%), neutropenia (37.0%), platelet count decreased (33.3%), anemia (29.6%), 
nausea (25.9%), cough (22.2%), diarrhea (22.2%), and WBC decreased (22.2%).
There have been 17 deaths reported in the ARV-471-mBC-101 study: 11 in Part A and 6 in 
Part B. None of these deaths were attributable to ARV-471.  No deaths have been reported in 
Part C. 
There was evidence of preliminary clinical activity in the Part A monotherapy dose 
escalation of Study ARV-471 mBC-101, with several patients achieving clinical benefit as 
defined by CBR and ORR as of 06 June 2022. CBR (rate of confirmed CR, PR, orSD ≥24 
weeks) was 36.2% (95% CI: 25.0 - 48.7) in 25 of 69 evaluable participants; the ORR was 
8.6% (95% CI: 2.9 -19.0), with 5 of 58 response-evaluable participants having confirmed PR 
(ARV-471 IB). No clear dose-dependent or exposure-response relationship for CBR was 
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observed, with exception of patients with ESR1 mutations showing a trend (not statistically 
significant) toward higher CBR with higher ARV-471 exposure (Arvinas, 2022). 
In Part B dose expansion the CBR in the overall population was 37.1% (95% CI: 21.5%, 
55.1%) and 38.9% (95% CI: 23.1%, 56.5%) at 200 mg and at 500 mg respectively.  The CBR 
in evaluable patients with estrogen receptor 1 gene (ESR1) mutations, was similar between 
the doses: CBR was 47.4% in patients at 200 mg QD (95% CI: 24.4%, 71.1%) and 54.5% at 
500 mg QD (95% CI: 32.2%, 75.6%). No exposure-response relationship for CBR was seen 
in the overall patient population or the ESR1 mutant patient population (Arvinas, 2022).
Clinical benefit (by CBR) was observed in CDK4/6 inhibitor-pretreated patients with 
ER(+)/HER2(-) BC in all Part A and B dose cohorts. 
Efficacy data collection is ongoing Part C. 
Preliminary PK data following single and multiple dosing from Part A monotherapy dose 
escalation of Study ARV-471-mBC-101 are available in mBC participants receiving ARV-
471 at total daily dose levels ranging from 30 mg to 700 mg (administered either as QD or 
BID) under fed conditions. The median Tmax ranged from 4 to 7 hours across the dose levels. 
The mean effective t1/2 at steady state ranged from 23 to 33 hours. Clinical exposure of ARV-
471 on Day 15 at 60 mg QD (geometric mean AUCtau 7324 ng.h/mL) has exceeded the 
nonclinical efficacious exposure associated with TGI (AUCinf=5,717 ng•h/mL) at 30 mg/kg 
single dose in mice. Following 200 mg QD dosing (N=8), a geometric mean accumulation 
ratio for AUCtau of 1.7 was observed between Day 1 and Day 15. ARV-471 can interconvert 
to its epimer, ARV-473. The ratio of ARV-473 / ARV-471, based on AUCtau, on Cycle 1 
Day 15 is 32%. 
Preclinical data showed ARV-471 has both antagonist and degradation activities against ER, 
whereas ARV-473 displays only antagonist activity (ARV-471 IB).
Safety and PK data in healthy volunteers is based on the Phase 1 clinical pharmacology 
study, Study ARV-471-CPhm-103, which is evaluating the effect of food or a PPI 
(esomeprazole) and the relative bioavailability of different tablet formulations on the single-
dose PK and safety of ARV-471 in healthy postmenopausal female volunteers. As of data 
cut-off date of 16 June 2022, a total of 47 healthy participants have been treated in Study 
ARV-471-CPhm-103 (14 participants in fed/fasted, 17 participants in PPI, and 16 
participants in rBA portions). Each participant received 2 doses of 200 mg ARV-471, 1 in 
each of the 2 periods, and the ARV-471 treatments were separated by a washout period of at 
least 14 days. Preliminary analysis results showed the median Tmax ranged from 6.0 to 8.0 
hours across the cohorts. The geometric mean t1/2 following a single 200 mg dose was about 
40 hours under fed condition. Food intake significantly increased ARV 471 Cmax and AUCinf
3- to 2- fold, respectively, as compared with fasted conditions. Thus, patients should be 
instructed to take ARV-471 with food. ARV-471 AUC values were similar when 
administered with PPI or without PPI when given with a moderate-fat meal, although PPI 
decreased ARV-471 Cmax about 18% which is not considered clinically meaningful. 
Analysis of 14 paired biopsies from patients treated in Part A (monotherapy dose escalation) 
at various doses of ARV-471 suggest robust ER degradation (up to 89% decrease, with a 
median ER decrease of 67%, [range: 21%, 89%])) across all doses up to 500 mg QD, 
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regardless of ESR1 mutation status with no apparent relationship between dose or exposure 
and ER degradation in patients with wild-type or mutant ER (Hamilton et al, 2022).
The totality of data from these nonclinical pharmacology, PK and metabolism, and 
toxicology studies and available safety and efficacy clinical data support continued clinical 
development of ARV-471 in ER(+) / HER2(-) advanced breast cancer.
2.2.3.4. QTc Evaluation Data
Nonclinical data in dogs identified an approximate 13 msec prolongation of QT/QTc
intervals at 90 mg/kg/day on Day 85 (nonadverse) of a 3-month dog toxicology study 
associated with comparative exposure margins to the 200 mg clinical dose of approximately 
5.8x and 5.9x for AUC and Cmax, respectively. Both single- and repeat-dose studies up to 
Day 28 were negative for this effect at higher or equivalent
dose/exposures. Neither ARV-471 nor ARV-473 inhibit the hERG channel
in vitro at concentrations greater than 100 times those of clinical relevance. Overall, a
potential concentration and time dependent impact on QT interval in the dog was observed.
Based on the categorical analysis of ECG data from 149 participants in Study 101 Part A and 
Part B (data cutoff date of 06 Jun 2022), 3 participants experienced a QTcF >500 msec (1 of 
each at 180 mg, 200 mg, and 500 mg daily dose) and 4 participants had QTcF change from 
baseline >60 msec (1 at 200 mg, 2 at 500 mg and 1 at 700 mg daily dose). From the ongoing 
ARV-471-mBC-101 study, as of 06 Jun 2022, 13 participants reported TEAEs of 
electrocardiogram QT prolonged (12 participants had TRAEs and in 1 participant the AE was 
considered as not related to ARV-471 per investigator). Most participants experienced grade 
1 or 2 QT prolonged events (11 out of 13), two patients reported Grade 3 events and no 
Grade 4/5 have been reported. No QT prolonged events were reported as serious. 
An external cardiology consultant review, including evaluation of the patient study treatment, 
laboratory and medical history as well as study ECGs, concluded that of the 13 participants 
who were reported to have experienced QTc prolonged events, only 2 participants had a true 
diagnosis of QTc prolongation, of which low potassium and concomitant medications were 
confounding factors.
Concentration-QTc modeling analysis of data from the ongoing ARV-471-mBC-101 study 
revealed a concentration-dependent increase in QTcF. Based on the model, a QTcF change 
from baseline is predicted to be 6.8 msec (90% CI: 5.7, 7.9) at the geometric mean Cmax for 
the sum of ARV-471 and ARV-473 (1,091 ng/mL) at steady-state after 200 mg QD dosing. 
(ARV-471 IB)
2.2.3.4.1. QTc Sub-study
In order to characterize the effect of ARV-471, a QTc sub-study will be conducted in a sub-
set of participants in Arm A in this study at selected sites.  To control potential significant 
confounding factors, concomitant use of ARV-471 with drugs of known risk of causing QT 
interval prolongation or Torsade de Pointes are prohibited or should be used with caution 
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(Section 6.9.3 and Appendix 10). The QTc interval via triplicate ECGs with time-matched 
PK draws (See Table 3 and Section 8.3.3) will be evaluated.
2.2.4. SERD
Fulvestrant is given as an intramuscular injection in a clinical setting and inhibits estrogen 
signaling through the ER primarily in 2 ways: 1) competitive inhibition of estradiol binding 
to the ER, blocking nuclear localization, and 2) accelerated degradation of the ER protein due 
to the instability of the fulvestrant-ER complex. After fulvestrant treatment, ER declined 
significantly compared to pre-treatment reaching its lowest levels at 6 months (6-mos median 
ER Hscore of 48 [2-135] versus pretreatment median ER Hscore of 130 [60-190]).  This ER 
level was generally maintained at time of fulvestrant progression (median ER Hscore of  50 
[8-130]) showing that no patient had lost all ER at relapse even in the longest interval 
between treatment and progression of 60.7 months, indicating a need for more effective ER-
degrading molecules (Agrawal et al, 2016). 
In this study, PFS improvement with ARV-471 over fulvestrant is expected in participants 
pretreated with endocrine-based treatment in view of the clinical data currently available for 
monotherapy fulvestrant. Fulvestrant has demonstrated activity in patients with both wild-
type and ESR1 mutant tumors in the second line treatment setting with 4.1 months (95% CI, 
3.6-5.5) mPFS in patients with ESR1 wild type tumors and 3.9 months (95% CI, 3.0-6.0) 
mPFS in patients with ESR1 mutant tumors (Turner et al, 2020). However, the clinical 
benefit reported in participants whose disease progressed after CDK4/6 inhibitor + ET 
therapy treated with fulvestrant (1.94 months mPFS [95% CI, 1.84–3.55] in the VERONICA 
study) (Lindeman et al, 2021) or with standard treatments (3.5 months mPFS [95% CI, 3.0–
5.4] in the ByLieve study) (Rugo et al, 2021) did not show robust enhancement and needs to 
be further improved. In this setting, SERDs are one of the treatments currently under 
investigation against aromatase inhibitor- or tamoxifen-resistance.
Recent investigational advances have allowed the development of new orally bioavailable 
SERDs, with elacestrant being approved by FDA and EMA in 2023. In a Phase 3 study, 
elacestrant, , has demonstrated a statistically significant improvement in PFS over SOC (ie 
AIs or fulvestrant) in participants with ER(+)/HER2(-) aBC in the second- and third-line 
settings. Approximately half of the participants enrolled had BC that harboured ESR1 
mutations. The study results showed a statistically significant improvement of mPFS in the 
elacestrant arm compared to SOC in all participants with a median PFS of 2.79 vs 1.91 
months (HR=0.697 [95% CI: 0.552, 0.880]; P=0.0018) and in participants with ESR1 mutant
BC with 3.78 vs 1.87 months mPFS (HR=0.546 [95% CI: 0.387, 0.768]; P=0.0005). 
Preliminary OS data, although not yet mature, demonstrated a trend in favor of elacestrant in 
all participants (HR=0.751 [95% CI: 0.542, 1.038]; P=0.0821) and in participants with ESR1
mutant BC (HR=0.592 [95% CI: 0.361, 0.958]; P=0.0325) (Bardia et al, 2022). These data 
support the rationale for assessing ARV-471 in this patient population. 
Currently, there is a gap in high-level evidence on the optimal sequencing of agents after 
progression on CDK4/6 inhibitors in the frontline setting. Unanswered questions include 
what is the efficacy of using CDK4/6 inhibitors beyond progression and what is the efficacy 
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of other therapies after progression, given the fact that most of the data generated with older 
regimens occurred in the era before CDK4/6 inhibitors were broadly used (McAndrew & 
Finn, 2021).
The development of ET-resistant phenotypes involves multiple mechanisms. These include 
(a) ERα mutations (where ESR1 gene mutations are one of the most studied) that lead to 
ligand-independent constitutive activation of ER, (b) in the absence of estradiol, the 
activation of ERα because of signaling pathway activation and (c) variation in the expression 
of ERα cofactors responsible for the ERα modulator activity. Investigation of potential 
mutations is highly recommended after progression, especially for PIK3CA and ESR1 
mutations, the most common mechanisms of acquired resistance to ET. ESR1 mutation may 
occur with an approximate 20-40% prevalence after progression on an AI (Brett et al, 2021).
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ARV-471 may be found in the IB which is the SRSD for this study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of fulvestrant are provided in the Faslodex EU SmPC which is the SRSD for 
this study. 
Potential risks of clinical significance and procedures are listed in the table below. 
These may include known or potential adverse events of study interventions based on: 
-
Observations in ARV-471 nonclinical studies, early clinical studies, or non-
toxicological studies 
-
ARV-471's mechanistic similarity to endocrine therapy, including SERDs 
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2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention(s) ARV-471 
QT prolongation
Potential risk based on nonclinical 
findings.
Concentration-QTc modeling analysis 
revealed a concentration-dependent 
increase in QTcF.
Thirteen participants were reported 
with non-serious AE of QT interval 
prolongation in the ongoing FIH study 
(ARV-471-mBC-101; Parts A, B and 
C) snapshot date of 06 June 2022, 
n=176); Per an external cardiology 
consultant review only 2 participants 
had a true diagnosis of QTc 
prolongation, of which low potassium 
and concomitant medications were 
confounding factors.
Clinical safety not yet fully 
characterized.
Participants will be monitored for QT interval changes with ECG monitoring at 
screening and during the study intervention period (Table 2).
Participants at high risk of QT prolongation as per EC #5 are excluded from 
participation in the study (see Section 5.2).
Concomitant drugs predisposing to Torsade de Pointes or QT prolongation are 
excluded or used with caution as per Section 6.9.3 and Appendix 10.
Study intervention will be temporarily interrupted, reduced, or permanently 
discontinued based on severity of the events occurred (see Section 6.6.2).
VE
Potential risk based on metastatic 
cancer setting and known class effect 
with ET (SERM, SERD, AI).
One Grade 3 related serious VE case, 
with confounding factors of obesity, 
diabetes and immobility due to recent 
biopsy procedure, and a Grade 3 
serious embolism case assessed as 
unlikely related to ARV-471 by the 
Participants with a history of clinically significant thromboembolic or 
cerebrovascular events are excluded from participation in the study as per EC 
#5 (see Section 5.2). 
Coagulation tests will be performed at screening and will be repeated on 
treatment as needed. Suspicious of VE should be investigated, per local 
standard practice (eg, D-Dimer, fibrinogen, imaging).
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
investigator, were reported in the FIH 
Study ARV-471-mBC-101. 
Study intervention will be temporarily interrupted, reduced, or permanently 
discontinued based on severity of the events occurred (see Section 6.6.2).
Developmental and 
reproductive toxicities
Based on mechanism of action. The 
loss of estrogen signaling leads to 
alterations estrogen signaling leads to 
alterations in the hormonal input and 
feedback loops that are necessary for 
the menstrual cycle (humans or
estrus in animals) and for the 
maintenance of pregnancy.
The summary of the non-clinical 
animal findings included:
Developmental (Embryo-Fetal) 
Toxicities. 
In 1-month rat study: loss of ability to 
maintain pregnancy, fetal death 
observed.
Reproductive Toxicities in animal 
studies:
Adverse microscopic changes in 
female tissues that impact organ 
function; Leydig cell hyperplasia and 
prostate changes in males; Clear 
impact on female fertility, potential 
risk for male fertility
ARV-471 may cause fetal loss or 
reproductive abnormalities when 
administered to the pregnant woman 
or WOCBP.
Protocol inclusion criteria specify allowable menopausal status and mitigations. 
.
Pregnant participants or participants <18 years are excluded in the clinical study 
protocols.
Risk minimization measures have been implemented, including 1) the 
requirement for LHRH agonist use for pre-/peri-menopausal women prior to 
and during treatment and 2) the requirement for ensuring highly effective 
contraceptive measures for WOCBP and for male participants with WOCBP 
partners.
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Clinical finding showed that no 
developmental or reproductive 
toxicities have been reported to date.
Study Intervention(s) Fulvestrant

thromboembolic 
events

injection site AEs (eg, 
sciatica, neuralgia, 
neuropathic pain, and 
peripheral neuropathy, 
risk of bleeding).

Osteoporosis

Increased exposure in 
patients with hepatic 
impairment
The potential risks are based on the 
Faslodex EU SmPC for fulvestrant.  
Participants with a history of clinically significant thromboembolic events are 
excluded from participation in the study as per EC #5 (see Section 5.2). 
Coagulation tests will be performed at screening and will be repeated on 
treatment as needed.
Injection will be completed by qualified and trained medical personnel and 
appropriate medication will be administered based on the severity of the AE.
Calcium level will be assessed at screening and during the study and supportive 
care (eg, Bisphosphonate or RANKL inhibitors) will be administered as needed.
Hepatic parameters will be collected at screening and during the study 
intervention. 
Study Procedures
Tumor biopsy requested for 
inclusion and end of treatment
Risks associated with any tumor 
biopsy include the following: 

Pain from local anesthetic.

Pain/discomfort from biopsy 
procedure.

Bleeding, swelling, scarring, pain 
or bruising at the biopsy site. 

Infection of wound.

Biopsies of certain sites may 
increase chances of life-
threatening complications, eg 
pneumothorax during biopsy of 
lung.
All procedures will be completed by qualified and trained medical practitioners.
Local anesthetic will be administered.
Sterile technique will be used.
Participants should not be subjected to a significant risk procedure to obtain 
biopsies. 
EOT biopsy (optional) will be collected only in participants who progressed, if 
clinically feasible.
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Blood sample collections for 
safety assessment,
pharmacokinetics and 
biomarkers
A blood draw may cause 
inflammation of the vein, pain, 
bruising, discomfort, redness, burning,
or bleeding at the site where the 
needle is placed to draw the blood. 
May cause participant to feel dizzy or 
faint. There is a slight chance of 
infection.
All blood draws will be completed by qualified and trained medical personnel. 
Sterile technique will be used. 
Blood sample collections will be conducted at facilities prepared for adverse 
reactions related to the collection.
Participants will have CT/MRI 
scans and bone scans during 
study participation
CT scans expose participants to small 
doses of radiation
Contrast dye used for CT scans may 
cause pain or burning upon injection, 
may worsen kidney function in 
participants with kidney disease and 
may cause allergic reactions that 
could be severe and life-threatening.  
Radioactive material for bone Scan 
may cause pain or burning upon 
injection.
Radiation exposure during the study will slightly exceed what a participant 
would receive under SOC and should not create a significant risk to health. 
Participants with renal function impairment are excluded (EC#13) (see Section 
5.2). 
CT scans will be conducted at facilities prepared for adverse reactions to the 
contrast dye. Hydration and/or premedication prior to contrast media 
administration or steroids administration in case of allergic reactions may to be 
instituted as per local standard practice.
A bone scan exposes participants to a small dose of radiation that should not 
create a significant risk to health.
Medical Device
Fulvestrant administration 
using prefilled-syringe
Medical devices non-conformities
Malfunction
Sponsor will provide high quality medical Prefilled Filled Syringe devices
Study staff will be instructed to report any medical device deficiencies to the 
sponsor as reported in the Section 8.4.9 and Appendix 9.
Decentralized/telehealth 
interactions study assessments 
may impact outcome 
assessments.
Decentralized study/telehealth study 
assessments may increase the chance 
of missing data.
Vital signs and a physical examination 
will not be performed for telehealth 
interactions, which may increase the 
Training will be provided to all parties involved in study conduct on data 
acquisition tools, including those used in home health visits, and their 
role/responsibilities to ensure complete and correct data flow.
Home heath visits will be performed by a registered nurse/other qualified health 
care provider and the investigator or designee must be available for 
consultation. If required by local regulations home heath visits will be 
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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
chance of not capturing clinically 
relevant information.
performed by the investigator or by a physician designee for specific 
assessments (eg, fulvestrant intramuscular administration, physical 
examinations and collection of adverse events).
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2.3.2. Benefit Assessment
In non-clinical studies ARV-471 demonstrated a potent (<1 nM) and robust (>90%) ER 
degradation, even in the presence of clinically relevant ER mutations (ARV-471 IB). ARV-
471 has demonstrated greater ER degradation compared to other novel SERDs in clinical 
development such as elacestrant/RAD1901 (Flanagan et al, 2018). In vivo, ARV-471 inhibits 
tumor growth in multiple mouse xenograft models including ESR1 mutant patient-derived 
xenograft model as single agent or in combination with palbociclib (Flanagan et al, 2018).
Preliminary clinical data from the ongoing FIH ARV 471-mBC-101 study Part A 
demonstrated that ARV-471 has antitumor activity (CBR of 36.2% [95% CI: 25.0–48.7] and 
ORR 8.6% [95% CI:2.9 - 19.0]) (ARV-471 IB).  
In Part B dose expansion the CBR in the overall population was 37.1% (95% CI: 21.5%, 
55.1%) and 38.9% (95% CI: 23.1%, 56.5%) at 200 mg and 500 mg QD, respectively. 
Overall, no exposure-response relationship for CBR was seen in the overall patient 
population or the ESR1 mutant patient population. Clinical benefit (by CBR) was observed in 
CDK4/6 inhibitor-pretreated patients with ER+/HER2- BC in all Part A and B dose cohorts 
(Arvinas, 2022).  In this study ARV-471 has shown robust ER degradation (up to 89% 
decrease with a median decrease of 67%, [range: 21% - 89%]) observed across doses up to 
500 mg daily, regardless of ESR1 mutation status (Hamilton et al, 2022). Safety data from 
the ongoing FIH ARV 471-mBC-101 study demonstrated that ARV-471 is safe and well 
tolerated all the tested doses (Hamilton et al, 2022).
2.3.3. Overall Benefit/Risk Conclusion
Preliminary data from the ongoing FIH Phase 1 ARV-471-mBC-101 study suggest that 
ARV-471 has the potential to provide clinical benefit to participants with ER(+)/HER2(-) 
aBC.
ARV-471 has been found to be safe and well-tolerated in the ongoing FIH study, up to a total 
daily dose of 700 mg. Coupled with the data from non-clinical studies, the risk of clinically 
significant toxicities in this study is assessed as low. In addition, ARV-471 was active in 
non-clinical models harboring clinically relevant ESR1 mutations associated with resistance 
to ET, including superior TGI compared to fulvestrant in a Y537S ESR1 mutant patient-
derived xenograft model. Preliminary clinical data from the ongoing FIH ARV 471-mBC-
101 study Part A demonstrated that ARV-471 has antitumor activity (CBR of 36.2% [95% 
CI: 25.0–48.7] and ORR 8.6% [95% CI:2.9-19.0]) (ARV-471 IB).  In Part B dose expansion 
the CBR in the overall population was 37.1% (95% CI: 21.5%, 55.1%) and 38.9% (95% CI: 
23.1%, 56.5%) at 200 mg and 500 mg QD, respectively. Overall, no exposure-response 
relationship for CBR was seen in the overall patient population or the ESR1 mutant patient 
population (Arvinas, 2022).Clinical benefit (by CBR) was observed in CDK4/6 inhibitor-
pretreated patients with ER+/HER2- BC in dose escalation and expansion cohorts (ARV-471 
IB).
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Taken together, these data show that ARV-471 may represent an important therapeutic 
option for participants with ER(+)/HER2(-) aBC who have progressed after prior endocrine-
based treatment(s) for their advanced disease.
Given current data, the anticipated benefits that may be afforded to participants with 
ER(+)/HER2(-) advanced breast cancer outweigh the potential risks identified in association 
with ARV-471. The clinical program will continue to monitor the benefit/risk profile of 
ARV-471.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary: 
Primary:
To demonstrate that ARV-471 
is superior to fulvestrant in 
prolonging PFS by BICR 
assessment in participants with 
ER(+)/HER2(-) aBC (all 
participants and participants 
with ESR1 mutation-positive 
BC) who have received prior 
endocrine-based treatment for 
their advanced disease
PFS, defined as the time from the 
date of randomization to the date 
of first documented disease 
progression, as determined by 
BICR assessment per RECIST 
v1.1, or death due to any cause, 
whichever occurs first
The primary estimand is to compare the 
treatment effect (as measured by HR) of 
ARV-471 versus fulvestrant on PFS in 
participants with ER(+)/HER2(-) aBC 
(all participants and participants with 
ESR1 mutation-positive BC) who have 
received prior endocrine-based treatment 
for their advanced disease. PFS will be 
analyzed using the stratified log-rank test 
and Kaplan-Meier method. PFS data will 
be censored for those who did not have a 
PFS event, discontinued the study 
treatment due to withdrawal of consent 
prior to an event, started a new anti-
cancer therapy prior to an event, had an 
event after an unacceptably long interval, 
or lost to follow-up.
Key Secondary: 
Key Secondary: 
Key Secondary:
To demonstrate that ARV-471 
is superior to fulvestrant in 
prolonging overall survival 
(all participants and 
participants with ESR1 
mutation-positive BC)
OS, defined as the time from the 
date of randomization to the date of 
death due to any cause
The estimand for OS is to compare the 
treatment effect (as measured by HR) of 
ARV-471 versus fulvestrant in 
participants with ER(+)/HER2(-) aBC 
(all participants and participants with 
ESR1 mutation-positive BC) who have 
received prior endocrine-based treatment 
for their advanced disease. OS will be 
analyzed using the stratified log-rank test 
and Kaplan-Meier method. OS data will 
be censored for those who did not have 
an OS event. 
Secondary:
Secondary: 
Secondary:
To compare measures of 
tumor control between 
treatment arms and to evaluate 
the DOR by BICR assessment 
within each treatment arm
OR: confirmed CR or PR by BICR 
assessment
CBR defined as confirmed CR or 
PR at any time or SD or non-
CR/non-PD ≥24 weeks by BICR 
assessment
DOR by BICR assessment
Not applicable.
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Objectives
Endpoints
Estimands
To evaluate safety and 
tolerability between the 
treatment arms
Type, incidence, severity (as graded 
by NCI CTCAE v5.0), seriousness 
and relationship to study 
medications of AEs and any 
laboratory and ECG abnormalities
Not applicable. 
To characterize the effects of 
ARV-471 on QTc
QTc
Not applicable. 
To evaluate patient reported 
outcomes between two 
treatment arms
EORTC QLQ-C30
EORTC QLQ-BR23 
EuroQol; EQ-5D-5L
BPI-SF
Not applicable. 
To determine plasma 
concentrations of ARV-471 
and ARV-473 after repeated 
dosing of ARV-471
Plasma concentrations of ARV-471 
and its epimer ARV-473 
Not applicable.
To assess changes from 
baseline levels in plasma 
ctDNA 
ctDNA plasma quantitative changes 
from baseline to evaluate their 
associations with clinical outcomes
Not applicable.
Tertiary/Exploratory: 
Tertiary/Exploratory: 
Tertiary/Exploratory:
To evaluate correlations of 
biomarkers with ARV-471 
exposure, efficacy and other 
clinical outcomes
Tumor tissue and/or blood 
biomarkers, to determine gene 
mutations (eg, ESR1, PIK3CA), 
and cell proliferation and 
oncologic driven proteins (eg, 
Ki67) involved in the biology 
aBC, mechanisms of resistance of 
ARV-471
Not applicable.
4. STUDY DESIGN
4.1. Overall Design
This is an international Phase 3 multicenter, randomized, open-label, parallel-group study 
aimed to demonstrate that ARV-471 is superior to fulvestrant in prolonging the progression-
free survival (PFS by BICR assessment) in participants with ER(+)/HER2(-) aBC who have 
progressed after prior endocrine treatment-based regimen(s) for advanced disease. 
Approximately 560 participants (of which approximately 280 are participants with ESR1 
mutation) will be randomly assigned to Arm A (ARV-471) or Arm B (fulvestrant).
Enrolment will continue until approximately 280 participants with the ESR1 mutation have
been enrolled.
Participants will be randomly assigned on a 1:1 basis to: 

Arm A: (Investigational Arm; n ≈ 280). Participants will receive ARV-471 200 mg 
orally, once daily on a 28-day continuous dosing schedule. 
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
Arm B: (Comparator Arm; n ≈280). Participants will receive fulvestrant 500 mg, 
intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting 
from C2D1 (28-day cycle).
Information on ARV-471 dose and administration is provided in Table 4 and Section 6.1.1.1. 
Details on dose modifications for toxicity for ARV-471 are provided in Section 6.6.2.
Information on fulvestrant dose and administration is provided in Table 4 and
Section 6.1.1.2. Dose reduction of fulvestrant is not permitted (See Section 6.6.1).
Analysis of ctDNA samples for ESR1 status evaluation (wild-type versus ESR1 mutated) 
will be performed (refer to the Laboratory Manual for specific information) during the pre-
screening period. Participants are required to give consent during the pre-screening period 
prior to collection of ctDNA samples sufficient for assessment or asking for approval to use 
an available ESR1 status result. 
Screening activities may be performed while waiting for ESR1 test results/approval of prior 
ESR1 status, but ESR1 status must be available before randomization. The sponsor will 
monitor the frequency of the ESR1 status (wild-type or mutated) across the study population 
(see Section 9.5) to evaluate the proportion of wild-type or mutated ESR1 status (targeting 
approximately 280 participants with wild type ESR1/280 participants with mutated ESR1).  
Sponsor approval for use of a previously performed test (with the exception of participants in 
China) may be obtained if all of the following criteria are met:

The test result confirms ESR1 mutated status (will not be accepted for wild-type 
status results)

Result is provided using an FDA approved test using ctDNA/tumor sample

Participant’s ctDNA sample/tumor sample was collected within 6 months from 
randomization in the current study.
The samples may be also used for development of companion diagnostics. 
Participants will be stratified by:

ESR1 mutational status (Mutant, Yes/No) 
In the event the ESR1 test is not informative (ie, test performed but the result is 
“unknown”) the participant will be stratified as participant with Mutant “NO” 

Visceral disease: (Yes/No)
Visceral refers to lung, liver, brain, pleural, and peritoneal involvement. 
Pre- and peri-menopausal female and male participants must receive therapy with an LHRH 
agonist starting on Cycle 1 Day 1 (if not already on treatment) and continued during the 
study as per Table 2.
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Participants will continue to receive assigned treatment until objective disease progression as 
per Section 7.1, unacceptable toxicity, death, participant refuses further treatment, or one of 
the other reasons for treatment discontinuation outlined in Section 7.1 is met. However, 
participants may continue treatment in the arm assigned at randomization beyond the time of 
RECIST-defined PD at the discretion of the investigator if that is considered to be in the best 
interest of the participant and as long as no new anticancer treatment is initiated (see 
Section 8.2.1.1). In this case, the participant should continue with routine safety and efficacy 
assessments as per the Table 2.
Crossover between treatment arms will NOT be allowed.
Participants will undergo efficacy assessments as outlined in Table 2. Efficacy analyses will 
be performed using the BICR tumor assessments as the primary data source. BICR will 
perform the review as per Section 8.2.1.2.  All radiographic images as well as other 
information as per section 8.2.1.2 will be collected and objectively verified by BICR as 
described in the Study Imaging Manual.   
Safety will be monitored at regular intervals through the study by laboratory tests and clinical 
visits as described in Table 2.
In Arm A, blood samples for pharmacokinetics analysis of ARV-471 and its epimer, ARV-
473, will be collected. These samples will also be used for exposure/response analysis for 
safety and efficacy findings. For additional details on the PK sample collections, refer to 
Table 3 and Section 8.5.
The study includes a QTc sub-study in approximately 80 participants in Arm A enrolled at 
selected sites which will evaluate the effect of ARV-471 on QTc interval via triplicate ECGs 
(central reading) time-matched with PK draws (See Table 3 and Section 8.3.3).
PRO assessments will be administered to evaluate the impact on quality of life, functioning, 
symptoms, and general health status using the EQ-5D-5L, Quality of Life questionnaires, 
both general cancer and breast specific (EORTC QLQ-C30), EORTC QLQ-BR23 (female 
and male questionnaire versions), and the BPI-SF. The mBPI-SF (worst pain severity [item 
3] and pain interference [item 9a]) and pain medication usage (Arm A and Arm B) and 
injection site pain (Arm B only) will also be captured using an evening daily diary (Table 2). 
Preference for route of administration (Arm A and Arm B) will be evaluated using a patient 
preference questionnaire (Appendix 14).
A blood sample for DNA extraction (ie, Retained Research Sample for Genetics) will be 
collected as outlined in the Table 2, unless prohibited by local regulations, IRBs/ECs. Serial 
ctDNA blood and tumor samples will be collected as outlined in Table 2.
Molecular profiling will be used to assess the association between breast tumor genomic 
alterations and tumor sensitivity/resistance to ARV-471.
An E-DMC will be established to review aggregate safety data to monitor safety and 
tolerability by treatment arm. The roles and responsibilities of the E-DMC are described in a 
separate charter.
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A Global Steering Committee will be established at the program level for ARV-471. It will 
be responsible for providing scientific advice and medical input on the ongoing and future 
clinical development plans for ARV-471 in ER(+) breast cancer, including for this study.
Participants discontinuing the active treatment phase will enter a Post-treatment Follow-up 
period (Section 7.1.1). After completion of Safety Follow-up as per Section 7.1.1.1, the 
participant enters in the Survival Follow-up (See Section 7.1.1.2) during which survival and 
information on administration of any new anticancer therapy will be collected every 3 
months from the EOT visit until one of the reasons for discontinuation from the study is met 
(as reported in Section 7.2). 
This study is designed to test the PFS superiority of ARV-471 compared to fulvestrant in 1) 
all randomized participants, and 2) participants with ESR1 mutation. 
It is anticipated that the final PFS analysis will occur at approximately 310 PFS events in all 
participants population and approximately 165 PFS events in the ESR1 mutant subgroup 
population. The final OS analysis will occur at approximately 194 OS events in the ESR1 
mutant population and 396 OS events in the all participants population.
4.2. Scientific Rationale for Study Design
In nonclinical studies, ARV-471 has demonstrated robust ER degradation, superior activity 
against clinically relevant ER mutated forms (eg, Y537S and D538G), and improved TGI as 
single agent compared to fulvestrant in ER wild type and ESR1 mutant patient-derived 
xenograft models. In the FIH study, ARV-471 administered orally as single agent appears to 
be safe and well tolerated across total daily doses of 30 mg to 700 mg with preliminary 
evidence of efficacy in participants pretreated with CDK4/6 inhibitor plus endocrine therapy.  
These results support the hypothesis that ARV-471 may represent an important therapeutic 
approach in participants with ER(+)/HER2(-) advanced breast disease.
For further details, refer to Section 2.1, Section 2.2, Section 2.3 and ARV-471 IB.
4.2.1. Patient Input Into Design
Patient Insight surveys have been conducted in several countries via interviews through a 
third party. The team gathered qualitative insights to develop a deeper understanding of the 
breast cancer patient journey, uncover their views on clinical trials and options on certain 
aspects of the protocol assessments. No significant findings preventing study participation in 
the study design and Schedule of activities have been identified. 
4.2.2. Diversity of Study Population
The diversity strategy will include high performing sites with the potential to support the 
recruitment of diverse and under-represented populations in the US. The strategy to ensure 
diversity includes:

Use of county level census data in the US to help drive the site selection process and 
the selection of new/diverse investigators.
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
Recognition that the presentation of aBC varies by gender, age, race, and geographic 
location. 

Inclusion of diversity in the steering committee and as principal investigators: 
leverage strong HCP networking across Black/African American and 
Hispanic/Latino(a)/Spanish participants, seeking sites that provide clinical care 
consistent with the known distribution of breast cancer in these populations.

Site Support: site-level training on clinical study diversity – helping investigators and 
site staff to be actively more inclusive and think differently to enroll more diverse 
patients in studies.

Portfolio level breast cancer education plan to community advocacy groups and 
breast cancer social media sites will drive potential patients to the site.
4.2.3. Choice of Contraception/Barrier Requirements
ARV-471 is known to cause reversible degenerative changes in the reproductive system 
organs of female rats and dogs and male dogs, which may be regarded as potential safety 
risks for women and men, and which are considered related to the pharmacologic activity of 
ARV-471. Therefore, there is a potential risk of male and female infertility. Studies to 
evaluate the effect of ARV-471 in pregnant women have not been conducted. However, 
based on mechanism of action, ARV-471 may cause fetal harm when administered to the 
pregnant woman. 
Fulvestrant has been shown to cross the placenta after single intramuscular doses in rat and 
rabbit. Studies in animals have shown reproductive toxicity including an increased incidence 
of fetal abnormalities and deaths.
Contraception is required in male and WOCBP participants as per Table 2 and Appendix 4 in 
both Arms. 
Refer to Faslodex EU SmPC for fulvestrant contraception requirements. Consultation with 
the sponsor medical monitor should be considered as needed, e.g. for male participants.
4.2.4. Collection of Retained Research Samples
Retained Research Samples will be collected and stored, as allowed per local regulations, 
IRBs and ECs, for further analyses which may, for example, provide greater understanding of 
the study intervention.
4.3. Justification for Dose
4.3.1. ARV-471
In the FIH ARV-471-mBC-101 study, ARV-471 monotherapy was safe and well tolerated 
across total daily doses of 30 mg to 700 mg, without DLTs observed in the Part A dose
escalation.  The 200 and 500 mg daily doses were selected as RP2Ds and are currently being 
evaluated in the Part B monotherapy dose expansion portion of ARV 471-mBC-101.
Nonclinical data in MCF7 tumor-bearing mice showed dose-dependent tumor growth 
inhibition at doses of 3, 10 and 30 mg/kg with ≥94% estrogen receptor degradation in 
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tumors at all 3 doses (ARV-471 IB). This suggests that doses/exposures required for maximal 
anti-tumor activity are higher than those required for maximal ER degradation. Therefore, the 
nonclinical exposure threshold for maximal efficacy was targeted for RP2D dose selection. 
Based on the desire to maintain clinical exposures of ARV-471 above this threshold in the 
majority of patients and the lack of notable differences in safety across the doses evaluated in 
the Part A monotherapy dose escalation, 200 mg QD was selected as the lower dose for the 
Part B dose expansion. The dose of 500 mg QD was selected as the higher dose option in the 
expansion because exposure was mostly non-overlapping between 500 mg and 200 mg and 
exposures had been observed to plateau above 500 mg.
ARV-471 demonstrates a dose-dependent increase in ARV-471 exposure up to 500 mg with 
no notable differences in safety, ER degradation, or efficacy (as measured by clinical benefit 
response) observations across this dose range. An apparent higher risk for potential QTc 
prolongation was observed at 500 mg QD, supported by concentration QTc modelling and 
observed data from Parts A and B. 
Data as of 06 June 2022 demonstrates that

No meaningful differences in overall safety, such as treatment-related AEs, adverse 
events leading to discontinuations, or dose interruptions were noted, except for an 
apparent higher risk of potential QTc prolongation at 500 mg QD. Dose reductions 
occurred only at the 500 mg QD dose in Part B. 

No clear differences are observed in efficacy (by CBR) and no significant dose-
response relationship is seen between the 200 mg and 500 mg daily doses in a heavily 
pretreated population.
Based on the totality of biologic evidence including clinical efficacy, safety, PK , PD, and 
nonclinical data, the 200 mg QD dose was selected as the RP3D for our proposed 
monotherapy Phase 3 studies (Arvinas, 2022).
4.3.2. Fulvestrant
For this device, the term “dose” refers to 500 mg (unit dose strength is 250 mg/5 mL) 
(Table 4) as per label.
4.4. End of Study Definition
The end of the study is defined when the approximate number of events required for final OS 
analysis is achieved 
For information on continuation of the study treatment after the end of study, refer to 
Section 6.7.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
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prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in this study only if all of the following criteria apply:
Age and Sex:
1.  Participants aged 18 years or older (or the minimum age of consent in accordance with 
local regulations) at screening.
a.
Female participants under 60 years of age, with cessation of regular menses 
for 12 consecutive months and with no other alternative medical cause, 
must have a FSH level within the post-menopausal level, as per local 
laboratory reference range.  
b. Pre/ peri-menopausal female and male participants must agree to initiate or 
continue to use an LHRH agonist as per Table 2 and Section 6.9.1. 
c.
WOCBP female and male participants must agree to use contraception. 
Refer to Appendix 4 for further details.
Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, lifestyle considerations, and other study procedures.
3. Histological or cytological confirmation of breast cancer with evidence of locoregional 
recurrent or metastatic disease which is not amenable to surgical resection or radiation 
therapy with curative intent.  
a.
Documented ER(+) tumor, defined as ER(+) ≥10% stained cells by an assay 
consistent with local standards, on the most recent tumor biopsy, ie, at 
diagnosis of recurrence or metastatic disease (Allison et al, 2020). The sole 
exception is those participants with bone only disease and participants in whom 
the collection of a biopsy is clinically contraindicated, for whom ER(+) using 
archival tissue at initial diagnosis is acceptable.
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b.
Documented HER2(-) tumor by either IHC or in-situ hybridization per 
ASCO/CAP guidelines (Wolff et al, 2018)on the most recent tumor biopsy and 
as per above in inclusion criterion a.
c.
Participants who have bilateral breast cancers which are both ER(+)/HER2(-) are 
eligible.
d. Participants must provide a blood sample AND a tumor sample collected at the 
time of diagnosis of locoregional recurrent or metastatic disease. If not available, 
a de novo biopsy is required unless the participant has bone only disease or in 
whom the collection of a biopsy is clinically contraindicated. In these cases,  an 
archival tumor tissue at initial diagnosis is acceptable. Refer to Section 8.7.1 for 
details.
4. Prior therapies for locoregional recurrent or metastatic disease must fulfill all the 
following criteria: 
Note: Progression during or within 12 months from the end of adjuvant therapy is counted 
as a line of therapy in advanced/metastatic setting
a.
One line of CDK4/6 inhibitor therapy in combination with ET. Only one line of 
CDK4/6 inhibitor is allowed in any setting.
b. ≤1 endocrine therapy in addition to CDK4/6 inhibitor with ET. 
c.
Most recent endocrine treatment duration must have been given for ≥6 months 
prior to disease progression. This may be the endocrine treatment component of 
the CDK4/6 inhibitor line of therapy.
d. Radiological progression during or after the last line of therapy 
5. At least one measurable lesion as defined by RECIST version 1.1. Bone only disease: 
participants with only non-measurable disease are eligible. Refer to Section 8.2.1.   
Other Inclusion criteria:
6.  ECOG PS ≤1
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5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1.  History of any other solid tumor malignancies within the past three years, except for the 
following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) 
curatively treated in situ carcinoma of the cervix. For all other solid tumors, must have 
been curatively treated and with no evidence of disease for >3 years. Participants with 
inflammatory breast cancer are excluded.
2. Participants with newly diagnosed brain metastasis or symptomatic CNS metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Participants with a history of CNS metastases 
or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, 
stereotactic surgery) and clinically stable (including participants with residual CNS 
symptoms/deficits) off enzyme-inducing anticonvulsants and steroids for at least 14 days 
prior to randomization.
3. Major surgery or radiotherapy or prior endocrine therapy, CDK4/6 inhibitor, or other 
anticancer treatments within 14 days of randomization (28 days or 5 half-lives, whichever 
is shorter, for anticancer therapy containing an antibody- based agent, approved or 
investigational). Participants who received prior radiotherapy to ≥ 25% of bone marrow 
are not eligible independent of when it was received (Appendix 12).
4. Participants in visceral crisis at risk of immediately life-threatening complications in the 
short term, including participants with massive uncontrolled effusions (pleural, pericardial, 
and peritoneal), pulmonary lymphangitis, or liver involvement > 50%.
5. Impaired cardiovascular function or clinically significant cardiovascular diseases, 
defined as:

Any of the following in the previous 6 months: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure (New York Heart Association Class III or IV), 
cerebrovascular accident, transient ischemic attack, or symptomatic pulmonary 
embolism or other clinically significant episode of thromboembolic disease,
congenital long QT syndrome, Torsade de Pointes, clinically important 
arrhythmias, left anterior hemiblock (bifascicular block), ongoing cardiac 
dysrhythmias of NCI-CTCAE Grade ≥2, atrial fibrillation of any grade.

Participants with cardiac rhythm device/ pacemaker (QTc Sub-study).
For all the other participants with cardiac rhythm device/pacemaker eligibility must 
be discussed in detail with the sponsor medical monitor.  

QTcF interval >470 msec on screening ECG.
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
Symptomatic cardiac valve disease. Participants with mitral valve prolapse which 
is asymptomatic or not associated with clinically significant sequelae (eg, mitral 
regurgitation) are eligible.
6.  Refractory nausea and vomiting, chronic GI disease, GI ulcer, GI bleeding, inability to 
swallow the formulated product, or previous significant gastric (total or partial) or bowel 
resection that would preclude adequate absorption of study drug.
7.  Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of study 
participation or, in the investigator’s judgment, make the participant inappropriate for the 
study.
Prior/Concomitant Therapy:
8. Concurrent administration of medications, food or herb supplements that are strong 
inhibitors and inducers of CYP3A and drugs known to predispose to Torsade de Pointes or 
QT interval prolongation (see Section 6.9 and Appendix 10 for the list of prohibited 
medications). Prior use of strong CYP3A inhibitors must be stopped 7 days and strong 
inducers of CYP3A must be stopped 14 days before randomization.  
9. Prior treatment with:
a) ARV-471, fulvestrant, elacestrant, mTOR, PI3K, AKT pathway inhibitors, PARP 
inhibitor, other investigational agents (including novel endocrine therapy any 
SERDs, SERCAs, CERANs) for any setting 
b) prior chemotherapy for advanced/metastatic disease
Participation in other studies involving investigational drug(s) within 28 days prior 
to randomization. If in the FU Phase, the participant is eligible provided at least 5 
half-lives have elapsed from the last dose. 
10. Any unresolved toxicities from prior surgeries or therapies Grade >1 (Grade > 2 for 
peripheral neuropathy) by NCI-CTCAE Version 5.0 at the time of randomization except 
for alopecia.
Diagnostic Assessments:
11. Hepatic dysfunction defined as:

Total bilirubin >1.5 x ULN unless the participant has documented Gilbert’s 
syndrome (in this case total bilirubin ≥3 x ULN);

AST and ALT >3 x ULN; >5.0 x ULN if liver metastases present; 

Alkaline phosphatase >2.5 x ULN; >5 x ULN in case of bone metastasis.
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
aPTT >1.25 x ULN and INR >1.25 unless the participant is receiving 
anticoagulation, then aPTT and INR should be within the therapeutic range of the 
intended use.
12. Hematologic abnormalities defined as: 

ANC <1500/mm3 or <1.5 x 109/L;

Platelets <100,000/mm3 or < 100 x109/L;

Hemoglobin <9 g/dL. One transfusion allowed ≤2 weeks before 
randomization.
13. Renal impairment defined as an eGFR <45 mL/min/1.73m2 as calculated using the 
2021 CKD-EPI Equations as outlined in Appendix 7.
14. Known active infection including SARS-CoV-2 infection, HBV, HCV, and HIV or 
AIDS-related illness (screening for chronic conditions is not required).
Other Exclusion Criteria:
15.  Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
Restrictions regarding lifestyle for study eligibility and/or participation are reported in the 
Sections below. The food requirement for ARV-471 intake is detailed in Section 5.3.2.
5.3.1. Contraception 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is using an appropriate method of contraception for the individual participant and 
their partner(s) from the permitted list of contraception methods (see Appendix 4) and will 
confirm that the participant has been instructed in its consistent and correct use. As 
applicable, at time points indicated in Table 2, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart. 
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer use abstinence 
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as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions
Participants must be instructed to take ARV-471 with food.  Participants should be instructed 
to take ARV-471 at approximately the same time preferably in the morning.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, 
have completed the pre-screening period, but are not subsequently randomized in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the CONSORT publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes screen failure details, and 
any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only once. Rescreened participants must be assigned a unique participant number 
that is different from the participant number used for the initial screening.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and, medical devices, and other 
interventions (eg, surgical and behavioral) intended to be administered to the study 
participants during the study conduct.
For the purposes of this protocol, study intervention refers to ARV-471, and the drug for the 
control arm refers to fulvestrant.
6.1. Study Intervention(s) Administered
Table 4.
Study Interventions Administered
Intervention Name
ARV-471 (PF-07850327)
Fulvestrant
ARM Name
A
(Investigational)
B
(Comparator)
Type
Drug
Drug
Intervention Name
ARV-471
Fulvestrant
Dose Formulation
Tablet
Solution for IM injection
Unit Dose 
Strength(s)
100 mg
250 mg/5 mL
Dosage Level(s)
200 mg
500 mg
Route of 
Administration
Oral
IM
Use
Experimental
Active comparator
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Table 4.
Study Interventions Administered
IMP or NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor.
Please refer to the IPM.
Provided centrally by the sponsor.
Please refer to the IPM.
Packaging and 
Labeling
Study intervention will be provided in a 
high-density polyethylene bottle with 
child-resistant cap. Each bottle will be 
labeled as required per local regulations.
Study intervention will be supplied as 
two 5 mL glass (Type 1) prefilled-
syringe, each containing 250 mg / 5 mL 
of fulvestrant for IM injection. Each 
carton will be labeled per local 
regulations.
Current/Former 
Names or Aliases
ARV-471 
(PF-07850327)
Fulvestrant, Faslodex®
Study intervention may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the study 
intervention. Pfizer does not permit the shipment of study intervention by mail. The tracking 
record of shipments, including temperature monitoring data, and the chain of custody of the 
study intervention must be kept in the participant’s source documents/medical 
records. Fulvestrant preparation and administration must be performed by a physician, 
registered nurse, or other qualified health care provider and documented in the participant’s 
source documents/medical records. Please refer to IPM for dosing instructions. 
6.1.1. Administration
Participants in Arm A will receive ARV-471, and participants in Arm B will receive 
fulvestrant. Study drugs will be provided open-label.  ARV-471 will be administered in tablet 
form and be self-administered.  Fulvestrant will be administered intramuscularly by a 
physician, registered nurse, or other qualified health care provider. Participants must receive 
study intervention within 3 days after randomization.   
Refer to the IPM for detailed administration instructions for all the study drugs administered 
in this study.
6.1.1.1. ARV-471
ARV-471 will be administered open-label as 100 mg tablets to participants in Arm A 
(Table 5).  ARV-471 will be administered orally, once daily on Days 1-28 of each 28-day 
cycle according to Table 2.  Recommended dose modifications for toxicity related to study 
intervention are presented in Table 6 and Table 7.
Participants must be instructed to take ARV-471 with food.  Participants should be instructed 
to take ARV-471 at approximately the same time preferably in the morning, and to not take 
more than the pre-specified dose at any time. Participants will swallow ARV-471 whole, and 
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not manipulate or chew ARV-471 prior to swallowing. No tablet should be ingested if it is 
broken, cracked, or otherwise not intact.
On visit days, participants must be instructed to not take their ARV-471 dose and to wait to 
take ARV-471 dose until they have completed their pre-dose study assessments as per 
Table 2 and Table 3.  On these days, ARV-471 doses should be taken under the supervision 
of the study personnel.
Each participant treated with ARV-471 will be given a dosing diary and should be instructed 
to record the daily administration of the study drug.  Study personnel must ensure that 
participants clearly understand the directions for self-medication. Participants will be given a 
sufficient supply of study drug for administration on each dosing day until their next 
scheduled study visit. Participants should be instructed to maintain ARV-471 in the bottles 
provided throughout the course of dosing. Unused drug and/or empty bottles should be 
returned to the site/ provided to the vendor (in case of home health visit) at the next study 
visit. Returned unused study intervention MUST NOT be re-dispensed to a participant.
If a participant misses a day of treatment, they must be instructed not to double-up or “make 
up the dose”, but to resume dosing on the next day of the dosing cycle as prescribed.
If a participant vomits any time after taking a dose, they must be instructed not to “make it 
up”, but to resume dosing on the next day of the dosing cycle as prescribed. If a participant 
inadvertently takes 1 extra dose during a single dosing day, the participant should not take 
the next dose of study intervention for the next day (see Section 6.8). 
6.1.1.2. Fulvestrant
Fulvestrant preparation and administration will be performed by a physician, registered 
nurse, or other qualified health care provider. Refer to the IPM for detailed administration 
instructions. 
Fulvestrant should be administered intramuscularly on Days 1 and 15 (±2) of Cycle 1. Then 
from cycle ≥2, on Day 1 of each cycle.  
Dose reductions for fulvestrant are not permitted for any reason.
6.1.2. Medical Devices
Fulvestrant, the open label comparator detailed in Table 4, will be provided as a prefilled 
syringe and, in which case should be considered a medical device.  All medical device 
deficiencies (including malfunction, use error, and inadequate labeling) shall be documented 
and reported by the investigator throughout the clinical investigation (see Section 8.4.9) and 
appropriately managed by the sponsor.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
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2. Only participants enrolled in the study may receive study intervention. Only 
authorized staff may supply, prepare, and/or administer fulvestrant. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business.
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions, as 
soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. Site staff will instruct participants on the proper storage 
requirements for take home study intervention.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 
form/record. All study intervention that is taken home by the participant, both used 
and unused, must be returned to the investigator/vendor (in case of home health visit) 
by the participant. Returned study intervention must not be redispensed to the 
participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
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6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention for Arm A and Arm B using 
the IRT system via unique container numbers on the bottles or prefilled syringe and provided 
in sufficient quantities according to the dosing schedule outlined in Table 2. A second staff 
member will verify the dispensing.  
Bottles (ARV-471):
The participant/caregiver should be instructed to maintain the product in the bottle provided 
throughout the course of dosing and return to the site /provide to the vendor (in case of home 
health visit) the bottle at the next study visit.
Pre-Filled Syringe (fulvestrant):
Fulvestrant is supplied as two 5 mL glass (Type 1) single-dose pre-filled syringes, each 
containing 250 mg/5 mL of fulvestrant solution for IM injection and fitted with a tamper 
evident closure.  Refer to IPM for instructions and steps necessary for drug preparation and 
administration. Drug preparation and administration will be performed by a physician, 
registered nurse or other qualified health care provider. 
6.3. Assignment to Study Intervention
This is an open-label, Phase 3 study; however, the specific study intervention dispensed to 
each participant will be assigned using an IRT.  Participants will be randomized based on a 
1:1 randomization allocation ratio to receive either ARV-471 (Arm A) or fulvestrant (Arm 
B), provided they have satisfied all participant selection criteria.
Eligible participants will be stratified by:

ESR1 mutational status (Mutant, Yes/No)
In the event the ESR1 test is not informative (ie, test performed but the result is 
“unknown”) the participant will be stratified as participant with Mutant “NO”.

Visceral disease: (Yes/No)
Visceral refers to lung, liver, brain, pleural and peritoneal involvement. 
Stratification factors should be carefully verified before randomization. Randomized 
participants cannot be de-randomized.
This stratified randomization will be centrally allocated using an IRT system (IWR). 
The site will record the study intervention assignment on the applicable CRF, if required. The 
site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, 
and the participant number.  The site personnel will then be provided with a treatment 
assignment, randomization number, and dispensable unit or container number when study 
intervention is being supplied via the IRT system.  The IRT system will provide a 
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confirmation report containing the participant number, randomization number, and DU or 
container number assigned.  The confirmation report must be stored in the site’s files. 
Study treatment must start within 3 days after a participant’s randomization. Study 
intervention will be dispensed at the study visits summarized in Table 2.  
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
6.4. Blinding
This is an open-label study. 
6.5. Study Intervention Compliance
When participants self-administer study intervention at home compliance with ARV-471 will 
be assessed at each cycle, prior to the dispensing of study intervention for the next cycle 
Participants will receive a dosing diary to document self-administered dosing of study 
intervention in each cycle to include the dose of study intervention taken, the date of dosing, 
if any doses were missed and the reason for the missed dose.
Compliance will be assessed by a review of diary entries and/or direct questioning and/or 
counting returned tablets during the visits. Deviation(s) from the prescribed dosage regimen 
should be recorded in the eCRF and study staff will document their follow-up with the 
participant in the source records when they discover compliance discrepancies. Participants 
must be instructed to return or to provide to the vendor (in case of home health visits) all 
bottles of study intervention, as well as the completed participant dosing diary at each cycle 
for drug compliance. The number of remaining tablets will be documented in the source 
document. In absence of toxicity requiring dose modifications (ie, reduction, interruption 
and/or delay), each study participant is considered underdosed if less than 80% of the 
prescribed dose for the given cycle has been administered. A record of the number of ARV-
471 tablets dispensed to and taken by each participant must be maintained and reconciled 
with study intervention and compliance records.  Study intervention start and stop dates, 
including dates for intervention interruptions and/or dose reductions, will also be recorded in 
the CRF.
Fulvestrant will be administered by a physician, registered nurse, or other qualified health 
care provider in accordance with the IPM. Fulvestrant administration will be documented on 
the corresponding study drug administration CRF. The date administered will be recorded in 
the source documents and recorded in the CRF.  The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study 
staff other than the person administering the study intervention. Any dose delay or dose 
skipped (only at C1D15) for reasons other than treatment related toxicity will be considered 
as non-compliance.  
6.6. Dose Modification 
Every effort should be made to administer study treatment on the planned dose and schedule.  
However, in the event of significant treatment toxicity, administration of study intervention 
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may need to be modified based on the toxicity observed. In the event of multiple toxicities, 
dose modification should be based on the worst toxicity observed. Participants are to be 
instructed to notify investigators at the first occurrence of any adverse symptom.  In addition 
to dose modifications, investigators are encouraged to employ best supportive care according 
to local institutional clinical practices.  
6.6.1. Fulvestrant
No dose reduction for fulvestrant is permitted. In case of fulvestrant-related toxicities, 
C1D15 may be delayed as per the investigator’s best medical judgment, but for no more than 
7 days. If more than a 7 day delay is required then the C1D15 dose should be skipped and 
C2D1 will be performed as per Table 2.  If C1D15 is delayed, C2D1 fulvestrant injection 
should be performed at least 14 days (+/- 2 days) from the last dose. 
Dosing from cycle ≥2 can be delayed for fulvestrant-related toxicities as per the 
investigator’s best medical judgment.
See Faslodex EU SmPC of fulvestrant treatment details.
Following treatment delay, the day when treatment is restarted will be counted as Day 1 of 
the next cycle. Procedures required as per Table 2 and Table 3 on Day 1 of the given cycle 
will be performed when study treatment is resumed.  In the event of a treatment delay lasting 
>28 days, then study treatment should be permanently discontinued, unless the investigator’s 
benefit/risk assessment suggests otherwise after discussion with the sponsor medical monitor.  
See Faslodex EU SmPC for fulvestrant treatment details.
6.6.2. ARV-471
Dose modifications may occur in 1 of 3 ways:

Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 

Between cycles: next cycle administration may be delayed due to persisting 
toxicity when a new cycle is due to start;

In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle.
6.6.2.1. ARV-471 Dose Reductions
Following dosing interruption or cycle delay due to toxicity, ARV-471 study intervention 
dose may need to be reduced when treatment is resumed.
No specific dose modifications are recommended for Grade 1 or 2 treatment-related toxicity.  
However, investigators should always manage participants according to their medical 
judgment based on the particular clinical circumstances.
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Participants experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at the 
next lower dose level once recovery to Grade ≤1 or baseline is achieved.
Dose reduction of ARV-471 by 1 dose level (Table 5) will be allowed depending on the type 
and severity of toxicity encountered.  Participants requiring more than 1 dose reduction will 
be discontinued from the treatment and enter the Follow-up phase.  All dose modifications 
must be clearly documented in the participant's source notes and CRF. 
Table 5.
ARV-471 Dose Modification Levels for Adverse Reactions
Dose Level
Dose
Administration of Dose
Starting Dose
200 mg daily
Two 100 mg tablets once daily
-1
100 mg daily* 
One 100 mg tablet once daily
*ARV-471 dose de-escalation below 100 mg/day is not allowed.
Once a dose has been reduced for a given participant, all subsequent cycles should be 
administered at that dose level. 
However, if the participant has demonstrated significant benefit, dose re-escalation of ARV-
471 may be considered after consultation with the sponsor medical monitor, if the AE was 
rapidly reversible, and re-escalation is not expected to pose a significant risk to the 
participant.
Depending on the nature of the toxicity and the rapidity of recovery following dose 
interruption, resumption of the same dose may be considered after a related Grade 3 AE.
6.6.2.2. Recommended ARV-471 Dose Modifications
Recommended dose modifications for study intervention are described in Table 6.
Table 6.
Recommended Dose Modifications for ARV-471 -Related Toxicity 
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
Continue at the 
same dose level.
Continue at the 
same dose level. 
Refer to Table 7
for QTc 
prolongation 
management.
Withhold dose until 
toxicity is Grade ≤1, 
(Grade ≤2 if not 
considered a safety risk 
for the participant). 
Then resume treatment 
at the same dose level or 
at the next lower dose 
level at the discretion of 
the investigator*.
Exceptions:

Laboratory values 
that do not have any 
clinical correlate 
(eg, amylase or 
lipase abnormality 
Withhold dose until 
toxicity is Grade ≤1.
Then resume 
treatment at the next 
lower dose level or 
discontinue at the 
discretion of the 
investigator.
Exceptions:
Laboratory values 
that do not have any 
clinical correlate.
(eg, amylase or 
lipase abnormality 
that is not 
associated with 
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Table 6.
Recommended Dose Modifications for ARV-471 -Related Toxicity 
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
that is not 
associated with 
symptoms or 
clinical 
manifestations of 
pancreatitis).
Refer to Table 7 for QTc 
prolongation 
management.
symptoms or 
clinical 
manifestations of 
pancreatitis).
Refer to Table 7 for 
QTc prolongation 
management.
Hematologic**
Continue at the 
same dose level.
Continue at the 
same dose level.
Withhold dose until 
toxicity is Grade ≤2.
Then resume treatment 
at the same dose level.
Withhold dose until 
toxicity is Grade ≤2.
Then resume 
treatment at the next 
lower dose level.
* Grade 3 fatigue lasting <7 days, grade 3 nausea/vomiting/diarrhea lasting <72 hours in the absence of 
maximal medical therapy do not require dose reduction. 
**Recommendation applies to all hematologic adverse reactions except lymphopenia (unless associated with 
clinical events, eg, opportunistic infections). 
6.6.2.3. ARV-471/QTc prolongation management
In the event of QTc prolongation, possible alternative reversible causes such as serum 
electrolytes abnormalities or potential usage of concomitant medications with the potential to 
prolong the QTc interval should be evaluated.
If such reversible causes are identified, they should be corrected accordingly (ie, correction 
of electrolyte abnormalities with supplements to within normal limits and/or discontinuation 
of concomitant medications known to prolong the QT interval). 
No specific dose modifications are recommended for Grade 1 treatment-related toxicity.  
Recommended dose modifications in the event of QTc prolongation are provided in Table 7.
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Table 7.
Recommended ARV-471 Dose Modification in the event of QTc 
Prolongation
Grade 2 QTc prolongation
(Average QTc 481 - 500 ms)
Grade 3 QTc 
prolongation
(Average QTc ≥ 501 ms; 
or >60 ms change from 
baseline)
Grade 4 QTc
Prolongation
(Torsade de pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms of 
serious arrhythmia)
Reversible
cause
identified
Treat reversible cause;
Initiate more frequent ECG
monitoring according to
investigator’s best medical
judgment until QTc ≤480 msec.
Continue at the same dose level(1)
Treat reversible cause;
If QTc ≥501 msec 
withhold treatment until 
recovery to ≤Grade 2; 
Then resume treatment at 
the same dose level; 
Monitor ECG more 
frequently as per
investigator’s best medical 
judgment until
QTc ≤480 msec.
If QTc >60 msec change 
from baseline but QTc 
<501 ms continue at the 
same dose level with more 
frequent ECG monitoring 
until QTc ≤480 msec AND 
≤60 msec change from 
baseline.
Treat reversible 
cause;
Permanently
discontinue
No reversible
cause
identified
Initiate more frequent ECG
monitoring according to
investigator’s best medical
judgment until QTc≤480 msec.
Continue at the same dose level(1)
If QTc ≥501 msec 
withhold treatment until 
recovery to ≤Grade 2; 
Then resume treatment at 
the LOWER dose level2; 
Monitor ECG more 
frequently as per
investigator’s best medical 
judgment until
QTc ≤480 msec.
If the increase of QTc is 
>60 ms from baseline but 
QTc <501 msec continue at 
the LOWER dose level2
with more frequent ECG 
monitoring until QTc ≤480 
msec AND ≤ 60 msec 
change from baseline.
Permanently
discontinue
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Table 7.
Recommended ARV-471 Dose Modification in the event of QTc 
Prolongation
Grade 2 QTc prolongation
(Average QTc 481 - 500 ms)
Grade 3 QTc 
prolongation
(Average QTc ≥ 501 ms; 
or >60 ms change from 
baseline)
Grade 4 QTc
Prolongation
(Torsade de pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms of 
serious arrhythmia)
1 If the QTc remains above 480 msec for more than 2 cycles or if Grade 2 QTc prolongation recurs in the absence of 
other alternative causes or despite correction of alternative causes, dose modification and/or discontinuation should be 
considered in consultation with a cardiologist and the study medical monitor, taking into account the emerging safety 
data from ARV-471 trials and the investigator’s best medical judgment.
2 If the Grade 3 QTc prolongation recurs after one dose reduction, discontinuation should be discussed with study 
medical monitor in consultation with a cardiologist, taking into consideration the emerging safety data from ARV-471 
trials and the investigator’s best medical judgment.
6.6.2.4. ARV-471 Dosing Interruptions
With respect to ARV-471 study intervention, participants experiencing the following AEs 
should have their treatment interrupted as reported in Table 6 and Table 7.
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the investigator.  Criteria required before treatment can resume are described in 
Section 6.6.2.5.
Doses may be held up to 28 days until toxicity resolution.  Depending on when the AE 
resolved, a treatment interruption may lead to the participant missing all subsequent planned 
doses within that same cycle or even to a delay of the initiation of the subsequent cycle. 
If the AE that led to the treatment interruption recovers within the same cycle, then re-dosing 
in that cycle is allowed.  Doses omitted for toxicity are not replaced within the same cycle.  
The need for a dose reduction at the time of treatment resumption should be based on the 
criteria defined in Section 6.6.2.2 and Section 6.6.2.3 (See Table 6 and Table 7), unless 
expressly agreed otherwise following discussion between the investigator and the sponsor 
medical monitor. 
In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) lasting >28 days, treatment resumption will be decided in consultation 
with the sponsor/medical monitor.
6.6.2.5. ARV-471 Dose Delays
Re-treatment following treatment interruption for treatment-related toxicity or at the start of 
any new cycle may not occur until all of the following parameters have been met:

ANC ≥1000/mm3.
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
Platelet count ≥50,000/mm3. 

Grade ≥3 nonhematologic toxicities have returned to Grade ≤1 severity (or, at the 
investigator’s discretion, Grade ≤2 if not considered a safety risk for the 
participant). See exception in Table 6.

QTc <501 msec and potential reversible causes (eg, electrolyte imbalance, 
concomitant medications known to prolong QTc) corrected.  If QTc remains 
above 480 msec, ECG should be monitored more frequently as per the 
investigator's best medical judgement until QTc ≤ 480 msec.
If a treatment delay results from worsening of hematologic or biochemical parameters, the 
frequency of relevant blood tests should be increased as clinically indicated.
If these conditions are met within 28 days of treatment interruption, ARV-471 may be 
resumed.  Refer to Table 6 and Table 7 for AEs requiring dose reduction at the time of 
treatment resumption. 
If participants require interruption of ARV-471 for more than 28 days at any time during the 
study, then study treatment should be permanently discontinued, unless the investigator’s 
benefit/risk assessment suggests otherwise after discussion with the sponsor medical monitor.  
If a treatment interruption continues beyond Day 28 of the current cycle, then the day when 
treatment is restarted will be counted as Day 1 of the next cycle. Procedures required as per 
Table 2 and Table 3 on Day 1 of the given cycle will be performed when study treatment is 
resumed.
6.7. Continued Access to Study Intervention After the End of the Study
No intervention will be provided per protocol to study participants beyond the end of the 
study. Availability of study drugs following closure of the study through expanded 
access/continued use mechanism if the investigator and participant desire to continue 
treatment would be at the discretion of the sponsor and subject to local conditions and 
regulations.
6.8. Treatment of Overdose
For this study, any dose of ARV-471 or fulvestrant greater than the prescribed dose assigned 
at Cycle 1 day 1 as per Section 6.1 will be considered an overdose.
The sponsor does not recommend specific treatment for an overdose; treatment should be 
supportive.
In the event of an overdose, the investigator should:

Contact the study medical monitor within 24 hours.
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
Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). 

Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.

Overdose is reportable to Pfizer Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.  
6.9. Prior and Concomitant Therapy
Participants must be instructed not to take any additional medications (over the counter or 
other products) during the study without prior consultation with the investigator. Any 
medications including herbal supplements, vitamins, or treatment (as reported in the sections 
below) taken by the participant from signature of the informed consent and up to 28 days 
following the last dose of investigational product must be recorded on the CRF along with:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency. 
The sponsor Medical Monitor or designee should be contacted if there are any questions 
regarding concomitant or prior therapy.
Concomitant treatment considered necessary for the participant’s well-being may be given at 
the discretion of the investigator. All concomitant treatments, blood products, as well as non-
drug interventions (eg, paracentesis) received by participants from signature of the informed 
consent in the main study and up to 28 days following the last dose of investigational product 
must be recorded on the CRF.
6.9.1. Luteinizing Hormone-Releasing Hormone Agonist 
Ovarian/testicular suppression therapy with an LHRH agonist (eg, goserelin or leuprolide 
acetate or equivalent agents) must be administered in pre/peri-menopausal female and male 
participants, starting on Cycle 1 Day 1 (if not already on treatment) and then administered 
every 28 days/3 months (depending on the LHRH formulation) irrespectively of cycle 
duration up to 28 days after the last dose of study intervention (Table 2). 
Participants already on treatment with the 28-day/3-month LHRH formulation can continue it 
for the duration of the trial. Formulations given at intervals >3 months are NOT allowed. The 
Investigator will determine and supply the appropriate LHRH agonist locally approved for 
use in BC considering any potential DDI based on the product prescribing information. If 
required by local regulations, LHRH may be provided by the Sponsor if available to source 
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in-country. If LHRH agonist is administered at home, the administration details will be 
collected in a diary.  The completed diary should be provided to the study personnel at every 
visit.
LHRH agonist treatment continuation during the survival FU will be at the discretion of the 
PI in both arms.
6.9.2. Prohibited Inhibitors/Inducers
The concurrent use of the following medications, food or herb supplements is prohibited 
throughout the duration of the active treatment phase: 
Arm A

Strong CYP3A inhibitors/inducers: CYP3A4 is involved in ARV-471 
metabolism based on in vitro assays. Co-administration with drugs that are strong 
CYP3A inhibitors and inducers may change the plasma concentrations of ARV-471 
in humans.  Refer to Appendix 10 for examples of drugs that are strong CYP3A 
inhibitors/inducers.
Arm B

No DDI is expected by the concomitant use with fulvestrant. Refer to Faslodex 
EU SmPC. 
6.9.3. Other Prohibited and/or Anti-Cancer or Experimental Drugs, or Procedures
The following treatments are also prohibited throughout the duration of the active treatment 
phase in both Arms:

Anticancer agents: No additional investigational or commercial anticancer agents 
such as chemotherapy, immunotherapy, targeted therapy, biological response 
modifiers, or endocrine therapy other than the initiated treatment by the investigator 
will be permitted during the active treatment phase. No switching will be permitted.  
In general, any drugs containing “for the treatment of breast cancer” on the product 
insert are not permitted on study.

Hormone replacement therapy, topical estrogens (including any intravaginal 
preparations), megestrol acetate and selective estrogen receptor modulators (e.g., 
raloxifene).

Drugs known to predispose to Torsade de Pointes or to QT interval 
prolongation: refer to Appendix 10 for a list of drugs known.  
Exception: sevoflurane, azithromycin, ondansetron, chloroquine may be used with 
caution during the active treatment for all the participants with the exception of the 
participants in the QTc sub-study in Arm A for whom the use is prohibited during 
Cycles 1, 2 and 3.
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6.9.4. Concomitant Treatments to be used with caution or not recommended
The following treatments are to be used with caution throughout the duration of the active 
treatment phase:
Arm A only:

P-gp sensitive substrates: based on in vitro data ARV-471 may inhibit P-gp 
substrates. Drugs that are P-gp sensitive substrates should be used with caution as 
ARV-471 may increase the drug exposure. Consult the respective local product label 
of the P-gp substrate before use. Refer to Appendix 10 for examples of drugs that are 
sensitive substrates of P-gp.

H2 receptor antagonists (eg, cimetidine, famotidine) or antacids (eg, aluminum 
hydroxide, calcium carbonate, bismuth subsalicylate) may be used, but should be 
staggered.  Administer ARV-471 ≥2 hours before or after antacids. Administer ARV-
471 ≥2 hours before or 10-12 hours after H2 receptor antagonists. Alternatively, H2 
receptor antagonists or antacids can be administered anytime when ARV-471 is taken 
with a moderate-fat meal (400-800 calories, approximately 35% fat).
The following treatments are NOT recommended throughout the duration of the active 
treatment phase in:
Arm A only:

PPIs: co-administration of gastric acid-reducing agents may reduce ARV-471 absorption. 
The concomitant use of PPIs with ARV-471 is not recommended.  If PPI treatment is 
required, ARV-471 drug intake with a moderate-fat meal (400-800 calories, 
approximately 35% fat) is recommended.  Refer to Appendix 10 for examples of drugs 
that are PPIs.
Both Arms:

Herbal medicine: use of herbal medicine.
Consider, whenever possible, to replace the concomitant treatments to be used with caution 
or not recommended with other drugs with the same indication for use. If one of the 
treatments to be used with caution or not recommended is deemed necessary, consultation 
and agreement with the sponsor medical monitor is encouraged prior to treatment initiation. 
6.9.5. Supportive Care
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to the specific supportive care product Prescribing 
Information or the current ASCO guidelines. 
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Participants should receive appropriate supportive care measures throughout duration of the 
active treatment phase as deemed necessary by the treating investigator including but not 
limited to the items outlined below:

Standard therapies for preexisting medical conditions, medical and/or surgical 
complications, and palliation. Any medication intended solely for supportive care 
(e.g., analgesics, antidiarrheals, antidepressants) may also be used at the 
investigator’s discretion. 

Bisphosphonates and receptor activator of nuclear factor kappa B ligand
inhibitors for the treatment of osteoporosis or management of existing bone 
metastases may be continued for participants who have been receiving them at a 
stable dose for at least 2 weeks prior to randomization. However, the need to initiate 
or increase the dose of these therapies during the study will be considered as 
indicative of disease progression leading to the discontinuation of participant from the 
active treatment phase unless disease progression can be completely ruled out and the 
exact reason for the use of these therapies clearly documented in the subject’s source 
documentation.

Vaccines locally approved vaccinations and booster doses are allowed, including 
Influenza and SARS-CoV-2 as appropriate.

Transfusion: RBC and PLT transfusion may be used as per Investigator’s discretion

Anti-infectives may also be used at the investigator’s discretion. Before 
administration verify any potential drug-drug interaction with the study treatments as 
per Appendix 10.

Anticoagulant’s use:
Arm A only: Participants who need to be on anticoagulant therapy during treatment 
should be treated with low molecular weight heparin.  If low molecular weight 
heparin cannot be administered, warfarin or other warfarin derivatives or other oral 
anticoagulants (eg, direct Xa inhibitors) may be allowed.  When using oral 
anticoagulants, close monitoring for signs of bleeding is recommended.  Consult the 
product prescribing information for the appropriate coagulation test to be used for 
monitoring, as required. Refer to Appendix 10 for potential DDI with P-gp sensitive 
substrates. 
Arm B: refer to the Faslodex EU SmPC for fulvestrant for anticoagulant’s use.
6.9.6. Hematopoietic Growth Factors
Hematopoietic growth factors (eg, GCSF and GMCSF) may be used as indicated by the 
ASCO guidelines (Smith et al, 2015).
Erythropoietin may be used at the investigator’s discretion for the supportive treatment of 
anemia. For those countries where the indication and dosage of GCSF compounds may 
differ from ASCO guidelines, refer to the local product prescribing information or follow the 
country’s clinical practice.
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6.9.7. Antidiarrheal, Antiemetic Therapy
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
Antidiarrheal: All participants who experience diarrhea should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion. Anti-diarrheal agents should be administered as 
needed.
Antiemetic Therapy: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 
antiemetic therapy according to standard institutional practice. Participants should be 
strongly encouraged to maintain liberal oral fluid intake. 
The choice of the prophylactic drug, as well as the duration of treatment, is up to the 
investigator with sponsor approval assuming there is no known or expected drug-drug 
interaction and assuming the drug is not included in the Concomitant Therapy section 
(Section 6.9).
6.9.8. Corticosteroids
Chronic immune suppressive therapies, including systemic corticosteroid use (prednisone 
>10 mg/day or equivalents) for palliative or supportive purposes is not permitted. Steroids 
given as hormonal replacement (prednisone ≤10 mg/day or equivalents) is allowed.
Acute emergency administration, topical applications, inhaled sprays, eye drops, local 
injections of corticosteroids or as premedication prior to contrast media administration as per 
local guidelines is allowed.
6.9.9. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered as needed assuming there is no 
known or expected DDI and assuming the drug is not included in the Concomitant Therapy 
section (Section 6.9). Acetaminophen/paracetamol to a maximum total daily dose of 2 g is 
permitted.  Daily intake over 2 g is prohibited.
6.9.10. Concurrent Surgery and Radiotherapy
Any concurrent radiotherapy (excluding palliative radiotherapy as per specifications below) 
or cancer related surgery are prohibited throughout the duration of the active treatment phase 
of the study. Participants requiring any of these procedures will be discontinued from the 
active treatment phase and will enter the follow-up phase.
Caution is advised for any participant undergoing surgical procedures during the study.  The 
appropriate interval of time between surgery and ARV-471 administration required to 
minimize the risk of impaired wound healing and bleeding has not been determined. It is 
recommended to stop ARV-471 administration at least 7 days prior to surgery. 
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Postoperatively, the decision to reinitiate ARV-471 treatment should be based on a clinical 
assessment of satisfactory wound healing and recovery from surgery.  
Palliative radiotherapy is permitted for the treatment of painful bony lesions providing the 
lesions were known to be present at the time of study entry and the investigator clearly 
documents that the need for palliative radiotherapy is not indicative of disease progression.
ARV-471 treatment is recommended to be interrupted during palliative radiotherapy, 
stopping 7 days before and resuming treatment after recovery of any radiotherapy associated 
signs and symptoms.
For participants with bone involvement, it is suggested to institute palliative radiotherapy 
before study initiation if possible and clinically appropriate (eg, lesions at risk for 
spontaneous micro-fractures or painful lesions). Information related to the administration of 
palliative radiotherapy (eg date and site of radiotherapy) should be recorded on the 
appropriate CRFs.
No contraindication is reported for concomitant surgery and radiotherapy in respect to the 
use of fulvestrant. Refer to Faslodex EU SmPC.
6.9.11. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with ARV-471 or fulvestrant; 
standard medical supportive care must be provided to manage the AEs.  
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following:

Objective disease progression assessed by Investigator; however, participants 
with disease progression as per RECIST v1.1 who are continuing to derive 
clinical benefit from the study intervention (ie, positive benefit/risk assessment as 
assessed by investigator), will be eligible to continue study intervention. See 
Section 8.2.1.1 for details;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;

Pregnancy;

Significant protocol violation;

Lost to followup;
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
Participant refused further treatment;

Study terminated by sponsor;

Death.
Discontinuation of study intervention does not represent withdrawal from the study.  If study 
intervention is permanently discontinued, the participant should remain in the study to be 
evaluated for safety and survival.  See Table 2 for data to be collected at the time of 
discontinuation of study intervention and follow-up for any further evaluations that need to 
be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Post-treatment Follow-up
Participants discontinuing the Active Treatment Phase will enter to the Post-treatment 
Follow-up period, which comprises Safety and Survival Follow-up Periods (see Table 2 for 
required assessments).
7.1.1.1. Safety Follow-up
At least 28 calendar days, and no more than 35 calendar days after discontinuation of study 
intervention or prior initiation of any new anticancer therapy whichever comes first, 
participants will undergo the safety FU assessments as reported in Table 2.
Any SAEs occurring during the 28-day from last dose must still be reported to Pfizer Safety 
irrespective of any intervening treatment. See Section 8.4.1 for details for AE/SAE reporting 
requirements.
7.1.1.2. Survival Follow-up
During the Survival Follow-up period, poststudy survival status (including all poststudy 
anticancer therapies) will be collected every 3 months after the EOT visit. Participants will 
be contacted (eg, telephone, email, site visits, family member contact) approximately every 3 
months after the EOT visit for survival status and subsequent anticancer therapies (eg, start 
and stop dates, date of PD of the therapy), until death, withdrawal of consent, lost to follow-
up, or end of study, whichever occurs first. On sponsor request, participants may be 
contacted for survival information (including all poststudy anticancer therapies), eg prior to 
each protocol-specified interim and final analysis. As permitted by local law, study site 
personnel may use public databases, perform an internet search, or review obituaries to 
determine date of death. Survival information should be recorded in the CRFs.
7.1.2. COVID-19 
While SARS-CoV-2 testing is not mandated for this study, local clinical practice standards 
for testing should be followed. A participant should be excluded if he/she has a positive test 
result for SARS-CoV-2 infection, is known to have asymptomatic infection, or is suspected 
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of having SARS-CoV-2. When the infection resolves, the participant may be considered for 
re-screening. 
If a participant has COVID-19 during the active treatment phase, this should be reported as 
an AE or SAE (as appropriate) and appropriate medical intervention provided considering 
potential DDIs for any concomitant medication administered for treatment of SARS-CoV-2 
infection (see Section 6.9). Study treatment should continue unless the investigator is 
concerned about the safety of the participant, in which case temporary or permanent 
discontinuation may be required. In case of temporary discontinuation, prior restarting 
treatment, the participant should be afebrile for 72 hours, and SARS-CoV-2-related 
symptoms should have recovered to Grade ≤1 for a minimum of 72 hours. Notify the study 
team when treatment is restarted.
It is recommended that the investigator discuss permanent discontinuation of study 
intervention with the study medical monitor. 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following:

Lost to follow-up;

Death;

Study terminated by sponsor;

Withdrawal by participant.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
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7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative and Baseline Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in Table 2. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the Table 2, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, tumor 
assessments by imaging as per Section 8.2.1) and obtained before signing of the ICD of the 
study may be utilized for screening purposes provided the procedures meet the 
protocol-specified criteria and were performed within the time frame defined in Table 2.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
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test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
from minimum of 10 mL up to approximately 40 mL per study visit. The actual collection 
times of blood sampling may change. Additional blood samples may be taken for safety 
assessments at times specified by Pfizer, provided the total volume taken during the study 
does not exceed 550 mL during any period of 56 consecutive days.
8.1.1. Pre-screening
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated prescreening ICD before performing any study-specific procedures.  
Study procedures are summarized in Table 1.
Three mandatory whole blood samples (10 mL each) (only two samples for China) for 
ctDNA will be collected during pre-screening period as per Table 1. Available ESR1 results 
(with the exception of participants in China) may also be considered upon sponsor approval 
as per Table 1. 
The samples will be collected as follows:

All participants with the exception of China: The collection of the 3 samples is 
mandatory for all the participants and will be used either for ESR1 status evaluation 
or for retrospective ESR1 confirmation after randomization (only for the participants 
with an acceptable and approved prior ESR1 status result) and may also be used for 
the development of companion diagnostics. One of the 3 samples is to be processed 
into plasma at the study site as per Laboratory manual instructions.  The other two 
whole blood samples will be sent directly to the laboratory identified for analysis. See 
Laboratory Manual.

For participants in China: Two samples are mandatory from participants in China for 
ESR1 status evaluation. The remaining sample may also be used for the development 
of companion diagnostics. The sample may be also used for tumor molecular 
profile/ctDNA level and ctDNA burden if the participants are randomized in the trial. 
See Laboratory Manual. 
ESR1 test will be performed using a NGS test that evaluates other genes in addition to ESR1 
gene. The results of the other genes will not be collected in the CRF.
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Some characteristics regarding the disease under study, demography and study procedure-
related AEs will be also collected. 
8.1.2. Baseline Procedures 
Medical history will be recorded at screening for each participant. Medical history includes 
any signs, symptoms, and history not associated to the disease under study before informed 
consent signature.
Oncological history will be recorded at screening for each participant and includes 
additional disease characteristics, and all prior treatments including prior systemic therapies, 
radiation, and surgical procedures.
8.1.3. Telehealth Visits 
Telehealth visits may be used to assess participant safety and collect data points upon written 
confirmation from the sponsor. Telehealth includes the exchange of healthcare information 
and services via telecommunication technologies (eg, audio, video, videoconferencing 
software) remotely, allowing the participant and the investigator to communicate on aspects 
of clinical care, including medical advice, reminders, education, and safety monitoring. The 
following assessments must be performed during a telehealth visit (see the Table 2): 

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.

Review and record any new concomitant medications/treatment (eg, radiotherapy or 
surgery as per Section 6.9.10) or changes in concomitant medications/treatment since the 
last contact.

Review laboratory tests and ECGs reports performed at alternative facilities, if 
applicable.

Review LHRH compliance for pre/peri-menopausal female and male participants 
(Section 6.9.1) and contraception for WOCBP and males. 
o
Review and record contraceptive method and results of pregnancy testing, 
(Section 8.3.5) as applicable. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol. Refer to Appendix 4. 

PRO assessment, as applicable (See Appendix 14) 
Participants should be instructed to bring original reports of assessments performed in 
alternative facilities and diaries at the next visit.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
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8.1.4. Home Health Visits  
A home health visit may be utilized to facilitate scheduled visits and will be allowed on a 
case-by-case basis. Confirmation from the sponsor will include which visits can be 
performed at home.  
Home heath visits will be performed by a registered nurse/other qualified health care 
provider and the investigator or designee must be available for consultation. If required by 
local regulations home heath visits will be performed by the investigator or by a physician 
designee for specific assessments (e.g. fulvestrant intramuscular administration, physical 
examinations and collection of adverse events). 
Home health visits include a healthcare provider conducting an in-person study visit at the 
participant’s location, rather than an in-person study visit at the site. The following may be 
performed during a home health visit (see Table 2):

Review and record study intervention(s), including compliance and missed doses; 
dispense dosing diary (if applicable)

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.

Review and record any new concomitant medications/treatment (eg, radiotherapy or 
surgery as per Section 6.9.10) or changes in concomitant medications/treatment since the 
last contact.

Collect local safety laboratory samples and review laboratory tests, perform and review 
ECGs, if applicable.

Collect central laboratory samples, including ctDNA samples and PK samples, if 
applicable.

Review LHRH compliance and provide diary, if applicable; administer LHRH (if 
applicable) for pre/peri-menopausal female and male participants (Section 6.9.1) and 
review contraception for WOCBP and males.  
o
Review and record contraceptive method and perform pregnancy testing (Section 
8.3.5) and review results, as applicable. Confirm that the participant is adhering to 
the contraception method(s) required in the protocol. Refer to Appendix 4. 

Perform physical examinations and collect vital signs 

Administer and provide PRO assessments, if applicable 
Dispense/administer ARV-471 or fulvestrant; fulvestrant preparation and administration must 
be performed by a physician, registered nurse, or other qualified health care provider. 
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Tumor assessments (ie, all tumor scans, photographs, etc) must be performed at the site, 
unless otherwise agreed between the investigator and the sponsor (see Section 8.1.5). 
8.1.5. Alternative Facilities 
In the event that an in-person visit is not feasible at the site, the following may be performed 
at alternative facilities, approved by the investigator upon written notification from the 
sponsor, if allowed by local regulations (see Table 2): 

Safety laboratory tests. See Section 8.3.4.1.

ECGs. See Section 8.3.3.1.

Tumor assessments (ie, all tumor scans, photographs, etc.). See Section 8.2.1.4
8.2. Efficacy Assessments
8.2.1. Imaging Tumor Response Assessments
Timely and complete disease assessments in this study are critical. Imaging assessments are 
to be scheduled according to the calendar, starting from the randomization date as the 
reference date for all time-points regardless of treatment delays/interruptions and are NOT to 
be scheduled based on the date of the previous imaging time-point. Imaging assessment delay 
to conform to treatment delay is NOT permitted.
Radiographic imaging, for all known or suspected disease sites, is required at screening and 
during the active treatment phase using the same imaging techniques.  The CT and MRI 
scans (including brain CT/MRI, if applicable) should be performed with contrast agents 
unless contraindicated for a medical reason. Premedication prior to contrast media 
administration as per local guidelines is allowed. 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. However, CT of the chest 
should not be substituted by chest MRI even if IV contrast is contraindicated. In such case 
CT will be performed without contrast. If MRI is used to follow up bone lesion(s) it must be 
performed a few days before any treatment that may affect bone marrow cellularity (ie, G-
CSF).
Screening tumor assessment will be carried out within 28-day period before randomization 
unless otherwise specified. Disease assessment for all participants at screening will include:

Imaging assessments of chest, abdomen and pelvis (CAP), by computerized 
tomography (CT) or magnetic resonance imaging (MRI) mandatory.

CT/MRI scan of any other sites of disease (including brain), as clinically indicated.

Clinical assessment of superficial lesions, as clinically indicated.
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
Bone scan (whole body), mandatory 
Screening CT/MRI scans obtained per the participant’s standard of care prior to the signature 
of the informed consent do not need to be repeated and are acceptable to use as baseline 
evaluations, (1) obtained within 28 days before randomization, (2) they were performed 
using the method requirements outlined in RECIST v1.1, (3) the same technique/modality 
can be used to follow identified lesions throughout the trial for a given participant, and (4) 
appropriate documentation indicating that these radiographic tumor assessments were 
performed as standard of care is available in the participant’s source notes.
Screening brain scan is only required if signs and symptoms suggest the presence of 
metastatic brain disease.  Brain scans performed before the signing of informed consent as 
routine procedures (but within 6 weeks before randomization) do not need to be repeated and 
may be used as screening assessments as long as (1) tests were performed using the method 
requirements outlined in RECIST v1.1, (2) the same technique/modality can be used to 
follow identified lesions throughout the trial for a given participant, (3) appropriate
documentation indicating that these radiographic tumor assessments were performed as 
standard of care is available in the participant’s source notes. Post-baseline brain scans are 
required only if brain metastases are present at screening or in case new brain lesion/s is/are 
suspected. 
Clinical assessment of superficial lesions will include assessment with caliper of all 
identified superficial metastatic lesions. For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested.
Screening bone scan is mandatory to detect bony sites of disease. Bone scans performed 
before the signing of informed consent as routine procedures (but within 12 weeks before 
randomization) do not need to be repeated and may be used as screening assessments as long 
as (1) tests were performed using the method requirements outlined in RECIST v1.1 (2)  the 
same technique/modality can be used to follow identified lesions throughout the trial for a 
given participant (3) appropriate documentation indicating that these radiographic tumor 
assessments were performed as standard of care is available in the participant’s source 
notes. Any suspicious abnormalities (ie, hotspots) identified on the screening bone scans and 
on subsequent bone scans MUST be confirmed by X-ray, CT scan with bone windows or 
MRI. Bone lesion(s) identified at screening by bone scan can be further assessed at screening 
by CT with bone windows or MRI as per local practice and subsequently re-assessed on 
treatment by CT with bone windows or MRI (consistently with the technique used at 
screening) as per tumor assessment schedule (ie, every 8 weeks for the first 48 weeks from 
the date of randomization and then every 12 weeks thereafter). Areas that have received 
palliative radiotherapy cannot be used to assess response to study treatment. 
All lesions identified at screening, measurable and/or non-measurable, must be recorded in 
the CRF and evaluated during the active treatment phase.
Of note: Tumor lesions previously irradiated or subjected to other locoregional therapy will 
only be deemed measurable if progression as per RECIST 1.1 at the treated site after 
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completion of therapy is clearly documented. A target lesion biopsied during the screening 
period will NOT be considered as a measurable lesion.
Active Treatment Phase Tumor Assessments will include: 

Imaging assessments of chest, abdomen and pelvis (CAP) by CT or MRI mandatory.

CT/MRI scan of any other sites of disease (including brain), if lesions identified at 
screening assessment.

Clinical assessment of superficial lesions, if lesions identified at screening.

Bone scan, mandatory only if it is the preferred technique to follow bone lesions
identified at screening.
CT/MRI and bone scans (as applicable and if bone scan is the preferred technique to follow 
them on treatment) must be repeated on treatment as per Table 2 (every 8 weeks for the first 
48 weeks from the date of randomization and then every 12 weeks thereafter for CT/MRI and 
every 24 weeks for bone scan from the date of randomization) until radiographically and/or 
clinically (eg for photographed or palpable lesions)  documented PD as per RECIST v1.1, 
study treatment discontinuation (for participants continuing treatment beyond RECIST-
defined disease progression, see Section 8.2.1.1), or discontinuation of participant from 
overall study participation (ie, death, participant's request, lost to follow up), whichever 
occurs first. 
CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial 
documentation of response.
Brain scan or scans of any other anatomical site will be repeated on the active treatment 
phase only if lesion/s present at screening or new lesions are suspected.
Clinical assessment of superficial disease should be carried out preferably on the same date.  
If no bone lesions were identified at screening, bone scans will only be repeated during the 
active treatment phase when clinically indicated (ie, participant describes new or worsening 
bone pain, or has increasing alkaline phosphatase level, or other signs and symptoms of 
new/progressing bone metastases) or at the time of confirmation of CR. Any suspicious
abnormality identified by bone scan on treatment, must also be confirmed by X-ray, CT scan 
with bone windows or MRI. 
Further imaging assessments may be performed at any time if clinically indicated (eg, 
suspected PD, symptomatic deterioration, etc). 
Participants who have already demonstrated objective disease progression as per RECIST 
v1.1 are expected to discontinue study therapy and begin the follow up phase of the trial. See 
Section 8.2.1.1 for treatment continuation beyond progression.
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For participants who do NOT have documented objective disease progression at time of 
study treatment discontinuation, tumor assessment will continue to be performed as per 
Table 2 (every 8 weeks for the first 48 weeks from date of randomization and then every 12 
weeks thereafter for CT/MRI and every 24 weeks from date of randomization for bone scan)
until radiographically and/or clinically (eg, for photographed or palpable lesions) confirmed 
objective disease progression, or discontinuation of participant from overall study 
participation (e.g., death, participant's request, lost to follow up).    
For participants having effusions or ascites, cases having cytological proof of malignancy 
should be recorded as non-target lesions on the tumor assessment CRFs. Effusions that have 
not been evaluated using cytology or were found to be non-malignant should not be recorded 
on the non-target lesion CRF.
BICR will review all radiological images as well as other information as per section 8.2.1.2.  
All radiographic images as well as other information will be collected and objectively 
verified by an independent third-party core imaging laboratory as described in the Study 
Imaging Manual. 
Objective tumor response will be measured using Response Evaluation Criteria in Solid 
Tumor (RECIST v1.1) (also refer to Appendix 13).
All participants’ files and radiologic images and pathology samples must be available for 
source verification and for potential peer review.
8.2.1.1. Treatment Beyond Progression in Both Arms
Participants should be discontinued from study intervention when investigator assessed PD. 
However, participants with disease progression by RECIST v1.1 who are continuing to 
derive clinical benefit from the study intervention (ie, positive benefit/risk assessment as 
assessed by investigator) according to the investigator’s clinical judgment, may be eligible to 
continue study intervention (crossover between treatment arms is not permitted) after 
discussion between the investigator and the sponsor medical monitor. The investigator’s 
judgment should be based on the overall benefit/risk assessment for study intervention 
continuation considering the participant’s clinical condition, including performance status, 
clinical symptoms, AEs and laboratory data. 
The participant must consent to continue treatment beyond progression.
Participants who continue treatment after progression should discontinue study intervention 
upon evidence of further progression by imaging as per RECIST v1.1 as outlined in 
Appendix 13, from time of initial PD, or worsening of participant’s clinical condition 
suggesting a negative benefit/risk assessment for study intervention continuation, unless 
otherwise agreed between the investigator and the sponsor medical monitor. 
In participants who continue treatment beyond progression, the oncologic assessments (as 
well as the other safety assessments as per Active Treatment Phase) should continue to be 
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performed as per Table 2 and recorded in the CRF until the study intervention is permanently 
discontinued.
8.2.1.2. Independent Review of Disease Assessments
A blinded independent third-party central imaging laboratory will perform a review of 
radiographic images as well as all the other information reported below collected on study to 
determine the protocol defined endpoints of disease response and progression. 
It is important to the integrity of the study that all imaging studies, clinical assessment of 
superficial lesions and clinical information (as applicable) are provided to BICR on an 
ongoing basis (as soon as they are available) until confirmation of objective disease 
progression by BICR as per RECIST v1.1, regardless of the initiation of a new anticancer 
therapy.
The following materials need to be forwarded for BICR of images:

All imaging studies performed on study

clinical assessment of superficial lesions

Clinical information, as applicable.
8.2.1.2.1. Expedited Blinded Independent Central Review for Disease Progression 
To mitigate the potential for bias in determining disease progression, expedited BICR review 
will be performed for investigator assessed disease progression.  Upon investigator assessed 
disease progression, the radiographic image as well as all the other information as reported in 
the Section 8.2.1.2 will be submitted to the BICR for expedited review.  See the Study 
Imaging Manual for process details. 
8.2.1.3. Management of Incidental Findings
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study 
but is unrelated to the purpose and beyond the aims of the study.
Tumor assessment images will be reviewed by a central review facility. The purpose of this 
review is to evaluate images for disease assessment. Central image review is not a complete 
medical review of the participant, and no incidental findings will be shared with the PI, site 
staff, or the participant. All safety reviews will be the sole responsibility of site staff.
8.2.1.4. Alternative Facilities for Tumor Assessment
Tumor assessment may be performed at an alternative facility as long the equipment is 
adequate (eg, qualification/calibration/maintenance) and the images can be uploaded to the 
investigative site for overall tumor response assessments and for submission to the BICR (see 
Section 8.2 and Section 8.2.1.2), if approved upon written confirmation from the sponsor.
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8.2.2. Survival Follow-up Analysis
The study Survival Follow-up period will conclude at the time of the final OS analysis (See
Section 9.3.3.1).
8.3. Safety Assessments
Planned time points for all safety assessments are provided in Table 2. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Physical Examinations
At screening, a complete physical will include assessments of all the major body systems.  
The complete physical examination should include the examination of general appearance 
(head, eyes, ears, nose, mouth, throat, skin, heart, lung, lymph nodes, gastrointestinal, 
genitourinary, neurologic, and muscle-skeletal). Sites of disease identified by physical 
examination will be recorded on the tumor assessment pages and recorded as Target or Non-
target lesion. Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
Height and weight will be collected as per Table 2. For measuring weight, a scale with 
appropriate range and resolution must be used and placed on a stable, flat surface. 
Participants must remove shoes, bulky layers of clothing, and jackets so that only light 
clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
PEs may be conducted by a physician, trained physician's assistant, or nurse practitioner as 
acceptable according to local regulation. On dosing days physical examinations must be 
performed prior to study intervention administration.
Symptom-directed physical examinations will be performed at subsequent visits as per 
Table 2. Additional physical examinations may be performed if clinically indicated.  
PE findings collected during the study will be considered source record and will not be 
required to be reported, unless otherwise noted. Any untoward physical examination findings 
that are identified during the active collection period and meet the definition of an AE or 
SAE (Appendix 3) must be reported according to the processes in Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
Vital signs will be measured per institutional standards and will include systolic and diastolic 
blood pressure, and pulse rate. 
All vital sign measurements as per Table 2 should be performed prior to study intervention 
administration. 
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Vital signs will be assessed while the participant is in a sitting position or semi-recumbent 
position (recommended).  It is recommended that the same position be used consistently 
throughout the duration unless circumstances, e.g., hospitalization, dictate otherwise. 
Vital signs should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions (eg, television, cell phones). 
Abnormal readings should be repeated and confirmed.
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3.
8.3.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in Table 3 using the study ECG machine supplied by the Sponsor 
that automatically calculates the mean heart rate and measures QTc interval and also collects 
QT interval, PR interval, and QRS complex. Alternative lead placement methodology using 
torso leads (eg, Mason-Likar) should not be used given the potential risk of discrepancies 
with ECGs acquired using standard limb lead placement. 
All scheduled ECGs should be performed after the participant has rested quietly for at least 5 
minutes in a supine position.  Triplicate ECGs are defined as three consecutive ECGs 
performed approximately 2 minutes apart but within 10 minutes for all 3 measurements as 
per Table 3 to determine the QTc interval. Blood sample for electrolytes (sodium, potassium, 
magnesium, total calcium) must be collected at Day 1 (-2 days) pre-dose of the required 
cycles (see Table 3 for details ).
The ECGs tracings for all participants (including the participants belonging to the QTc Sub-
study) will be read and interpreted by qualified personnel at investigational site to determine 
eligibility and for safety monitoring.
ECG assessment will be performed as follows:

Approximately the first 80 participants in Arm A at selected sites will have their QTc 
monitored to evaluate the effect of ARV-471 on QT interval via triplicate ECGs time-
matched with PK draws (QTc sub-study). ECGs will be obtained as specified in 
Table 3. All ECGs (with the exception of the ECG performed at screening) 
should be obtained after a fast of at least 1 hour. ECGs should be performed 
immediately before PK blood draws at respective time points.  All triplicate ECGs 
will be electronically transmitted to the central ECG vendor for storage and analysis. 
The anonymized semi-manual interval measurements of the ECG performed at each 
time point (with the exception of the ECG performed at screening) and obtained from 
the central ECG laboratory will be used for primary statistical analysis of ECG data. 
The Investigator should review and sign the ECG tracings and final ECG report from 
the vendor (and file them with the participant’s source documents).
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
All the remaining participants in Arm A and those in Arm B will have triplicate 
ECGs performed as per Table 3. No central reading is required, but ECGs will be 
electronically transmitted the to the central ECG vendor for storage.
ECGs should be performed immediately before PK blood draws at respective time 
points (Arm A).
When an ECG is to be performed at the same time point as a blood collection (eg, safety 
laboratory assessments, PK samples), the ECG is to be performed first prior to the nominal 
time of the blood collection. 
At any time, additional triplicate ECGs as well as electrolytes laboratory assessments (ie, 
sodium, potassium, magnesium, total calcium) may be performed as clinically indicated.  
The ECG must be reviewed by qualified personnel at the site as soon as any abnormality is 
observed, including verifying that the machine reading is accurate, and that the Fridericia 
correction formula is applied. In some cases, it may be appropriate to repeat abnormal ECGs 
(ie at least two times approximately 2 minutes apart) to rule out improper lead placement as 
contributing to the ECG abnormality.  It is important that leads be placed in the same 
positions each time in order to achieve precise ECG recordings.   
If readings confirm a QTc of ≥ 501 msec or >60 msec change from baseline, immediate 
search for reversible causes (including electrolyte abnormalities, hypoxia and concomitant 
medications for drugs that may potentially prolong the QTc interval) should be performed.
Repeat ECG should be performed when one of the following conditions apply:

When a post dose QTc interval remains > 60 msec from the baseline OR is ≥501 
msec, repeat ECGs should be performed immediately as per the investigator's best 
medical judgement until the QTc interval is ≤ 60 msec from the baseline or QTc 
interval falls ≤ 480 msec  

QTc intervals get progressively longer.
A cardiologist should be consulted if QTc intervals do not return to less than the criteria 
listed above after 8 hours of monitoring (or sooner, at the discretion of the investigator). 
If QTc interval reverts to less than 501 msec or ≤ 60 msec change from baseline, and in the 
judgment of investigator(s) in consultation with the sponsor medical monitor the cause is 
determined to be other than study drug, treatment may be continued with regular ECG 
monitoring under hospital supervision.
Prior to concluding that an episode of prolongation of the QTc interval is due to study 
intervention, thorough consideration should be given to potential precipitating factors (eg, 
change in participant clinical condition, effect of concurrent medication, electrolyte 
disturbance) and possible evaluation by specialist should be performed.
If study intervention causality cannot be ruled out, study intervention dose modifications 
and/or interruption or permanent discontinuation, as applicable, should be performed 
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according to instructions provided in Table 7 for ARV-471 in Arm A or on the Faslodex EU 
SmPC for fulvestrant in Arm B, as applicable. 
ECG values of potential clinical concern are listed in Appendix 8.
8.3.3.1. Alternative Facilities for Electrocardiograms 
The participant may visit an alternative facility to have the ECGs performed (see 
Section 8.1.5) only when an unscheduled ECG is done as clinically indicated (ECG 
scheduled as per Table 3 cannot be performed in alternative facilities) . Qualified study site 
personnel must order, receive, and review results. ECGs can also be performed at home 
through home health vendors or through remote device collection, upon written confirmation 
from the sponsor.
Tests results are to be provided to the site staff as soon as possible. Participants should be 
instructed to bring original reports in at the next visit. ECG reports should be filed in the 
participant’s source documents/medical records. Relevant data from the ECG report should 
be recorded on the CRF.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.4. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and Table 2 for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and Table 2. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.  
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified, and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
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8.3.4.1. Alternative Facilities for Clinical Safety Laboratory Assessment
Protocol-specified safety laboratory evaluations as per Table 2 may be conducted at a local 
laboratory, if permitted by local regulations. The local laboratory may be a standalone 
institution or within a hospital. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible.  Participants should be instructed to bring original reports in at the next 
site visit. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF.
8.3.5. Pregnancy Testing
A serum pregnancy test is required at screening (Table 2).  Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. If a 
urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test 
is required.  In such cases, the participant must be excluded if the serum pregnancy result is 
positive. Pregnancy tests will be performed in WOCBP at the times listed in  Table 2. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced, and a second negative pregnancy test result will be required at baseline visit 
prior to starting the study intervention. Pregnancy tests will be done until 28 days after the 
last dose.
Pregnancy tests may also be repeated if requested by IRBs/ECs or if required by local 
regulations. 
8.3.5.1. At-Home Pregnancy Testing
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant
to perform the test at home, if compliant with local regulatory requirements. The pregnancy 
test outcome should be documented in the participant’s source documents/medical records 
and relevant data recorded on the CRF. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
The definitions of device-related safety events (ADEs and SADEs) can be found in 
Appendix 9. Device deficiencies are covered in Section 8.4.9.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
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authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant or legally 
authorized representative will be questioned about the occurrence of AEs in a nonleading 
manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention, through and including a minimum of 28 calendar days after the last 
administration of the study intervention. 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form/ PSSA.
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the CT SAE Report Form/ PSSA.
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8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form/ PSSA immediately 
upon awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3.  The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.  Note that a switch to a commercially available version of the study intervention is 
considered as a new anticancer therapy for purposes of SAE reporting.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF.  
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
If a participant begins a new anticancer therapy, the recording period for nonserious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the CRF during the above-indicated active collection period.  Note that a switch to a 
commercially available version of the study intervention is considered as a new anticancer 
therapy for the purposes of SAE reporting.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
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In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 
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
A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP:  

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by, skin contact, ingestion or 
injection.

A male family member or healthcare provider who has been exposed to the study 
intervention by, skin contact, ingestion, or injection then inseminates his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form/PSSA and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until at least 28 
days after the last dose of ARV-471 and for at least 9 months after the last dose of 
fulvestrant. 

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form/PSSA and EDP 
Supplemental Form. Since the exposure information does not pertain to the 
participant enrolled in the study, the information is not recorded on a CRF; however, 
a copy of the completed CT SAE Report Form/PSSA is maintained in the investigator 
site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
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for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion or injection.  
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form/PSSA. When EDB occurs in the setting of environmental 
exposure, the exposure information does not pertain to the participant enrolled in the study, 
so the information is not recorded on a CRF. However, a copy of the completed CT SAE 
Report Form/PSSA is maintained in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form/PSSA, regardless of 
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whether there is an associated SAE. Since the information about the occupational exposure 
does not pertain to a participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed CT SAE Report Form/PSSA must be maintained in 
the investigator site file.
8.4.6. Cardiovascular and Death Events
Cardiovascular events will be reported as AE/SAE as per Section 8.4.6 and Appendix 3. 
Cardiovascular events are to be managed per the dose modifications outlined in Section 6.6.
AEs and SAEs that result in death are to be reported per guidelines as outlined in Section 8.4.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. Should an aggregate analysis indicate that 
these prespecified events occur more frequently than expected, eg, based on epidemiological 
data, literature, or other data, then this will be submitted and reported in accordance with 
Pfizer’s safety reporting requirements. Aggregate analyses of safety data will be performed 
on a regular basis per internal SOPs. 
AEs that are considered AESIs for ARV-471 include QT Prolongation and VE. Based on 
current understanding of the safety profile, no expedited reporting by the investigator to 
sponsor is required for non-serious AESIs. Additional details and mitigation strategies are 
summarized in Section 2.3.1.
AESIs for fulvestrant and mitigation strategies are summarized in Section 2.3.1. 
All AESIs must be reported as an AE or SAE following the procedures described in Section 
8.4.1 through 8.4.4 An AESI is to be recorded as an AE or SAE on the CRF. In addition, an 
AESI that is also an SAE must be reported using the CT SAE Report Form/ PSSA.
8.4.8.1. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.  
8.4.9. Medical Device Deficiencies
Medical devices being provided for use in this study are those listed in Section 6.1.2. In order 
to fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of device deficiency that occur 
during the study with such devices.
The definition of a medical device deficiency can be found in Appendix 9.
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Note: AEs and/or SAEs that are associated with a medical device deficiency will follow the 
same processes as other AEs or SAEs, as outlined in Section 8.4.1 through 8.4.4 and 
Appendix 3 of the protocol.
8.4.9.1. Time Period for Detecting Medical Device Deficiencies
Medical device deficiencies that result in an incident will be detected, documented, and 
reported during all periods of the study in which the medical device is used.
Importantly, reportable device deficiencies are not limited to problems with the device itself 
but also include incorrect or improper use of the device and even intentional misuse, etc. 
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and such incident is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device deficiencies is provided in Appendix 9.
8.4.9.2. Follow-up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on a follow-up form with all changes signed 
and dated by the investigator.
8.4.9.3. Prompt Reporting of Device Deficiencies
When a device deficiency occurs: 
1. The investigator notifies the sponsor by contact method, eg, telephone, email within 1 
business day of determining that the incident meets the protocol definition of a 
medical device deficiency.  
2. The device deficiency must be recorded on the Medical Device Complaint form.
3. If an AE (either serious or nonserious) associated with the device deficiency occurs, 
then the AE must be entered into the AE section of the CRF.
If an SAE associated with the device deficiency is brought to the attention of the investigator, 
the investigator must immediately notify Pfizer Safety of the SAE (see 8.4.1.1 All relevant 
details related to the role of the device in the event must be included in the CT SAE Report 
Form /or via PSSA as outlined in Section 8.4.1.1and 8.4.1.2. The sponsor will be the contact 
for the receipt of device deficiency information.
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8.4.9.4. Regulatory Reporting Requirements 
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfill the legal responsibility 
to notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of device deficiencies to the IRB/EC.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form/PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Other examples include, but are not limited to:

The administration of expired study intervention;

The administration of an incorrect study intervention (ie, incorrect randomized 
assignment, or incorrect study intervention being used in this study);

The administration of an incorrect dosage defined as underdose (see Section 6.5) or 
overdose (See Section 6.8);

Device deficiency.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
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Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, such medication errors occurring to a study participant are recorded on the 
medication error page of the CRF which is a specific version of the AE page and, if 
applicable, any associated  serious and nonserious, AE(s), are recorded on the AE page of the 
CRF.
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form/PSSA only when associated with an SAE.
8.5. Pharmacokinetics 
Pharmacokinetics will be assessed in Arm A only. A single 3 mL whole blood sample at each 
time point will be collected for determining concentrations of ARV-471 and ARV-473 as 
specified in Table 3. The 3 mL blood samples to provide approximately 1.5 mL plasma will 
be collected into appropriately labeled tube containing K2 EDTA for ARV-471 and ARV-
473.  Instructions for the collection and handling of biological samples will be provided in 
the laboratory manual or by the sponsor.  The actual date and time (24-hour clock time) of 
each sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of 
samples within the sampling time window specified in Table 3 will not be considered 
protocol deviations as long as they have a documented actual time and date of collection and 
relevant time and date of dosing. 
On visit days, participants must be instructed to not take their ARV-471 dosing and to wait to 
take their daily dose of ARV-471 until the pre-dose assessments listed in Table 2 and 
Table 3 have been completed.  On these days, ARV-471 dose should be taken under the 
supervision of the study personnel.
PK draws will be done immediately after triplicate ECGs have been performed at all time 
points so that the PK samples are collected at the nominal time.
The actual time of the sample collection and the most recent dosing time before and after 
each collection will be recorded on the eCRF. The date of missing/reduced dose should also 
be recorded in the eCRF.
If a scheduled blood sample collection cannot be completed for any reason, the missed 
sample time may be re-scheduled with agreement of the clinical investigator, participant, and 
sponsor. In addition to samples collected at the scheduled times, every effort should be made 
to collect an additional blood sample from participants experiencing unexpected and/or 
serious AEs and to document the date and time of sample collection and of last dosing prior 
to PK collection on the CRF.
Samples collected for concentration analyses of ARV-471 and its epimer, ARV-473, may 
also be used to evaluate safety or efficacy aspects related to concerns arising during or after 
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the study, for metabolite identification and/or evaluation of the bioanalytical method, or for 
other internal exploratory purposes.
Genetic analyses will not be performed on these samples unless consent for this was included 
in the informed consent.  Participant confidentiality will be maintained.
Samples collected for measurement of plasma concentrations of ARV-471 and its epimer,
ARV-473, will be analyzed using a validated analytical method in compliance with 
applicable SOPs.  Potential metabolites may be analyzed with either validated or exploratory 
methods.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PK sample 
handling procedure (ie, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised. Refer to Laboratory Manual for detailed collection, 
processing, and shipping procedures.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic (analyses) are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
A single 4-mL whole blood sample optimized for DNA isolation Prep D1; K2 EDTA will be 
collected according to Table 2, as local regulations and IRBs/ECs allow. 
Retained Research Samples may be used for research related to the study intervention(s) and 
aBC.  Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be studied 
using the banked samples.  
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment of these samples can be found in Laboratory Manual. 
NOTE: Retained Research Samples for genetics are not applicable for participants in China.
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8.7. Biomarkers
Tumor tissues and/or blood samples will be used to evaluate biomarkers (genes and proteins) 
involved in the biology of the participant’s disease, and mechanisms of sensitivity or 
resistance to ARV-471, to conduct genomic, and/or molecular profiling analyses. The 
biomarkers involved in cellular proliferation, oncologic driver, and immunologic regulations, 
for example, but not limited to, Ki67 for protein marker, ESR1 and PIK3CA gene mutations, 
will be investigated. In addition, the quantitative changes (on treatment from baseline) of cell 
free tumor DNA concentration in the participant’s blood will be analyzed to estimate its 
potential as treatment responses. Refer to Table 2 for sample collection time points and 
Laboratory Manual for sample processing and shipping.
Unless prohibited by local regulations or IRBs/ECs, the following samples for biomarker 
research are required and will be collected from all participants in this study as specified in  
Table 2:

Tumor Biopsy- See Section 8.7.1

Blood samples See Section 8.7.2
Optional samples for biomarker research that should be collected from participants in the 
study as appropriate are the following:

Tumor tissue sample collection at the EOT visit.
Additional information on tissue collection procedures, sample preparations including 
processing, storage, and shipment to the sponsor designated laboratories for biomarkers 
analysis will be provided in the Laboratory Manual.
Note: for participants in China, sample collection for biomarkers and biomarker testing will 
not be performed unless approved by HGRAC.
8.7.1. Tumor Biopsies
Tumor biopsy collected at the time of presentation with locoregional recurrent, or metastatic 
disease is mandatory for study participation. If no tissue taken at the time of presentation 
with locoregional recurrent/metastatic disease is available a de novo biopsy is needed at 
screening. 
Exception: for participants with bone lesions only and for participants in whom the collection 
of a biopsy is clinically contraindicated an archival tumor tissue (ie tumor sample from initial 
diagnosis) is acceptable. 
Only core needle or excisional biopsies, or resection specimen are suitable.  Cytologic 
preparations, such as fine needle aspirate biopsies, are not acceptable. 
Bone biopsies are not acceptable since the decalcification process renders the sample 
unusable for biomarker analysis. 
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For all participants submission of FFPE tumor samples (blocks or 15 unstained slides [10 
minimum] of 5 micron thickness on positively charged slides) will be required. Collected 
samples will be sent to the sponsor designated laboratories for assessment of biomarkers. 
An optional de novo tumor biopsy may be collected at the EOT visit only for participants 
who discontinue treatment due to disease progression and when, in the investigator’s 
judgment, such biopsy is feasible and can be safely performed. The EOT tumor tissue will be 
used to determine possible mechanisms of resistance. Tissue samples from all participants 
will be used for additional biomarker analyses.
8.7.2. Blood Samples
The peripheral blood and derivatives may be used to characterize potential correlations of 
tumor molecular profile and ctDNA level with response to study treatment and to understand 
potential mechanisms of acquired resistance to study treatment. Assessment of the 
relationship between ctDNA burden and outcome is a secondary objective of this study. 
Additional analyses may be warranted based on emerging data.
Two 10 mL whole blood samples (one 10 mL sample for China) optimized for plasma 
preparation for ctDNA analysis will be collected pre-dose at each time point as per Table 2.  
DNA samples will be analyzed for the purpose of tumor molecular profile and the assessment 
of quantitative changes in plasma ctDNA following treatment with ARV-471.
C1D1 samples may also be used for the development of companion diagnostics, if needed.
For China the ctDNA sample collected during the pre-screening period may be also used for 
tumor molecular profile/ctDNA level and ctDNA burden if the participants are randomized in 
the trial.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
PRO assessments will be administered to evaluate the impact on quality of life, functioning, 
symptoms, and general health status using the Dimension Health State EuroQoL Score (EQ-
5D-5L) and EORTC QoL questionnaires (QLQ-C30 and QLQ-BR23 (female and male 
questionnaire versions) and BPI-SF. The mBPI-SF (worst pain severity [item 3] and pain 
interference [item 9a]), and pain medication usage (Arm A and Arm B) and injection site 
pain (Arm B only) will also be captured using an evening daily diary (Table 2). Preference 
for route of administration (Arm A and Arm B) will be evaluated using a patient preference 
questionnaire.
Self-assessment questionnaires (EQ-5D-5L, QLQ-C30, QLQ-BR23, BPI-SF and patient 
preference questionnaire) should be completed by the participants before any other study 
activities or medical procedures as per Table 2.
Refer to Appendix 14 for further information on the PRO assessments administered. 
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9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
The study will perform the statistical hypotheses tests for primary endpoint (PFS) and the key 
secondary endpoint (OS) in two participant populations: 1) all randomized participants, and 
2) participants with ESR1 mutation.
9.1. Statistical Hypotheses
PFS assessed by BICR as per RECIST v1.1 will be the primary endpoint for the study. 
The study is designed to test the null hypothesis vs. the alternative hypothesis for PFS noted 
below in each of the two participant populations: 1) all randomized participants, and 2) 
participants with ESR1 mutation. The following statistical hypotheses will be tested to 
address the primary objective: 
H0 all participants: HRPFS ≥ 1 vs H1 all participants: HRPFS < 1 
H0 ESR1 mutant participants: HRPFS ≥ 1 vs H1 ESR1 mutant participants: HRPFS < 1 
where HRPFS is the hazard ratio (ARV-471 vs fulvestrant) of PFS.
As the key secondary endpoint, the study is also designed to test the null hypothesis vs the 
alternative for OS noted below in each of the two participant populations: 1) all randomized 
participants, and 2) participants with ESR1 mutation. 
The following statistical hypotheses will be tested to address this key secondary objective for 
OS:
H0 all participants: HROS ≥ 1 vs H1 all participants: HROS < 1 
H0 ESR1 mutant participants: HROS ≥ 1 vs H1 ESR1 mutant participants: HROS < 1 
where HROS is the hazard ratio (ARV-471 vs fulvestrant) of OS.
Evaluation of treatment effect in participants without ESR1 mutation: 
The study is not designed for a formal hypothesis testing in participants without ESR1 
mutation. However, to address emerging evidence of differential efficacy of SERDs in ESR1 
mutation positive vs ESR1 mutation negative participants, a minimum efficacy effect is pre-
specified following Rothmann criteria for the subgroup of participants ESR1 mutation 
negative (McShane et al, 2023). Specifically, the minimum effect size of PFS is set to be HR 
≤ 0.789, which is the critical HR boundary of the hypothesis testing for all participants 
population with 3/4 α level and 310 PFS events. 
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9.1.1. Estimands
9.1.1.1. Primary Estimand/Coprimary Estimands
The primary estimand of this study is based on a hypothetical strategy, which estimates the
treatment effect if participants maintain their randomized treatment and adhere to the 
protocol. The estimand is defined according to the primary objective and is in alignment with 
the primary endpoint. 
Treatment: ARV-471 vs fulvestrant
Population: Participants with ER(+)/HER2(-) advanced breast cancer who have progressed 
after prior endocrine-based treatment(s) for their advanced disease, in 1) all randomized 
participants, and 2) randomized participants with ESR1 mutation.  
Variable: BICR-assessed PFS defined as the time after randomization to the first 
documentation of objective PD per RECIST v1.1, or death due to any cause, whichever 
occurs first.
Intercurrent events: PFS data will be censored on the date of the last adequate tumor 
assessment for participants with the following intercurrent events
o
Discontinue the study treatment due to withdrawal of consent prior to an event
o
Start a new anti-cancer therapy prior to an event
o
Have an event after an unacceptably long interval (2 or more missing, incomplete 
or non-evaluable assessments)
o
Lost to follow-up
Population-level summary: A stratified log-rank test will be used to compare PFS between 
the two treatment arms. HR for PFS with the corresponding 2-sided 95% CI will be 
calculated based on Cox’s proportional hazard model. PFS time associated with each 
treatment arm will be summarized using the Kaplan-Meier method and median PFS time 
with the corresponding 2-sided 95% CI will be reported. 
9.1.1.2. Secondary Estimands
The key secondary estimand of this study is defined according to the secondary objective for 
OS and is in alignment with the secondary endpoint OS. This secondary estimand is based on 
a treatment policy strategy, which estimates the treatment difference regardless of whether an 
intercurrent event occurs. 
Treatment: ARV-471 vs fulvestrant 
Population: Participants with ER(+)/HER2(-) advanced breast cancer who have progressed 
after prior endocrine-based treatment(s) for their advanced disease in 1) all randomized 
participants, and 2) randomized participants with ESR1 mutation. 
Variable: OS defined as the time from the date of randomization until the date of death due 
to any cause. Survival status is expected to be collected irrespective of study treatment 
discontinuation or participant’s request to discontinue study procedures.  All participants who 
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have not withdrawn consent for further participation in the study should be followed for 
survival until the end of the study.
Intercurrent events: All data will be used regardless of the occurrence of intercurrent events 
(discontinuation of study treatment, use of subsequent treatments, discontinuation of study, 
etc.)
Population-level summary: A stratified log-rank test will be used to compare OS between 
the two treatment arms. HR for OS with the corresponding 2-sided 95% CI will be calculated 
based on Cox’s proportional hazard model. OS time associated with each treatment arm will 
be summarized using the Kaplan-Meier method and median OS time with the corresponding 
2-sided 95% CI will be reported.  
9.1.2. Multiplicity Adjustment
The study will perform the following statistical hypotheses tests. 
Primary endpoint family: 
H0 all participants: HRPFS ≥ 1 vs H1 all participants: HRPFS < 1 
H0 ESR1 mutant participants: HRPFS ≥ 1 vs H1 ESR1 mutant participants: HRPFS < 1 
And secondary endpoint family:
H0 all participants: HROS ≥ 1 vs H1 all participants: HROS < 1 
H0 ESR1 mutant participants: HROS ≥ 1 vs H1 ESR1 mutant participants: HROS < 1 
The four null hypotheses are denoted by H1 through H4 and are grouped into two families 
(primary efficacy endpoint PFS and key secondary efficacy endpoint OS). The null 
hypotheses H1 and H3 correspond to the comparisons in ESR1 mutant population, while H2 
and H4 correspond to the comparisons in ITT population. 
ESR1 mut
ITT
PFS family
H1
H2
OS family
H3
H4
To control the family-wise type I error rate within 0.025 (1-sided) at the whole study level, a 
graphical multiple testing strategy will be used. Specifically, 3/4 α (0.01875) is allocated for 
PFS endpoint family to test superiority of PFS by BICR and 1/4 α (0.00625) is allocated for 
OS endpoint family to test superiority of OS (see Figure 1). 
Within each endpoint family, a gate keeping procedure will be applied in which the ESR1 
mutation positive population will be tested first. If positive, the ITT population will then be 
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tested. The significance level for PFS family is 3/4 α (0.01875). The significance level for 
OS family depends on the results from the PFS family. If the PFS tests are positive in both 
testing populations, 3/4 α used for PFS testing will be reallocated to OS endpoint family and 
OS can be tested with full α (0.025). Otherwise, only the original allocated 1/4 α (0.00625) 
will be used for OS test. 
Figure 1.
Statistical hypothesis testing strategy
Note: value 1 in the figure between the hypotheses (circles) represent the full amount of alpha to be passed from 
one hypothesis test to the next when the hypothesis test is positive.
No interim analysis is planned for the primary endpoint PFS. 
Two interim analyses for efficacy are planned for the key secondary endpoint of OS in each 
co-primary population: ESR1 mutant subgroup and all participants population.  The Lan-
DeMets/O’Brien-Fleming boundary will be used to control alpha spending for the second OS 
interim analyses in both populations.  See Section 9.4 Interim Analysis.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined.
Participant Analysis Set
Description
Enrolled 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and 
randomization to study intervention.
Full Analysis Set 
All enrolled participants who were randomized. Participants are 
analyzed according to the treatment they have been randomized to 
receive.
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Participant Analysis Set
Description
Safety Analysis Set 
(SAS)
All randomized participants who receive at least 1 dose of study 
intervention.  
PK Concentration Set
All participants who are in the Safety Analysis Set and have at least 1 
concentration of either ARV-471 or ARV-473.
QTc Analysis Set
A subset of SAS participants in Arm A, who are randomized at 
selected sites and have ECG measurements to evaluate the effect of 
ARV-471 on QT interval via triplicate ECGs, must have baseline ECG 
measurement (Cycle 1 Day 1 pre-dose) and at least one ECG 
measurement on Day 1 of Cycle 2 or Cycle 3.
Biomarker Analysis 
Set(s)
Biomarker analysis population is defined as all randomized
participants with at least 1 of the Biomarkers evaluated at pre and/or 
post dose.
PRO Analysis Set
The PRO analysis set will include all participants in the full analysis 
set who completed a baseline (PRO assessment prior to or on first dose 
of study treatment) and at least one post-baseline PRO assessment.
9.3. Statistical Analyses
The SAP will be developed and finalized before any formal statistical analyses are performed 
and will describe the analyses and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints.
9.3.1. General Considerations
All efficacy analyses will be performed using the FAS, and all safety analyses will be 
performed using the SAS. Statistical analyses will be performed in each of the two 
populations: 1) all randomized participants, and 2) participants with ESR1 mutation. 
In general, descriptive summaries will be presented for the efficacy and safety variables 
collected. Continuous variables will be summarized using mean, standard deviation, 
minimum, median, and maximum. Categorical variables will be summarized using frequency 
counts and percentages. 
All primary and secondary endpoints based on radiological assessments of tumor burden (ie, 
PFS, OR, DOR, CBR) will be based on BICR assessments as per RECIST v1.1. 
Tumor assessments based on programmatically derived version of local radiologist’s 
/investigator’s assessment (target lesion measurements, non-target lesion status, and new 
lesion status recorded on the CRF) will be used as sensitivity analyses to support the primary 
analyses.
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis
The primary endpoint is - PFS assessed by BICR which is defined as the time from the date 
of randomization to the date of the first documentation of objective PD per RECIST v1.1, or 
death due to any cause, whichever occurs first, in each of the two populations: 1) all
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randomized participants, and 2) participants with ESR1 mutation. The final PFS analyses will 
be performed when the required number of events are reached in both testing populations. 
PFS will be calculated in months as: 
PFS (months) = (date of event or censoring– randomization date +1) / 30.4375 
PFS will be censored on the date of the last adequate disease assessment for participants who 
do not have an event (PD per RECIST v1.1 or death due to any cause), before the new 
anticancer therapy for participants who start a new anticancer therapy prior to an event, or 
before the gap for participants with an event after a gap of 2 or more missing disease 
assessments. Participants who do not have an adequate post-baseline disease assessment will 
be censored on the date of randomization unless death occurs on or before the time of the 
second planned disease assessment (ie, ≤18 weeks after the date of randomization) in which 
case the death will be considered an event. 
The treatment effect HR will be estimated using a Cox’s proportional hazard model stratified 
by randomization strata to calculate the hazard ratio for PFS, along with the 95% 
corresponding 2-sided CI. 
PFS time will be estimated using the Kaplan-Meier method and displayed graphically by 
treatment arm. The median PFS and associated 95% CIs will be presented by treatment arm. 
Per regulatory request, a supplemental analysis will be performed based on a treatment policy 
strategy, which estimates the treatment difference regardless of whether an intercurrent event 
occurs. In this supplemental analysis, any PD or deaths captured in the study will be counted 
as PFS events regardless of protocol violations, discontinuation of study treatments, or 
receiving new anti-cancer therapies. The details of the analysis will be specified in SAP. 
Sensitivity analyses for PFS (including PFS assessed by investigators) will be specified in the 
SAP. 
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis
9.3.3.1. Key Secondary Efficacy Endpoint
OS is the key secondary endpoint. The study is also designed to perform the hypothesis 
testing to demonstrate that ARV-471 is superior to fulvestrant in prolonging OS in 
participants with ER(+)/HER2(-) advanced breast cancer whose disease has progressed on 
prior endocrine treatment(s) in each of the two populations: 1) all randomized participants, 
and 2) participants with ESR1 mutation. The final OS analyses will be performed when the 
required number of events are reached in both testing populations.
OS is defined as the time from date of randomization to date of death due to any cause. OS 
will be calculated in months as: 
OS (months) = [date of death or censoring – date of randomization +1] / 30.4375 
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For participants without documented death, OS time will be censored on the date last known 
to be alive. 
The treatment effect HR will be estimated using a Cox’s proportional hazard model stratified 
by randomization strata to calculate the hazard ratio for OS, along with the 95% 
corresponding 2-sided CI and RCI. 
OS time will be estimated using the Kaplan-Meier method and displayed graphically by 
treatment arm. The median OS and associated 95% CIs will be presented by treatment arm.
Sensitivity analyses for OS will be specified in the SAP.
9.3.3.2. Other Secondary Endpoints
9.3.3.2.1. ORR/DOR/CBR
ORR is defined as the proportion of participants in the FAS reaching a confirmed CR or PR  
by BICR assessment as per RECIST v1.1 criteria. Point estimates of ORR will be calculated 
along with the 2-sided exact 95% CIs using the Wilson Score method. The odds ratio and the 
corresponding 2-sided 95% confidence interval will be calculated to contrast the treatment 
effects on response rates. A Pearson test (un-stratified) and CMH test stratified by 
randomization stratification factors will be used to compare ORR between the two arms. 
ORR will be summarized in each of the two populations: 1) all randomized participants, and 
2) participants with ESR1 mutation. 
DOR will be summarized using the Kaplan-Meier methods and displayed graphically where 
appropriate. DOR will be calculated for the subgroup of participants with objective tumor 
response (CR/PR) by BICR assessment. The median event time and 2-sided 95% confidence 
interval for the median will be provided. DOR analyses will be performed in each of the two 
populations: 1) all randomized participants, and 2) participants with ESR1 mutation. 
CBR: CBR is defined as confirmed CR or PR at any time, or SD/Non-CR/Non-PD (for 
participants with non-measurable disease) ≥24 weeks according to the RECIST version 1.1 
recorded in the time period between randomization and disease progression by BICR 
assessment, or death of any cause, whichever occurs first. The number and proportion of 
participants achieving clinical benefit response (confirmed CR or PR at any time, or SD/Non-
CR/Non-PD ≥24 weeks) will be summarized in the FAS population along with the 
corresponding 2-sided 95% confidence interval calculated using the Wilson score method. 
The odds ratio and the corresponding 2-sided 95% confidence interval will be calculated to 
contrast the treatment effects on CBR rates. A Pearson test (unstratified) and CMH test 
stratified by randomization stratification factors will be used to compare CBR rate between 
the treatment arms. CBR analyses will be performed in each of the two populations: 1) all 
randomized participants, and 2) participants with ESR1 mutation.
9.3.3.2.2. Pharmacokinetic Analysis
Plasma concentration data of ARV-471 and ARV-473 will be listed, summarized, and plotted 
for all participants in the PK concentration set as defined in Section 9.2. For summary 
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statistics and mean/median plots by collection time/day, the nominal PK sample collection 
time/day will be used; for individual participant listing by time/day, the actual PK collection 
time/day will be used. PK sampling deviations from the protocol-specified collection 
time/day will be listed.
PK data from participants in the Arm A QTc sub-study will be analyzed separately according 
to the method described above. 
Population pharmacokinetic analysis of samples collected in this study will be performed in 
accordance with the FDA guidance on Population Pharmacokinetics (FDA, 2022).  The PK 
concentration data set from this study may be pooled with datasets from other ARV-471 
clinical studies.  In addition, population PK/PD modeling will be attempted to investigate any 
causal relationship between ARV-471 and/or ARV-473 exposure and biomarker, safety, 
efficacy, and/or laboratory data. These modeling analyses will be reported separately from 
the final Clinical Study Report.
9.3.3.2.3. PRO data analyses
The following patient reported outcome measurements will be collected in this study: 
EORTC QLQ-C30, EORTC QLQ-BR23 (female and male questionnaire versions), EQ-5D-
5L, and BPI-SF. The mBPI-SF (worst pain severity [item 3] and pain interference [item 9a]), 
pain medication usage and patient preference questionnaire (Arm A and Arm B) and 
injection site pain (Arm B only) will be captured as well. The analysis of the patient 
preference questionnaire and evening daily diary will be described in a separate SAP. 
For each of the four measurements (EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L, 
and BPI-SF), mean scores at each assessment time point and change from baseline scores 
will be compared between the treatment arms at various time points using a MMRM 
approach adjusting for specified covariates. In addition, analyses will be performed to 
determine if the change from baseline scores achieves the appropriate clinically meaningful 
threshold for the scale being examined. Participants who completed a baseline assessment 
and at least one post baseline assessment will be considered evaluable for the change from 
baseline analysis. In addition to the above analyses, an examination of the TTD also will be 
carried out using survival analysis methods. Deterioration will be defined based on clinically 
meaningful threshold. For the EORTC QLQ-BR23, female and male questionnaires will be 
analyzed separately. 
9.3.3.2.4. ctDNA analysis
Analysis summaries of baseline levels, changes from baseline (where appropriate), and their 
association with efficacy outcome will be reported. 
9.3.3.2.5. Safety analysis
All safety analyses will be performed on the SAS. Summaries of AEs and other safety 
parameters will be provided as appropriate. 
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9.3.3.2.5.1. Adverse Events
AEs will be coded using the medical dictionary for regulatory activities (MedDRA) 
classification system.  The severity of the toxicities will be graded according to the NCI 
CTCAE v5.0 whenever possible.  AE data will be reported in tables and listings.  Summaries 
of AE by appropriate MedDRA terms, toxicity grade, and seriousness and relationship to 
study treatment will be presented, as well as summaries of AEs leading to death and 
premature withdrawal from study treatment.  The number and percentage of participants who 
experienced any AE, SAE, treatment related AE, and treatment related SAE will be 
summarized according to worst toxicity grades.  The summaries will present AEs on the 
entire study period.
9.3.3.2.5.2. Laboratory Test Abnormalities
The number and percentage of participants who experienced laboratory test abnormalities 
will be summarized according to worst toxicity grade observed for each laboratory assay.  
The analyses will summarize laboratory tests on the entire study period.  For laboratory tests 
without CTCAE grade definitions, results will be categorized as normal, abnormal, or not 
done. 
9.3.3.2.5.3. Summary and Categorical Analysis of ECG 
All participants in the safety analysis set with baseline and on-treatment ECG data will be 
included in the ECG summary and analysis.  The triplicate data will be averaged, and all 
summary statistics and data presentations will use the triplicate averaged data. Any data 
obtained from ECGs repeated for safety reasons after the nominal time-points will not be 
averaged along with the preceding triplicates. 
Individual change in QTcF (and QTcS, as appropriate) will be calculated for each nominal 
time point. These individual changes will be summarized using descriptive statistics.
Categorical analysis of the ECG data will be conducted and summarized as follows:
1. The number and percentage of participants with maximum increase from baseline 
in the QTc (<30, 30-60, and >60 ms).
2. The number of and percentage participants with maximum post-dose QTc (<450, 
450-<480, 480- <501, and ≥501 ms).
3. PR changes from baseline ≥50% if absolute baseline value was <200 ms, and 
≥25% if absolute baseline value was >200 ms.
4. QRS changes from baseline ≥50% if absolute baseline value was <100 ms, and 
≥25% if absolute baseline value was >100 ms.
Central tendency of the effect of ARV-471 on the QT/QTc interval will be summarized by 
the mean (90% CI) change from baseline at each timepoint. 
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ECG measurements scheduled as per protocol (an average of the triplicate measurements) 
will be used for the statistical analysis and all data presentations.  Interval measurements 
from repeated ECGs will be included in the outlier analysis (categorical analysis) as 
individual values obtained at unscheduled time points.
The analyses described above will be repeated separately for the QTc Analysis Set using 
centrally-read ECG data.  
9.3.3.2.5.3.1. Electrocardiogram Analyses for QTc Analysis Set
Centrally-read QT measurements corrected by heart rate (QTc) will be used for the data 
analysis and interpretation and Fridericia’s (QTcF) method will be used for the primary 
analysis. In addition, a study specific correction method (QTcS) may be used for the 
exploratory analysis.
At each ECG measurement time point, a total of 60 evaluable participants is estimated to 
provide an upper limit of 90% confidence interval of 8 msec for a mean increase of 5 msec, 
or 10 msec for a mean increase of 7 msec in from baseline QTcF, based on an estimated 
standard deviation of 14 msec for the change in QTcF from Study ARV-471-mBC-101. 
Approximately 80 participants will be enrolled to ensure at least 60 participants are evaluable 
for the QTc analysis.
The changes in QTcF (and QTcS, as appropriate) on Day 1 of Cycle 2 and Cycle 3 from 
baseline will be summarized using descriptive statistics and categorical analysis by each time 
point.
9.3.3.2.5.3.2. Pharmacokinetic/Pharmacodynamic Analysis of QTc
Concentration-QTc analysis will be conducted using PK- matched ECG data from the Safety 
Analysis Set. Linear, log-linear, and/or saturable models will be examined for the 
concentration-QTc relationship. Exploratory analyses (via graphical displays and/or model 
fitting) include accounting for a delayed effect and the justification for the choice of 
pharmacodynamic model. Diagnostic evaluation will be included to explore the adequacy of 
the model. Refer to SAP for details of the analysis. The modeling analyses may be reported 
separately from the clinical study report. 
9.3.4. Other Analysis
Retained Research Samples may be collected as per Table 2 and retained for future analyses.
The results of such analyses are not planned to be included in the CSR.
9.3.5. Exploratory Analysis
9.3.5.1. Biomarker Analyses
Biomarker data, including but not limited to DNA, RNA, and protein from analyses of tumor 
tissues and/or blood samples will be analyzed. Analysis summaries of baseline levels, 
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changes from baseline (where appropriate), and mutation status will be reported. For 
continuous variables, summary statistics may include, but not limited to the mean, standard 
deviation, median, 25th and 75th quartile, minimum and maximum levels of biomarker 
measures; for categorical variables, summary may include number and percentage, odds ratio 
as appropriate. Exploratory graphical methods and statistical methods such as, but not limited 
to linear regression, t-test, and ANOVA may be used to investigate any possible relationship 
of biomarker levels and status and/or changes from baseline with ARV-471 anti-tumor 
efficacy and other clinical outcomes. Results of such analyses may not be included in the 
CSR. 
9.4. Interim Analysis 
No interim analysis is planned for the primary endpoint PFS. 
Two interim analyses for efficacy are planned for the key secondary endpoint of OS. 
The first OS interim analysis (IA1) will be performed at the time of the final PFS analysis for 
both co-primary populations. This is anticipated to occur approximately 18 months after the 
first participant is randomized into the study with approximately 49 and 107 deaths in ESR1 
mutant and all participants population, respectively. OS will be tested in ESR1 mutant 
subgroup first with the allocated alpha (plus passed alpha from PFS testing per testing 
procedure if applicable) under group sequential trial design consideration with Lan-
DeMets/O’Brien-Flemming boundary (O’Brien & Fleming, 1979). OS will be formally 
tested in all participants population only if OS testing in ESR1 mutant subgroup is positive.
Otherwise, an administrative alpha spending (0.0000001) will be spent for OS IA1 analysis 
among all participants due to unblinded descriptive analyses and the study will proceed to the 
second OS interim analysis.
The second OS interim analysis (IA2) will be performed at 130 deaths in ESR1 mutant 
subgroup (approximately 67% of total 194 events required for the final analysis). This is 
anticipated to occur approximately 38 months after the first participant is randomized into the 
study. Following the same alpha spending principle as described in IA1, if OS IA2 is positive 
for ESR1 mutant subgroup, OS will be formally tested among all participants population per 
pre-specified testing procedure with available deaths events at the time (for example, 
approximately 265 deaths). Otherwise, OS for ITT will not be formally tested at IA2 and the 
study proceeds to the OS final analysis (396 events).
The analysis details will be documented and approved in the SAP. 
Before any interim analysis is performed, the details of the objectives, decision criteria, 
dissemination plan, and method of maintaining the study blinding (if applicable) as per 
Pfizer’s SOPs will be documented and approved in a(n) DMC charter.  In addition, the 
analysis details will be documented and approved in the SAP.
9.5. Sample Size Determination
This is an international Phase 3 multicenter, randomized, open label, parallel-group study.
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The study is designed to test the null hypothesis vs. the alternative hypothesis noted below in 
each of the two participant populations: 1) all randomized participants, and 2) participants 
with ESR1 mutation. The following statistical hypotheses will be tested to address the 
primary objective:  
H0 all participants: HRPFS ≥ 1 vs H1 all participants: HRPFS < 1 
H0 ESR1 mutant participants: HRPFS ≥ 1 vs H1 ESR1 mutant participants: HRPFS < 1 
For all participant population, approximately 560 participants (including approximately 280 
ESR1 mutant participants) will be randomly assigned on a 1:1 basis to:
・Arm A: ARV-471, Investigational Arm – n ≈ 280 or
・Arm B: fulvestrant Comparator Arm – n ≈ 280
Participants will be stratified by ESR1 mutational status (Mutant, Yes/No) and visceral 
disease (Yes/No). 
The 1-sided α level of 1.875% was used for sample size calculation according to statistical 
hypothesis testing strategy. 
For PFS in all participants population, based on a 1:1 randomization allocation ratio, a total 
of 310 PFS events will provide 92.5% power for a 1-sided log-rank test at a 0.01875  
significance level to detect a HR < 0.67. For PFS in participants with ESR1 mutation, a total 
of 165 PFS events will provide 88% power for a 1-sided log-rank test at a 0.01875 
significance level to detect a HR<0.60.  It is estimated that approximately 560 participants 
will be needed to observe the 310 PFS events in all participants population, and out of which, 
approximately 280 ESR1 mutant participants are required to observe 165 PFS events in the 
subgroup population. 
For OS, approximately 396 death events will provide 80% power for a 1-sided log-rank test 
at 0.025 significance level to detect a HR < 0.75 in all participants population; and 194 death 
events in ESR1 mutant population provides 80% power to test a HR <0.667 in ESR1 mutant
population. 
The sample size calculation is based on the following assumptions:

The median PFS and OS for participants receiving fulvestrant are 4 months and 25 
months, respectively. 

The median PFS for participants receiving ARV-471 is 6 months in overall 
randomized population, which corresponds to a HR of 0.67 under an exponential 
assumption; and the median PFS is 6.7 months in ESR1 mutant population, which 
corresponds to a HR of 0.60 under an exponential assumption.  

The median OS for participants receiving ARV-471 is 33.2 months in overall 
randomized population, which corresponds to a HR 0.75 under an exponential 
assumption; and the median OS is 37.5 months in ESR1 mutant population, which 
corresponds to a HR of 0.67 under an exponential assumption. 

Participant dropout rate of 10% in each arm by the 20th month for PFS. 

Participant dropout rate of 10% in each arm by the 40th month for OS.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP Guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:

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;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory 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.
10.1.3. Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative 
and answer all questions regarding the study.  The participant or their legally authorized 
representative should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative (if allowed by local regulations) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, privacy and data protection requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant or their legally authorized 
representative, is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant or their legally authorized representative, must be informed that their 
personal study-related data will be used by the sponsor in accordance with local data 
protection law.  The level of disclosure must also be explained to the participant or their 
legally authorized representative.
The participant or their legally authorized representative, must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or their legally authorized 
representative, is fully informed about his or her right to access and correct their personal 
data and to withdraw consent for the processing of his or her personal data .
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The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICD.
Participants or their legally authorized representative, must be reconsented to the most 
current IRB/EC version of the IRB/EC-approved ICD(s) during their participation in the 
study as required per local regulations.
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations).
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
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.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
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10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will use an External Data Monitoring Committee (E-DMC). The E-DMC is 
independent of the study team and includes only external members. The E-DMC charter 
describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. The recommendations made by the E-DMC will be forwarded 
to the appropriate authorized Pfizer personnel for review and final decision. Pfizer will 
communicate such decisions, which may include summaries of aggregate analyses of safety 
data, to regulatory authorities and investigators, as appropriate. 
10.1.5.2. Steering Committee
A Global Steering Committee will be established at the program level for ARV-471. It will 
be responsible for providing scientific advice and medical input on the ongoing and future 
clinical development plans for ARV-471 in ER(+) breast cancer, including for this study.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements following the end 
of the study globally.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
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are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents. 
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
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Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source document and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor. 
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The investigator must maintain accurate documentation (source record) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Use of Medical Records
In certain situations, sponsor review of redacted copies of participant medical records for 
very complex cases (eg, including radiographic testing results or a hospital discharge report 
to better assess some adverse events, etc) may be performed, where ethically and 
scientifically justified and permitted by local regulations, to ensure participant safety.
Due to the potential for a participant to be re-identified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:

The investigator or site staff must redact personal information from the medical 
record. The personal information includes, but is not limited to, the following: 
participant names or initials, participant dates (eg, birth date, date of hospital 
admission/discharge, date of death), participant identification numbers (eg, Social 
Security number, health insurance number, medical record number, 
hospital/institution identifier), participant location information (eg, street address, 
city, country, postal code, IP address), participant contact information (eg, 
telephone/fax number, email address).

Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection 
of personal data (eg, Florence is the preferred system if available).

There may be unplanned situations where the sponsor may request medical records 
(eg, sharing medical records so that the sponsor can provide study-related advice to 
the investigator). The medical records should be submitted according to the procedure 
described above.
10.1.10. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
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The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the investigator; 

Discontinuation of further study intervention development;

Negative benefit/risk assessment.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.11. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
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confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results.  For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. The results of this study may be published or presented at 
scientific meetings by the investigator after publication of the overall study results or 1 year 
after the end of the study (or study termination), whichever comes first.  
10.1.12. Sponsor’s Medically Qualified Individual 
The sponsor will designate a medically qualified individual (MQI, also known as the medical 
monitor) to advise the investigator on study-related medical questions. The contact 
information for the study medical monitor is documented in the Study Team Contact List 
located in the Investigator Site File or equivalent.
Participants are provided with a Pfizer study information card at the time of informed consent 
which includes contact information for their investigator in case of study-related medical 
questions. The study information card contains, at a minimum, (a) study number, (b) 
participant’s study identification number, and (c) principal investigator contact information.
10.1.13. Transfer of Obligations Statement
Arvinas Estrogen Receptor, Inc. (“Arvinas”) and Pfizer entered into a collaboration 
agreement dated as of 21 July 2021 to co-develop the compound ARV-471.
 
 
 
 
 
 
 
 
 
For the purposes of this protocol, sponsor refers to Pfizer.
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in  Table 2 and 
Table 3.  
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2, respectively.
Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory, or as derived from calculated 
values.  These additional tests would not require additional collection of blood.  Unscheduled 
clinical laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
Please refer to Table 2 and Table 3 for the frequency of each assessment.
Laboratory assessments
Hematology
Hemoglobin
Platelets 
WBC 
Absolute Neutrophils (or % as per local practice)
Chemistry
ALT
AST
Alkaline Phosphatase
Sodium
Potassium
Magnesium
Total Calcium
Total Bilirubina
BUN or Urea 
Serum Creatinine  
eGFR as per 2021 CKD-EPI Equations (at screening only for eligibility)
Albumin
HbA1C (fasting)
Glucose (fasting)
Triglycerides (fasting)
Cholesterol (Total Cholesterol, LDL, HDL) (fasting)
Coagulation (only at screening)
aPTT
INR
PT
Additional Test 
FSH test (at screening only) to confirm a postmenopausal status of female participants under the age of 60 and with 
cessation of regular menses for 12 consecutive months and with no alternative medical cause.
Other Tests
HBV, HCV and HIV at screening only if required by local regulations
Pregnancy Test
For WOCBP participants only. Serum pregnancy test (at screening). Following screening pregnancy tests 
(urine or serum) must have sensitivity of least 25 mIU/mL. 
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Laboratory assessments
a
For Hy’s law potential cases, in addition to repeating AST and ALT, laboratory tests should include albumin, 
creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time /INR, and 
alkaline phosphatase. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.   
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal test results that 
meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms;

Requires additional diagnostic testing or medical/surgical intervention;

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Worsening of signs and symptoms of the malignancy under study should be 
recorded as AEs in the appropriate section of the CRF.  Disease progression 
assessed by measurement of malignant lesions on radiographs or other methods 
should not be reported as AEs.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic  
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within 
the active collection period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal 
outcome during the study, the event leading to death must be recorded as an AE on 
the CRF, and as an SAE with CTCAE Grade 5 (see the Assessment of Intensity
section) if it occurs during the active collection period.
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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the CT SAE Report Form or via PSSA to Pfizer Safety throughout 
the active collection period. These requirements are delineated for 3 types of events: (1) 
SAEs; (2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form/PSSA for reporting of SAE information 
is not the same as the AE page of the CRF. When the same data are collected, the forms 
must be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form/PSSA for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form/PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure to 
the product under study to 
a nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
nonparticipant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated SAE) using the CT SAE Report Form and EDP Supplemental 
Form or PSSA; 
** EDB is reported to Pfizer Safety using the CT SAE Report Form or PSSA, which would also 
include details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form or PSSA. 
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
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions that 
must be taken when medical records are sent to the sponsor or sponsor designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the categories listed below (as defined by the 
NCI CTCAE system).  
GRADE
Clinical Description of Intensity
1
MILD AE
2
MODERATE AE
3
SEVERE AE
4
LIFE-THREATENING; urgent intervention indicated
5
DEATH RELATED TO AE
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
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
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.

The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form/PSSA and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or 
to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria

Arm A: 
Male participants are eligible to participate if they agree to the following requirements 
during the intervention period and for at least 30 days after the last dose of study 
intervention, which corresponds to the time needed to eliminate reproductive safety risk 
of the study intervention(s): 

Refrain from donating sperm.
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom 
may break or leak when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant.

Arm B:
o
Refer to the Faslodex EU SmPC for fulvestrant contraception requirements. 
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion No. 1 (Age and Sex; Section 5.1) and 
specify the reproductive requirements for including female participants.  Refer to 
Section 10.4.4 for a complete list of contraceptive methods permitted in the study. 
A female participant is eligible to participate if she (a) is not pregnant or breastfeeding; and 
(b) at least 1 of the following conditions applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Arm A: 
o
Is WOCBP who agrees to use a highly effective contraceptive method
(failure rate of <1% per year), with low user dependency during the 
intervention period and for at least 30 days after the last dose of ARV-471, 
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which corresponds to the time needed to eliminate any reproductive safety 
risk of the study intervention. 
OR
o
Is WOCBP who agrees to use a highly effective (failure rate of <1% per 
year) user-dependent method of contraception during the intervention 
period and for at least 30 days after the last dose of study ARV-471, which 
corresponds to the time needed to eliminate any reproductive safety risk of 
the study intervention. 

Arm B: Refer to the Faslodex EU SmPC for fulvestrant contraception 
requirements.
The investigator should evaluate the effectiveness of the contraceptive method in relationship 
to the first dose of study intervention.
The investigator is responsible for reviewing the woman’s medical history, menstrual history, 
and recent sexual activity in order to decrease the risk of enrolling a woman with an early, 
undetected pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea or oligomenorrhea) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied 
to determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview.  The method of documentation should be recorded in the participant’s medical 
record for the study.
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2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 consecutive months 
without an alternative medical cause.  In addition, 

A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age with no alternative 
physiological (this includes drugs) or pathological cause. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. IUD. Hormone based IUD are NOT allowed
2. Bilateral tubal occlusion. (eg, bilateral tubal ligation)
3. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm 
has been confirmed.  If not, an additional highly effective method of 
contraception should be used.  The spermatogenesis cycle is approximately 90 
days.
Highly Effective Methods That Are User-Dependent
Sexual abstinence
4. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis.

The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation.

The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained as indicated:

Retained sample will be stored indefinitely or for another period as per local 
requirements. 

Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses. 

Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site. 
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments and 
Study Intervention Rechallenge Guidelines
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations (>2 × 
ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT is/are 
still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within the same 
laboratory sample). In rare instances, by the time T bili elevations are detected, AST/ALT 
values might have decreased. This occurrence is still regarded as a potential DILI. Therefore, 
abnormal elevations in either AST OR ALT in addition to T bili that meet the criteria outlined 
below are considered potential DILI (assessed per Hy’s law criteria) cases and should always 
be considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.
For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
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Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, eosinophils (%) and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute
hepatitis A, B, C, D, and E infection, total bile acids, liver imaging (eg, biliary tract), and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Kidney Safety Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury 
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat 
measurement to estimate kidney function [Screat-based eGFR] or creatinine clearance 
[eCrCl]). Baseline and postbaseline Scys makes it feasible to distinguish AKI from other 
causes of Screat increase. If Screat increase is confirmed after baseline, then reflex 
measurement of Scys is indicated. Screat and reflex Scys values are needed to estimate the 
combined Screat-Scys eGFR calculation to ascertain whether eGFR change from baseline is 
comparable for 2021 CKD-EPI eGFR Screat-only and for 2021 CKD-EPI eGFR combined 
Screat plus Scys.
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
eGFR  (mL/min/1.73m²)
2021 CKD-
EPI          
Screat Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤0.7
N/A
eGFR = 143 × (Screat/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
N/A
eGFR = 143 × (Screat/0.7)-1.200  ×  (0.9938)Age
Male
if ≤0.9
N/A
eGFR = 142 × (Screat/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
N/A
eGFR = 142 × (Screat/0.9)-1.200  ×  (0.9938)Age
(Inker et al, 2021)
10.7.3. Kidney Function Calculation Tool
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at Screening, Baseline, and post-Baseline visits. Site 
calculations of kidney function can be performed manually, using the age appropriate 
formulae (see Section 10.7.2.) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error. 
The United States National Kidney Foundation Online Calculators. 
•
Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator 
Please note that investigational sites are responsible to ensure that the accurate age-specific 
equation is selected and that the correct units for serum creatinine (mg/dL only), serum 
cystatin C (mg/L only), total body weight (kg only), and age (years). Investigators are 
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expected to (i) review and confirm correctness of the kidney function calculation results and 
(ii) evaluate the calculated value within the context of historical information available to 
them in the participant’s medical record. Investigators are responsible for the clinical 
oversight of the participant eligibility process, kidney function calculation, and dose selection 
and adjustments per study protocol. Investigators are encouraged to direct questions or 
uncertainties regarding kidney function and dosing to the Pfizer Clinical Team and Medical 
Monitor, if needed.
10.7.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to CTCAE 
criteria.
NCI CTCAE 
(2017) Criteria
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Acute Kidney 
Injury (AKI)
N/A
N/A
Hospitalization 
indicated
Life-
threatening 
consequences; 
dialysis 
indicated
Death
AKI:  A disorder characterized by acute loss of kidney function (within 2 weeks) and is traditionally classified 
as pre-renal (low blood flow into kidneys), renal (kidney damage), or post-renal causes (ureteral or bladder 
outflow obstruction.
Creatinine 
increased
>ULN to 1.5 x 
ULN
>1.5 to 3.0 x 
baseline OR 
>1.5 to 3.0 x 
ULN
>3.0 to 6.0 x 
baseline OR 
>3.0 to 6.0 x 
ULN
>6.0 x ULN
N/A
Chronic 
Kidney 
Disease 
(CKD)
eGFR ≥60 to 89 
mmL/min/1.73m² 
eGFR 30 to 59 
mL/min/1.73m² 
eGFR 15 to 29 
mL/min/1.73m² 
eGFR <15 
mL/min/1.73m²  
        OR            
dialysis 
indicated
Death
Proteinuria
Proteinuria 1+ 
OR                
Proteinuria >0.5 
to <1.0 g/24hr
Proteinuria 2+ 
or 3+               
OR                
Proteinuria 1.0 
to <3.5 g/24hr
Proteinuria 4+     
OR                
Proteinuria ≥
3.5 g/24hr
N/A
N/A
CKD: A disorder characterized by gradual and usually permanent loss of kidney function resulting in kidney 
failure.
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline.

New onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New onset type I second degree (Wenckebach) AV block of >30 second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

New STT changes suggestive of myocardial ischemia.

New onset LBBB (QRS complex >120 ms).

New onset right bundle branch block (QRS complex >120 ms).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented 
asystolic pauses ≥3 seconds or any escape rate <40 bpm, or with an escape 
rhythm that is below the AV node; 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more asystolic pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm 
(HR <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), 
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and monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
Torsades de Pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 second duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The major events of potential clinical concern listed above are recommended as “alerts” or notifications from 
the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all-inclusive of 
what is to be reported as AEs/SAEs.
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10.9. Appendix 9: AEs, ADEs, SAEs, SADEs, USADEs, and Device Deficiencies: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting in 
Medical Device Studies
Definitions of a Medical Device Deficiency
The definitions and procedures detailed in this appendix are in accordance with ISO 14155 
and the European MDR 2017/745 for clinical device research (if applicable). 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1.2 for the list of sponsor 
medical devices).
10.9.1. Definition of AE and ADE
AE and ADE Definition 

An AE is defined in Appendix 3 (Section 10.3.1). 

An ADE is defined as an AE related to the use of an investigational medical 
device.  This definition includes any AEs resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device as well as 
any event resulting from use error or from intentional misuse of the 
investigational medical device.
10.9.2. Definition of SAE, SADE, and USADE
SAE Definition

An SAE is defined in Appendix 3 (Section 10.3.2)
SADE Definition

An SADE is defined as an ADE that has resulted in any of the consequences 
characteristic of an SAE.

Any device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less 
fortunate.
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USADE Definition

A USADE (also identified as UADE in US Regulations 21 CFR 813.3) is a 
SADE that by its nature, incidence, severity, or outcome has not been identified 
in the current version of the risk analysis management file.
10.9.3. Definition of Device Deficiency
Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance.  Device 
deficiencies include malfunctions, use errors, and inadequate information 
supplied by the manufacturer.
10.9.4. Recording/Reporting and Follow-up of and Medical Device Deficiencies
Device Deficiency Recording

When a device deficiency occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.

The investigator will then record all relevant device deficiency information in the 
participant’s medical records, in accordance with the investigator’s normal 
clinical practice and will also capture the required information on the Medical 
Device Complaint Form.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of following the reporting process 
described in the Medical Device Complaint form.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions 
that must be taken when medical records are sent to the sponsor or sponsor 
designee.

If the investigator determines that the medical device deficiency may have 
injured the participant (ie, the medical device deficiency is associated with an AE 
or SAE), then the investigator will attempt to establish a diagnosis of the event 
based on signs, symptoms, and/or other clinical information. Whenever possible, 
the diagnosis will be documented in the participant’s medical record and 
recorded as the AE or SAE rather than the individual signs/symptoms. 
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Device Deficiency Recording
Requirements for recording and reporting an AE or SAE are provided in 
Appendix 3 (Section 10.3.3).

For device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing 
of a medical device where such action is necessary to prevent recurrence of a 
device deficiency.  This includes any amendment to the device design to 
prevent recurrence.
Assessment of Causality Occurring in Conjunction With a Medical Device 
Deficiency

If an AE or SAE has occurred in conjunction with a medical device deficiency, 
the investigator must assess the relationship between each occurrence of the AE 
or SAE and the medical device deficiency. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the product information in their assessment.

For each device deficiency, the investigator must document in the medical notes 
that they have reviewed the device deficiency and have provided an assessment 
of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the sponsor.

The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
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Assessment of Causality Occurring in Conjunction With a Medical Device 
Deficiency

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-Up of Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or
SAE/device deficiency as fully as possible.  This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation 
with other healthcare providers.

New or updated information regarding the nature of the device deficiency will be 
recorded in the originally completed Medical Device Complaint form.

New or updated information regarding any SAE that was potentially associated 
with the medical device deficiency will be submitted to Pfizer Safety on the CT 
SAE Report Form/PSSA within 24 hours of receipt of the information, according 
to the requirements provided in Appendix 3.
10.9.5. Reporting of SAEs
Reporting of an SAE to Pfizer Safety must be performed according to the processes 
described in Appendix 3 (Section 10.3.4).
10.9.6. Reporting of SADES
SADE Reporting to Pfizer Safety 
Note: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs (ie, a SADE) that must fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 

Any device deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device deficiency.

The sponsor shall review all device deficiencies and determine and document in 
writing whether they could have led to an SAE.  These shall be reported to the 
regulatory authorities and IRBs/ECs as required by national regulations.
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10.10. Appendix 10: Concomitant Medications That May Result in DDI
10.10.1. CYP3A inhibitors/inducers.  
The concurrent use of the following medications, food or herb supplements is prohibited 
throughout the duration of the active treatment phase.

ARV-471: CYP3A accounted for 85% of the CYP metabolism of ARV-471 based on 
in vitro data. Co-administration with drugs that are strong CYP3A inhibitors and 
inducers may change the plasma concentrations of ARV-471 in humans.  

Fulvestrant: No DDI is expected by the concomitant use with fulvestrant. Refer to 
Faslodex EU SmPC. 
Prior use of medications, food or herb supplements that are strong inhibitors of CYP3A must 
be stopped 7 days before randomization. Strong inducers of CYP3A must be stopped 14 days 
before randomization. 
Examples of prohibited concomitant medications are provided below. 
This is not an all-inclusive list (examples including, but not limited to the drugs 
provided below).
Site staff should consult with the sponsor or designee with any questions regarding potential 
DDI. 
Investigators should consult the product prescribing information for any other medication 
used throughout the duration of the active treatment phase for information regarding 
medication that is prohibited for concurrent use. 
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Drug Category
Drugs
Strong CYP3A 
inhibitors*
Antibiotics: clarithromycin, josamycin, telithromycin, 
troleandomycin
Antidepressants: nefazodone
Antifungals: itraconazole, ketoconazole, posaconazole, 
voriconazole
Antiprogestins: mifepristone
Antivirals: boceprevir, danoprevir, elvitegravir, ensitrelvir, 
indinavir, lopinavir, nelfinavir, paritaprevir and ritonavir and 
(ombitasvir and/or dasabuvir), ritonavir, saquinavir, telaprevir, 
tipranavir
Calcium channel blocker: mibefradil
Pharmacokinetic enhancer: cobicistat
Vasopressin antagonists: conivaptan
Food products: grapefruit, grapefruit juice or any product 
containing grapefruit
Farnesyltransferase inhibitor: lonafarnib
Strong CYP3A 
inducers*
Antibiotics: rifampin, rifapentine
Anticonvulsants: carbamazepine, phenytoin
Cystic fibrosis treatments: lumacaftor
Herbal medications: St. John’s wort
* University of Washington (UW) Drug Interaction Database (DIDB) (University of 
Washington, 2022) and Food and Drug Administration (FDA) listings as sources:

UW: https://www.druginteractionsolutions.org/ 

FDA: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-
and-drug-interactions-table-substrates-inhibitors-and-inducers
10.10.2. Drugs Known to Predispose to Torsade de Pointes or QT interval prolongation
Concurrent use of ARV-471 with drugs of known risk of causing Torsade de Pointes or QT 
interval prolongation is prohibited for the majority of the drugs listed in the table below. 
The concurrent use of fulvestrant with drugs of known risk of causing Torsade de Pointes or 
QT interval prolongation is also prohibited.
Exception: sevoflurane, azithromycin, ondansetron, chloroquine may be used with caution
during the active treatment for all the participants with the exception of the participants in the 
QTc sub-study in Arm A for whom the use is prohibited during Cycles 1, 2 and Cycle 3.
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This is not an all-inclusive list (examples including, but not limited to the drugs 
provided below). 
Drug Category
Drugs
Drugs known to 
predispose to 
Torsade de 
Pointes
Anesthetic: sevoflurane1, propofol
Antianginal: bepridil
Antiarrhythmic: ibutilide, dofetilide, dronedarone, flecainide, 
nifekalant, hydroquinidine, quinidine, disopyramide, amiodarone, 
sotalol, procainamide
Antibiotic: azithromycin1, ciprofloxacin, clarithromycin, erythromycin, 
gatifloxacin*, grepafloxacin*, levofloxacin, moxifloxacin, 
roxithromycin, sparfloxacin*
Antidepressant: citalopram, escitalopram
Antiemetic: domperidone, ondansetron1
Antifungal: pentamidine, fluconazole
Antihistamine: terfenadine*, astemizole*
Antilipemic: probucol*
Antimalarial: halofantrine, chloroquine1, hydroxychloroquine
Antiparasitic: meglumine antimoniate
Antipsychotic: thioridazine, levomepromazine (methotrimeprazine), 
mesoridazine*, haloperidol, chlorprothixene, levosulpiride, pimozide
Antipsychotic/antiemetic: chlorpromazine, droperidol, sertindole, 
sulpiride, sultopride
Cholinesterase inhibitor: donepezil
GI stimulant: cisapride*
Muscle relaxant: terodiline
Opioid agonist: methadone, levomethadyl acetate*
Phosphodiesterase 3 inhibitor: anagrelide, cilostazol
Psychedelic: ibogaine
Vasoconstrictor: terlipressin
Vasodilator: papaverine HCl (intra-coronary)
1 Allowed to be used with caution (per USPI and SmPC) during the active treatment for 
all the participants with the exception of the participants in the QTc sub-study in Arm A 
for whom the use is prohibited during Cycles 1, 2 and 3.
*Removed from US market
Adapted from crediblemeds.org (organization that curates the University of Arizona Cancer 
Center for Education and Research on Therapeutics database: “Risk Categories for Drugs 
that Prolong QT & induce Torsades de Pointes (TdP) – Known Risk of TdP)”.
See website for current list: crediblemeds.org/index.php/druglist
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10.10.3. P-gp Sensitive Substrates
ARV-471 is an in vitro inhibitor of P-gp.  Treatment with ARV-471 has potential for 
increasing exposure of concomitant medications that are sensitive substrates for P-gp 
transporters. Sensitive P-gp substrates should be used with caution.
This is not an all-inclusive list (examples including, but not limited to the drugs 
provided below).
Drug Category*
Drugs
P-gp sensitive 
substrates 
Anticoagulants: dabigatran etexilate
Antiarrhythmics: digoxin/digitoxin
Histamine H-1 receptor antagonists: fexofenadine
* University of Washington (UW) Drug Interaction Database (DIDB) (University of Washington, 2022) and 
Food and Drug Administration (FDA) listings as sources:

UW: https://www.druginteractionsolutions.org/ 

FDA: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
No interaction with P-gp has been observed for fulvestrant.
10.10.4. PPI
Co-administration of PPIs may reduce ARV-471 absorption. The concomitant use of PPIs 
with ARV-471 is not recommended. If PPI treatment is required, drug intake with a 
moderate-fat meal (400-800 calories, approximately 35% fat) is recommended.
This is not an all-inclusive list (examples including, but not limited to the drugs provided 
below). 
Drug Category
Drugs
Proton pump 
inhibitors (PPIs)*
Esomeprazole, lansoprazole, omeprazole, pantoprazole, 
rabeprazole, dexlansoprazole.
* Refer to corresponding concomitant drugs USPIs or local product prescribing information.
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10.11. Appendix 11: Country Specific Requirements
10.11.1. European Union
This study will be conducted in compliance with Regulation (EU) No 536/2014. The 
recruitment plans for each EU Member State concerned are included in the respective 
Recruitment and Informed Consent Procedure documents.
The sponsor will notify EU Member States concerned of the following: 

Any SUSAR via reporting to the EudraVigilance database

Any unexpected event that affects the benefit risk-profile of the study, but are not 
SUSARs, no later than 15 days of becoming aware of that event

Any serious breach, as described in Section 10.1.1.1, no later than 7 days of 
becoming aware of that breach

Any urgent safety measure, as described in Section 10.1.1.1, no later than 7 days of 
the measure being taken

Any inspection report of a third-country authority concerning the study
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 25 years or longer if required by other European Union 
law.
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10.11.2. France
Contrat Unique
1. GCP Training 
Before enrolling any participants, the investigator and any sub-investigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer. Any investigators who later join 
the study will do the same before performing study-related duties. For studies of 
applicable duration, the investigator and sub-investigators will complete Pfizer GCP 
Training or equivalent every 3 years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
2. Study Intervention 
No participants or third-party payers will be charged for study intervention.
3. Urgent Safety Measures 
In addition, the investigator will inform Pfizer immediately of any urgent safety 
measures taken by the investigator to protect the study participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.
4. Termination Rights 
Pfizer retains the right to discontinue development of ARV-471 at any time.
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10.12. Appendix 12: Bone Marrow Reserve in Adults
Adapted from R.E. ELLIS: The Distribution of Active Bone Marrow in the Adult, Phy. Med. 
Biol.  5, 255-258, 1961(Ellis, 1961)
Marrow Distribution of the Adult
SITE
MARROW
wt. (g)
FRACTION 
RED 
MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
CRANIUM
Head:
136.6
AND
Cranium
165.8
0.75
124.3
13.1
13.1
MANDIBLE
Mandible
16.4
0.75
12.3
Upper Limb Girdle:
86.7
HUMERI,
SCAPULAE,
2 Humerus, 
head & neck
26.5
0.75
20.0
8.3
8.3
CLAVICLES
2 Scapulae 
67.4
0.75
50.5
2 Clavicles
21.6
0.75
16.2
Sternum
39.0
0.6
23.4
2.3
Ribs: 
82.6
1 pair
10.2
All 0.4
4.1
2 
12.6
5.0
3
16.0
6.4
STERNUM
4
18.6
7.4
AND
5
23.8
9.5
7.9
10.2
RIBS
6
23.6
9.4
7
25.0
10.0
8
24.0
9.6
9
21.2
8.5
10
16.0
6.4
11
11.2
4.5
12
4.6
1.8
Sacrum 
194.0
0.75
145.6
13.9
PELVIC 
BONES
2 os coxae
310.6
0.75
233.0
22.3
36.2
FEMUR
2 Femoral head 
and neck
53.0
0.75
40.0
3.8
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Marrow Distribution of the Adult (cont’d)
SITE
MARROW
wt. (g)
FRACTION 
RED MARROW
AGE 40
RED 
MARROW
wt. (g)
AGE 40
% TOTAL
RED MARROW
Vertebrae
(Cervical):
35.8
1
6.6
All 0.75
5.0
2
8.4
6.3
3
5.4
4.1
3.4
4
5.7
4.3
5
5.8
4.4
6
7.0
5.3
7
8.5
6.4
Vertebrae
(Thoracic):
147.9
1 pair
10.8
All 0.75
8.1
2
11.7
8.8
3
11.4
8.5
4
12.2
9.1
VERTEBRAE
5
13.4
10.1
14.1
28.4
6
15.3
11.5
7
16.1
12.1
8
18.5
13.9
9
19.7
14.8
10
21.2
15.9
11
21.7
16.3
12
25.0
18.8
Vertebrae
(Lumbar):
114.1
1 pair
27.8
All 0.75
20.8
2
29.1
21.8
10.9
3
31.8
23.8
4
32.1
24.1
5
31.4
23.6
TOTAL
1497.7
1045.7
100.0
100.0
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10.13. Appendix 13: RECIST (Response Evaluation Criteria in Solid Tumors) version 
1.1 Guidelines
Adapted from E.A. Eisenhauer, et al: New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228–247 
(Eisenhauer et al, 2009)
CATEGORIZING LESIONS AT BASELINE
All sites of disease must be assessed at screening as close as possible to randomization date 
(≤ 28 days prior to randomization date as defined in the protocol unless otherwise specified 
in Section 8.2). If screening assessment is inadequate, subsequent statuses generally should 
be not evaluable. 
Lesions are selected at screening and followed as either target or non-target lesions. All 
target lesions must be measurable. Any lesions or sites of disease not classified as target 
lesions including those that are non-measurable are classified as non-target. Definitions of 
measurable, non-measurable, target, and non-target lesions are provided below.
Measurable Lesions  
Measurable lesions (including both nodal and non-nodal) are lesions that can be accurately 
measured as follows:

Lesions with longest diameter ≥ 10 mm in the axial plane (bone lesions are not included 
except for soft tissue expansile masses arising from bone) when assessed by CT or MRI  

Lesions with longest diameter ≥ 20 mm when assessed by Chest X-ray  

Superficial lesions with longest diameter ≥ 10 mm when assessed by caliper  

Malignant lymph nodes with the short axis ≥ 15 mm. Nodal size is normally reported as 
2 dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the smaller of the axial, sagittal or coronal will be 
considered the short axis). 
NOTE: Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
Non-measurable disease 
All other disease including lesions too small to be considered measurable, pleural or 
pericardial effusions, ascites, bone disease, inflammatory breast disease, leptomeningeal 
disease, lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately 
measured with calipers, abdominal masses identified by physical exam that are not 
measurable by reproducible imaging techniques, nodes with short axis ≥ 10 mm but < 15 
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mm, disease documented by indirect evidence only (eg, by lab values), or previously radiated 
lesions that have not progressed, are considered non-measurable.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. Target 
lesions should be selected on the basis of size (lesions with longest diameter for non-lymph 
nodes ≥ 10 mm and nodes with longest short axis ≥ 15 mm) and suitability for accurate 
repeated measurements. Measurements are recorded in mm and must be provided for target 
lesions.
Non-Target Lesions 
All non-measurable lesions are non-target. All measurable lesions not identified as target 
lesions are also included as non-target lesions. 
OBJECTIVE STATUS AT EACH EVALUATION   
Response is assessed by the investigators, with objective status at each assessment recorded 
on the Investigator Overall Objective Tumor Assessment (IOTA) CRF. 
Objective Status is to be recorded at each post-baseline evaluation. 
Sites of disease should be assessed using the same technique as baseline, including consistent 
administration of contrast agents (see Section 8.2.1 ). If a change needs to be made the case 
should be discussed with the radiologist and the sponsor to determine if substitution is 
possible. 
If target lesions were present at screening, screening sum of diameters is calculated as the 
total sum of the longest diameters for non-nodal lesions and short axis for nodal lesions. Sum 
of diameters at subsequent assessments can be calculated in the same manner using the same 
set of target lesions. 
Response evaluation of target lesions 

Complete Response (CR): Complete disappearance of all target lesions, with the 
exception of nodal disease. All nodes must decrease to normal (short axis < 10 mm). All 
target lesions must be assessed.

Partial Response: At least a 30% decrease from baseline in the sum of diameters of all 
target lesions. The short diameter is used in the sum for nodal target lesions, while the 
longest diameter is used in the sum for non-nodal target lesions. All target lesions must 
be assessed.
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
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
measurable lesions above nadir (smallest sum observed considering baseline and all 
assessments prior to the timepoint under evaluation), with a minimum absolute increase 
of 5 mm relative to nadir. If only a subset of target lesions is assessed, and the sum of the 
non-missing lesion diameters results in an increase of at least 5 mm and at least 20% 
above the nadir then the progression criteria will have been met. 

Stable Disease (SD): Does not qualify for CR, PR, PD. All target lesions must be 
assessed.

Not Evaluable (NE): PD has not been documented, and at least one of the following is 
true:
o
one or more target lesions have not been assessed 
o
assessment methods used were inconsistent with those used at baseline (unless 
considered “interchangeable”)
o
one or more target lesions cannot be measured accurately unless due to being too 
small to measure
o
one or more target lesions were excised or irradiated and have not reappeared or 
increased. 
General considerations on Response Evaluation of Target lesions: 

A target lesion that is irradiated or excised post-screening is no longer measurable 
and generally should be assessed as Not Evaluable. Increase or reappearance of such 
lesions should constitute progression. 

For lesions that become necrotic in the center, the longest diameter should still be 
used in the sum of diameters.

Measurements for target lesions that become small should continue to be recorded; 
o
if the lesion is considered to have disappeared, 0 mm should be recorded;
o
if a lesion is determined to be present but too small to measure (ie lesion less 
than 10 mm and exact measurement cannot be performed), the lesion status 
will indicate “too small to measure” and 5 mm will be used in the calculation 
of the sum of the diameters. 

If 2 target lesions coalesce, the measurement of the coalesced mass is used. If a large 
target lesion splits, the sum of the parts is used.
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
If a subset of the target lesions identified at baseline were not measured post-baseline, 
the objective status of target lesions at the visit is Not Evaluable, unless the partial 
sum of diameters for the subset of target lesions assessed at the visit already meets the 
PD criteria, ie, at least 5 mm and 20% increase above the smallest sum of diameters 
observed, in which case the objective status of target lesions at the visit is PD.

If a lesion disappears and reappears at a subsequent time point, it should continue to 
be measured. The participant’s response at the point in time when the lesion reappears 
will depend upon the status of his/her other lesions and previous response. For 
example, if the participant’s tumor had reached a CR status and a non-lymph node 
target lesion reappeared, then the participant’s response would be considered PD at 
the time of reappearance. 

In contrast, if the tumor status was a PR or SD and 1 lesion which had disappeared 
then reappears, its maximal diameter should be added to the sum of the remaining 
lesions for a calculated response. 
Response evaluation of non-target lesions 

Complete Response (CR)/Absent: Complete disappearance of all non-target lesions. All 
nodes must decrease to normal (short axis < 10 mm). All disease sites must be assessed.

Non-CR/Non-PD/Present without unequivocal progression: Persistence of 1 or more 
non-target lesion(s). 

Progressive Disease (PD)/Unequivocal progression: Unequivocal progression of 
existing non-target lesions. 

Not All Evaluated/Inevaluable: Progression has not been documented and non-target 
lesions are not all assessable or disease assessed with inconsistent methods (unless 
considered “interchangeable”), or one or more target lesions were excised or irradiated 
and have not reappeared or increased. 
Note: there is no standard RECIST method of using non-target disease assessments to 
determine unequivocal progression in non-target disease; by the nature of non-measurable 
disease, this is not possible. Unequivocal progression is based on clinical judgment. 
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New lesions evaluation criteria

If a lesion is identified in a location not scanned previously, this will be considered 
progression of disease (new lesion).

If a new lesion is equivocal at one assessment (classified as “Equivocal”) and verified 
at the next, (classified as “Unequivocal”), the earlier date is used as the progression 
date. 
Objective Response Status at each assessment
Assessment is based on the target and non-target lesions response as described above and in
Table 8. 
Table 8.
Objective Response Status at Each Assessment for Participants with 
Measurable Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Objective Status
CR
CR
No
CR
CR
Non-CR/Non-PD or 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
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; NE = not 
evaluable.
Note: cases for which target disease is assessed as SD or better but non-target assessments
are missing, must be reviewed carefully. By considering the whole sequence, it may be 
reasonable to assume missed non-target assessments were not progression. 
For participants with only non-target disease Table 9 will be used. 
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Table 9.
Objective Response Status at Each Assessment for Participants with Non-
Target Disease Only
Non-Target Disease
New Lesions
Objective Status
CR/Absent
No
CR
Non-CR/Non-PD/Present without 
unequivocal progression
No
Non-CR/Non-PD
Not all evaluated/Inevaluable
No
NE
PD/Unequivocal progression
Yes or No
PD
Any
Yes*
PD
*New lesions must be unequivocal
CR = complete response; PD = progressive disease; NE = not evaluable.
Date of Response
If there are multiple scan dates associated with a tumor evaluation, ie, radiological 
assessments occur over a series of days rather than the same day, the earliest scan date 
associated with the evaluation will be used as the date of the assessment. The same 
convention should be used for the investigator assessment (IOTA CRF page).
Best Overall Response 
The BOR will be assessed based on reported overall lesion responses at different evaluation 
time points from the randomization date until the first documentation of progressive disease 
PD. For CR and PR, the participant’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. CR and PR must be confirmed 
by 2 measurements at least 4 weeks apart. In the case of SD, follow up measurements must 
have met the SD criteria at least once after randomization.
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10.14. Appendix 14: Additional Study Assessments, Inventories, and Questionnaires
10.14.1. Patient-reported Outcomes Assessments
These questionnaires will be collected:

EuroQol 5 Dimensions, 5-Level (EQ-5D-5L) and Visual Analog Scale (VAS) 

EORTC QLQ-C30

EORTC QLQ-BR23 (female and male questionnaire versions)

Brief Pain Inventory (BPI) short form 

Modified Brief Pain Inventory Short Form 

Pain medication usage

Injection site pain

Patient preference questionnaire
The EQ-5D-5L, is a 5-item participant-completed questionnaire designed to assess health 
status in terms of a single index value or utility score. There are 2 components, a Health State 
Profile which has individuals rate their level of problems (none, slight, moderate, severe, 
extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), and a VAS in which participants rate their overall health status from 0 
(worst imaginable) to 100 (best imaginable). Published weights are available that allow for 
the creation of a single summary score. Overall scores range from 0 to 1, with lower scores 
representing a higher level of dysfunction (Rabin & de Charro, 2001).
The EORTC QLQ-C30 is a well-known, validated and self-administered PRO. The EORTC 
QLQ-C30 is a 30-question survey, which can be grouped into 5 functional domain subscales, 
including a physical functioning subscale, a role functioning subscale, an emotional 
functioning subscale, a cognitive functioning subscale and a social functioning subscale.  
Higher scores on the functional domains are indicative of higher levels of functioning.  
Oncology related symptoms assessed by the EORTC QLQ-C30 include fatigue (3 items), 
pain (2 items), nausea and vomiting (2 items), and dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial impact (1 item each).  Higher scores are reflective of a 
greater presence of symptoms (Aaronson et al, 1993).  
The EORTC QLQ-BR23 (female and male versions) is a 23-item breast cancer-specific 
companion module to the EORTC QLQ-C30 and consists of four functional scales (body 
image, sexual functioning, sexual enjoyment, future perspective) and four symptom scales 
(systemic side-effects, breast symptoms, arm symptoms, upset by hair loss). Like the QLQ-
C30, higher scores represent a better level of functioning/QoL than lower scores on 
functional and global QoL scales. However, for symptom-oriented scales, higher scores 
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represent greater symptom severity (Sprangers et al, 1996). Female and male questionnaire 
versions will be used depending on participant’s gender. 
The BPI is one of the most widely used tools to assess clinical pain. There are two versions, 
the long and short form. The short-form version of the BPI will be used in C4891001 and 
consists of items intended to measure participant perceptions of pain severity, items to assess 
the degree of interference of pain on daily functioning, body diagrams on which participants 
indicate the location of pain, an item to record pain medication usage, and a visual analogue 
scale to assess the degree of pain relief in the last 24 hours. Items in the pain severity scale 
evaluate the participant's pain “at its worst”, “at its least”, and “on average” over the previous 
24 hours, as well as “pain now” (at the time of assessment). Participants respond on a 10-
point numerical rating scales, where 0 = “no pain” and 10 = “pain as bad as you can 
imagine”. The pain interference scale asks participants to rate how their pain interferes with 
“enjoyment of life”, “general activity”, “walking ability”, “mood”, “sleep”, “normal work” 
and “relations with other people.” Responses for the interference scale are also based on 10-
point numerical rating scale anchored by 0 = “does not interfere” and 10 = “interferes 
completely”. Higher scores are indicative of higher levels of pain and the impact attributed to 
pain (Cleeland & Ryan, 1994). While the full BPI-SF will be assessed during each cycle for 
the first six cycles and followed by every other cycle thereafter, the item 3 and item 9a of the 
mBPI-SF will be collected daily for participants in Arms A & B. The item 3 of the mBPI-SF 
measures “worst pain in the last 24 hours” and the item 9a measures “pain interference with 
general activity in the last 24 hours. Injection site pain will be collected daily for participants 
in Arm B. Consumption of pain medication will also be collected daily for participants in 
Arms A & B 
The patient preference questionnaire (Arm A and Arm B) is a 3-item instrument designed to 
measure patients’ preference for a method of treatment administration (oral versus 
injectable). The response scale varies for each question. The first question inquires about the 
preferred method of administration with the following responses: oral, injectable, or no 
preference. The other two questions ask patients about the strength of preference (response 
options ranging from ‘very strong’ to ‘not very strong’) and rationale for their preferred 
method of administration (response options include a checklist of specific reasons derived 
from qualitative interviews). Items are assessed without the use of a specific recall period;
however, the respondents are asked to reflect on their experience with both methods of 
administration (oral or injectable) and preference when completing the instrument.
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10.14.2. Eastern Cooperative Oncology Group (ECOG) Performance
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature, ie, light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.
(Oken et al, 1982)
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10.15. Appendix 15: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC.  The protocol amendment summary of changes tables for past 
amendment(s) can be found below:
Amendment 2 (24 May 2023)
Overall Rationale for the Amendment: The protocol was amended to add lipid tests due to 
new drug class safety information as well as to incorporate regulatory feedback from specific 
countries and to address participant experience and operational issues.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Periodic cholesterol and 
triglyceride laboratory 
testing has been added.
Recent elacestrant 
(ORSERDU) approved 
USPI includes 
dyslipidemia in the 
Sections of “Warning and 
Precautions” and “Adverse 
Reactions”. The newly 
added lipid tests will 
support the 
characterization of these 
safety events for ARV-471 
and support participant 
safety.   
Section 1.3 Schedule of 
Activities (Table 2) 
Section 10.2 Appendix 2
The Inclusion Criterion #4 
has been slightly modified. 

Clarified the definition 
of adjuvant therapy to 
be counted as a line of 
therapy in 
advanced/metastatic 
setting 

Clarified that only one 
line of CDK4/6 
inhibitor is allowed in 
any setting.
To improve clarity. 
Section 1.1 Synopsis, Section 
5.1 Inclusion Criteria
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Description of Change
Brief Rationale
Section # and Name

Clarified that the most 
recent ET may be the 
endocrine treatment 
component of the 
CDK4/6 inhibitor line 
of therapy.
Exclusion Criterion #9:

Added “elacestrant” as 
prior treatment not 
allowed.

Removed prior CDK4/6 
inhibitor treatment in 
the 
neoadjuvant/adjuvant 
setting.

Clarified that other 
investigational agents 
(including novel ET, 
any SERDs, SERCAs, 
CERANs) are not 
allowed.
Elacestrant (oral SERD) 
was initially listed in the 
EC#9 as investigational 
novel endocrine therapy 
(ie, SERD, SERCA, 
CERAN) not allowed.  
Since elacestrant has been 
recently approved by the 
FDA this drug has been 
reported separately.
The sentence related to 
prior CDK4/6 inhibitor 
treatment removed to 
avoid duplication; 
clarification already added 
in the Inclusion Criterion 
#4.
The participants should not 
have received any other 
investigational drug 
including novel ET.
Section 1.1 Synopsis, 
Section 5.2 Exclusion Criteria
Non-substantial Modification(s)
ClinicalTrials.gov ID has 
been added.
To provide the 
ClinicalTrials.gov ID
Cover page 
Section 1.1 Synopsis
Synopsis has been 
streamlined and some 
further details (e.g. 
assessments) added.
To align with Sponsor 
protocol template.
Section 1.1 Synopsis
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Description of Change
Brief Rationale
Section # and Name
Clarified the timing for pre-
screening and screening 
activities. 
To improve clarity.
Section 1.3 Schedule of 
Activities (Table 1)
Added that ESR1 test will 
be performed using a next-
generation sequencing 
[NGS] test that evaluates 
other genes in addition to 
ESR1 gene.
To improve clarity.
Section 1.3 Schedule of 
Activities (Table 1)
Section 8.1.1. Pre-screening
Screening activities may be 
performed while awaiting
ESR1 test results/approval 
of prior ESR1 status. Added 
a trigger of 280 participants 
enrolled in either ESR1 
status for stopping and 
clarified the pause of one 
population in case of 
extreme imbalance in ESR1 
status enrollment. Once this 
trigger/pause is reached, 
enrollment of that 
population will cease/pause 
and the Sponsor will 
reinstate the sequential pre-
screening /screening 
procedure.
To accelerate the pre-
screening and screening 
activities and allow 
participants to access study 
treatment more quickly, 
the screening period may 
be initiated while the 
ESR1 test result/approval 
of prior ESR1 result is 
pending.
Section 1.3 Schedule of 
Activities (Table 1) 
Section 4.1 Overall Design
Added that the in China 
pre-screening ctDNA 
samples may be also used 
for tumor molecular 
profile/ctDNA level and 
ctDNA burden if the 
participants are randomized 
in the trial.
Clarification added to 
support the use of ctDNA 
level and tumor molecular 
profile from prescreening 
ESR1 test. This is also a 
support from protocol for 
China HGRAC 
application.
Section 1.3 Schedule of 
Activities (Table 1) 
Section 8.1.1 Pre-screening
Section 8.7.2. Blood Samples 
Clarified that ctDNA C1D1 
samples may also be used 
for potential development 
of the companion 
diagnostic.
ctDNA samples may also 
be used for CDX 
development in case the 
ctDNA samples collected 
during the pre-screening 
Section 1.3 Schedule of 
Activities (Table 1) 
Section 8.7.2. Blood Samples
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Brief Rationale
Section # and Name
period are insufficient 
quantities and/or missing 
in collection.   Samples to 
be tested as per regulatory 
requirements. 
Clarified that electrolytes 
should be performed on 
C1D1 when ECG is done.
Clarified that weight is 
collected at screening.
Paper PROs may be 
available. However, paper 
PROs should only be 
utilized if the electronic 
versions (on the electronic 
PRO devices) are not 
available for use (eg, not 
received at the site or not 
approved for use yet by the 
ethics committee).
Clarified which assessments 
may be done during the 
home health visits.
To improve clarity.
Section 1.3 Schedule of 
activities (Table 2)
Clarified that the daily 
questionnaires are collected 
in the evening using the 
“evening daily diary”.
To improve clarity.
Section 1.1 Synopsis Section 
1.3 Schedule of activities 
(Table 2)
Section 4.1. Overall Design
Section 8.9. Health Economics
Section 9.3.3.2.3. PRO data 
analyses
The time window for ECG 
and PK sample collected 
has been extended up to 2.5 
hours prior to dose.
To give more flexibility 
since performing all 
assessments in a more 
restricted time window 
may be challenging.
Section 1.3 Schedule of 
activities (Table 3)
Clarified that ECG at 
screening should be done 
without fasting condition.
Fasting condition is not 
applicable in the screening 
period because required 
only starting from C1D1 
Section 1.3 Schedule of 
activities (Table 3) 
Section 8.3.3 
Electrocardiograms
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Brief Rationale
Section # and Name
for participants belonging 
to the QTc Substudy in 
Arm A.
Benefit/Risk assessment 
text for QT prolongation 
slightly modified.
Risks for 
decentralized/telehealth 
interactions study 
assessments added.
To improve clarity and to 
align with Sponsor 
protocol template.
2.3. Benefit/Risk Assessment
Added a text description of 
the estimand corresponding 
to the primary and key 
secondary objective and 
removed the statistical 
reference section.
To align with Sponsor 
protocol template.
Section 1.1 Synopsis 
Section 3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS
LHRH may be provided by 
the Sponsor if available to 
source in-country.
To clarify that LHRH may 
be provided by the 
Sponsor in certain 
circumstances.
Section 6.9.1. Luteinizing 
Hormone-Releasing Hormone 
Agonist
Corticosteroids use has 
been added.
Limitation of the use of 
corticosteroids added for 
consistency with the EC#2.
Section 6.9.8 Corticosteroids
Updates have been added to 
align with Sponsor new 
protocol template.
To align with Sponsor 
protocol template.
Section 1.1 Synopsis 
Section 6.8. Treatment of 
Overdose
Section 8.3.5. Pregnancy 
Testing
Section 8.4. Adverse Events, 
Serious Adverse Events, and 
Other Safety Reporting
Section 9.2 Analysis Sets
Section 10.1 Appendix 1 
Regulatory, Ethical, and Study 
Oversight Considerations
Section 10.3. Appendix 3: 
Adverse Events: Definitions 
and Procedures for Recording, 
Evaluating, Follow Up, and 
Reporting
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Section # and Name
Section 10.4.3. Woman of 
Childbearing Potential
Section 10.6. Appendix 6: 
Liver Safety: Suggested 
Actions and Follow Up 
Assessments and Study 
Intervention Rechallenge 
Guidelines
Section 10.7. Appendix 7: 
Kidney Safety Monitoring 
Guidelines
Section 10.8. Appendix 8: 
ECG Findings of Potential 
Clinical Concern
Section 10.9. Appendix 9: 
AEs, ADEs, SAEs, USADEs, 
and Device Deficiencies: 
Definitions and Procedures for 
Recording, Evaluating, 
Follow-up, and Reporting in 
Medical Device Studies
Clarification provided on 
home heath visits to be 
performed by a registered 
nurse/other qualified health 
care provider or by the 
investigator or a physician 
designee for specific 
assessments (if required by 
local regulations).
Clarification added as per 
Health Authorities 
requirement.
Section 8.1.4. Home Health 
Visits  
For China: Clarified that 
Retained Research samples 
for genetics will not be 
collected and that sample 
collection for biomarkers 
and biomarker testing will 
be performed upon approval 
by HGRAC.
Clarification added as the 
collection of retained 
research samples will not 
be permitted by China 
HGRAC and will not be 
applied for HGRAC. 
Moreover, this clarification 
also emphasizes that the 
collection and analysis of 
biomarker samples must be 
applied after HGRAC 
approval; before that, no 
sample collection and 
Section 8.6.2 Retained 
Research Samples for 
Genetics
Section 8.7 Biomarkers
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Brief Rationale
Section # and Name
analysis should be applied 
in China.
Updated population 
definition. 
Simplified the definition of 
study population to avoid 
potential confusion.  
Section 9.1.1. Estimands
Added a supplemental 
analysis for the primary 
endpoint PFS. 
Requested by Health 
Authority.
Section 9.3.2 Primary 
endpoint analyses
For the PRO analysis, 
change from baseline and 
deterioration will be based 
on clinically meaningful 
threshold for the scale being 
examined.
To add further 
clarification.
Section 9.3.3.2.3. PRO data 
analyses
Added the reference of the 
methodology of group 
sequential Hochberg 
procedure for testing of OS 
in the two populations.
To add further clarification 
as requested by Health
Authorities.
Section 9.4. Interim Analysis
Japan-specific section 
removed.
The device-related incident 
whose recurrence might 
lead to death or serious 
deterioration in health are 
not required to be reported 
as per local laws based on 
the discussion with 
PMDA. 
Fulvestrant is administered 
using pre-filled syringe 
(medical device) whereas 
the investigation drug 
ARV-471 does not contain 
any medical device. As per 
local law the device-
related incident should be 
submitted to PMDA only 
in case fulvestrant contains 
the same medical device 
used in the investigational 
drug.
Section 10.11.2. Japan
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Description of Change
Brief Rationale
Section # and Name
Typographical errors were 
corrected, and minor edits 
were made.
For clarification and to 
ensure consistency.
Section 4.2. Scientific 
Rationale for Study Design
Table 6 “Recommended Dose 
Modifications for ARV-471  
Related Toxicity” 
Table 7 “Recommended 
ARV-471 Dose Modification 
in the event of QTc 
Prolongation”
Section 6.8. Treatment of 
Overdose status. 
Section 8.1.4. Home Health 
Visits  
Section 8.2.1 Imaging Tumor 
Response Assessments
Section 4.2. Scientific 
Rationale for Study Design
Section 10.14. Appendix 14: 
Additional Study 
Assessments, Inventories, and 
Questionnaires
Section 10.16. Appendix 16: 
Abbreviations
Section 11. REFERENCES
List of CYP3A inhibitors 
has been updated. 
To provide a more 
exhaustive list of drugs 
that are known to be 
CYP3A inhibitors.
Section 10.10. Appendix 10: 
Concomitant Medications 
That May Result in DDI
Sponsor Legal Addresses 
have been added.
This change incorporates 
the PACL dated 04 April 
2023.
To align with Sponsor 
protocol template and as 
requested by Health 
Authorities.
Cover page
HBV, HCV, HIV laboratory 
testing has been added. 
Tests added as per Health 
Authorities request and to 
be performed at screening 
Section 1.3 Schedule of 
activities (Table 2) and 
Section 10.2 Appendix 2.
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Description of Change
Brief Rationale
Section # and Name
This change incorporates 
the PACL dated 18 April 
2023.
only if mandated by 
Regulatory Agencies. 
Amendment 1 (25 October 2022)
Overall Rationale for the Amendment: The protocol was amended mainly to incorporate 
regulatory feedback and new available data following the Investigator Brochure (v. 4.0) 
update. 
Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Section 1.1 Synopsis, 
Section 3. OBJECTIVES, 
ENDPOINTS, AND 
ESTIMANDS, 
Section 4.1, Overall design, 
Section 8.2. Efficacy 
Assessments 
Section 9. STATISTICAL 
CONSIDERATIONS
PFS, tumor control 
and DOR between 
treatment arms will 
now be determined by 
BICR assessment. 
BICR will review all 
radiological images, 
clinical assessment of 
superficial lesions and 
clinical information 
(as applicable).  
The sensitivity 
analyses to support the 
primary analyses will 
be performed from 
local radiologist’s 
/investigator’s tumor 
assessment.
Health 
Authorities 
feedback 
recommended 
the primary end 
point (PFS) 
assessed by 
BICR due to the 
unblinded study.
Substantial
Section 1.1 Synopsis, 
Section 1.3 Table 2, 
Section 4.1. Overall Design, 
Section 8.9. Health 
Economics, 
Section 9.3.3.2.3. PRO data 
analyses 
The frequency of the 
PRO assessment has 
been increased and 
mBPI-SF (worst pain 
severity and pain 
interference), injection 
site pain, pain 
medication usage via 
analgesic log and 
Per Health 
Authorities 
feedback the 
frequency of the 
PRO assessment 
has been 
increased and 
additional 
questionnaires 
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Section 10.14.1. Patient-
reported Outcomes 
Assessments
patient preference 
questionnaires have 
been added.
have been added 
to potentially 
support labeling 
of PRO 
outcomes. 
Section 1.1, Synopsis, 
Section 1.3 Table 1 SoA 
prescreening
Section 4.1, Overall design
Section 5.1 Inclusion 
criteria 
  
Removed requirement 
of approximately 80% 
of participants treated 
with prior CDK4/6 
inhibitor and removed 
capping of 
approximately 20% for 
naïve participants. 
Updated IC#4 to 
mandate prior 
treatment with 
CDK4/6 inhibitor in 
combination with 
endocrine therapy and 
≤1 additional 
endocrine therapy.
Health 
Authorities 
feedback 
requires that all 
participants 
should 
additionally 
receive a 
CDK4/6 
inhibitor if not 
used previously 
according to 
guidelines. Since 
in this study no 
combination arm 
with CDK4/6 
inhibitor is 
planned, the 
eligibility criteria 
have been 
modified and all 
participants 
should have been 
previously 
treated with  
CDK4/6 
inhibitor.
Substantial
Section 1.3, Schedule of 
Activities, Table 1
Section 8.1.1 Pre-screening
Updated the total 
number of ctDNA 
samples. 
For all 
participants, one 
addition sample 
is required for 
potential 
companion 
diagnostic 
development
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Section 1.3, Schedule of 
Activities, Table 2
Section 8.3.5, Pregnancy 
Testing
Section 10.2 Appendix 2, 
Clinical Laboratory 
Assessments
Updated text on  
frequency of 
pregnancy tests 
requested for 
WOCBP.
To align with the 
LHRH product 
information in 
contraception 
and pregnancy 
tests for 
WOCBP due to 
the lack of 
effectiveness of 
LHRH agonist 
use to prevent 
pregnancy. 
Substantial
Section 1.1, Synopsis, 
Schema
Section 4.1, Overall design 
Section 6.3. Assignment to 
Study Intervention
Section 9. Statistical 
Consideration
Modified the 
randomization from 
2:1 to 1:1 and   
updated the total 
number of participants 
in the study and in 
each arm. 
Consequently, the 
number of statistical 
events has been 
updated. 
Randomization 
has been 
changed as per 
consultation with 
regulatory 
agencies. 
Substantial
Section 1.1 Synopsis
Section 1.3, Schedule of 
Activities, Table 2
Section 4.2.3, Choice of 
Contraception/ Barrier 
Requirements
Section 5.1 Inclusion 
criteria.
Section 8.1.2 Telehealth 
Visits
Section 8.1.3 Home Health 
Visits
Section 10.4 Appendix 4: 
Contraceptive and Barrier 
Guidance
Updated text to 
specify that 
contraception & 
compliance checks are 
required for WOCBP 
and male participants. 
IC#1 was updated 
accordingly.
Based on LHRH 
agonist 
prescribing 
information (eg, 
USPI Zoladex), 
an LHRH 
agonist must be 
associated with 
the use of non-
hormonal 
contraception. 
Substantial
Section 1.1 Synopsis
Section 5.2 Exclusion 
criteria
Updated EC #13: 
Renal impairment is 
defined as eGFR <45 
mL/min/1.73m2 as 
Health 
authorities 
require the use of 
eGFR equation 
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
calculated using the 
2021 CKD-EPI 
Equations. Serum 
creatine of >1.5 x 
ULN has been 
removed.
  
because is more 
inclusive and the 
most reliable 
overall index of 
kidney function.  
eGFR cutoff set 
to 45 
mL/min/1.73m2 
since renal 
clearance of 
ARV-471 is low.
Section 1.1 Synopsis, 
Section 4.1 Overall design 
Section 6.3. Assignment to 
Study Intervention
Section 9. Statistical 
Consideration.
Removed stratification 
factor for prior 
treatment with 
CDK4/6 inhibitor.
The stratification 
factor has been 
removed because 
participants must 
now be 
previously 
treated with a 
CDK4/6 
inhibitor to be 
eligible.
Substantial
Section 1.1 Synopsis
Table 3, Pharmacokinetic 
and ECGs
Section 4.1 Overall design 
Section 8.3.3. 
Electrocardiograms
Section 9.2 Analysis Sets
Section 9.3.3.2.2. 
Pharmacokinetic Analysis
Section 9.3.3.2.5.3. 
Summary and Categorical 
Analysis of ECG
Modified QTc study 
design and updated the 
total number of 
participants from 
approximately 60 to 
approximately 80 
participants (from 
approximately 50 
evaluable participants 
to approximately 60 
evaluable 
participants).
ECG and PK samples: 
the time points in the 
Arm A QTc sub-study 
has been reduced. 
ECG on C1D1 is 
mandatory for all 
participants.
Health 
Authorities 
agreed to a 
revised QT Sub-
study design 
based on 
estimation of 
effect size in lieu 
of the hypothesis 
testing for non-
inferiority. The 
new sample size 
calculation is 
based on new 
data from Study 
ARV-471-mBC-
101 and the 
revised QTc 
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Sub-study 
design.
Section 1.1, Synopsis 
Updated safety text
To align with 
updated IB
Substantial
Section 2.2.3, 
ARV-471
Added details on anti-
tumor activity of 
ARV-471.
To align with 
updated IB
Substantial
Section 2.2.3.1, Nonclinical 
Pharmacokinetics and 
Metabolism
Added details on 
ARV-471 and on CYP 
metabolism and doses 
administered in dogs 
to measure exposure 
of ARV-471 
To align with 
updated IB
Substantial
Section 2.2.3.2, Potential 
Drug- Drug Interaction
Section 10.10.3, P-gp 
Sensitive Substrates
Updated text about
impact of ARV-471 on 
CYP2B6 substrates 
and substrates of 
human transporters (P-
gp and BCRP) and 
effect of PPI on ARV-
471. Updated text for 
the use of antacids and 
H2 receptor 
antagonist. 
To align with 
updated IB
Substantial
Section 2.2.3.3, ARV-471 
Preliminary Safety, Efficacy 
and PK in Humans 
Updated safety, 
efficacy and PK data 
based on study ARV-
471-mBC-101 and 
ARV 471-CPhm-103. 
To align with 
updated IB
Substantial
Section 2.2.3.4 QTc 
Evaluation Data.
Section 10.10.2, Drugs 
Known to Predispose to 
Torsade de Pointes or QT 
interval prolongation
Updated safety data in 
non-clinical and 
clinical studies 
including 
concentration-QTc 
modeling analysis of 
data from the ongoing 
ARV-471-mBC-101 
study.
To align with 
updated IB
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Section 2.3.1, Risk 
Assessment 
Updated text about 
QTc prolongation and 
Venous embolism
To align with 
updated IB
Substantial
Section 2.3.2, Benefit 
assessment 
Section 2.3.3, Overall 
Benefit/Risk conclusion
Updated text about 
efficacy data based on 
study ARV-471-mBC-
101.
To align with 
updated IB
Substantial
Section 4.3.1. ARV-471
Updated safety, 
efficacy and QTc data.
To align with 
updated IB
Substantial
Section 1.1, Synopsis 
Section 1.3, Schedule of 
Activities, Table 2
Section 4.1, Overall Design 
Section 5.1 Inclusion 
Criteria
Section 6.9.1 Luteinizing 
Hormone-Releasing 
Hormone Agonist
Updated text on 
LHRH initiation and 
to allow participants 
already on treatment 
with every 3-month 
formulation to 
continue it. 
IC#1 updated 
accordingly.
To align with 
NCCN Breast 
Cancer 
guidelines.
Substantial
Section 6.9.3. Other 
Prohibited and/or Anti-
Cancer or Experimental 
Drugs, or Procedures
Section 10.10.2. Drugs 
Known to Predispose to 
Torsade de Pointes or QT 
interval prolongation
The use of 
sevoflurane, 
azithromycin, 
ondansetron, 
chloroquine has been 
prohibited during 
Cycle 3 for the 
participants in the 
QTc-Substudy in Arm 
A.
To align with the 
modified QTc 
study design as 
per Section 
9.3.3.2.5.3.1. 
Electrocardiogra
m Analyses for 
QTc Analysis 
Set
Substantial
Section 6.9.4 Concomitant 
Treatments to be used with 
Caution or Not 
Recommended
Updated details with 
reference to the use of 
H2 receptor 
antagonists and local 
antacids.
To align with 
updated IB
Substantial
Schedule of Activities, 
Table 2
Added weight 
collection on Day 1 of 
each cycle and at 
EOT.
Clarified that height is 
collected at screening.
To monitor the 
impact of 
endocrine 
therapy on body 
weight.
Substantial
Section 1.1, Synopsis
Added description of 
the program level 
For added 
clarity.
Non-
substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Section 4.1, Overall Design 
and Section 10.1.5.2. 
Steering Committee
Global Steering 
Committee 
Section 1.1, Synopsis 
Section 1.3, Schedule of 
Activities, Table 2
Section 4.1 Overall Design
Section 8.9 Health 
Economics
Section 9.3.3.2.3. PRO data 
analyses
Section 10.14. Appendix 14
Added clarification on 
EORTC QLQ-BR23 
questionnaire for 
which female and 
male versions are 
available.
To clarify that 
EORTC QLQ-
BR23 
questionnaire 
female and male 
versions will be 
analyzed 
separately.
Non-
substantial
Section 1.3, Schedule of 
Activities, Table 2 Notes 
Column
Updated text about 
C1D1 time window, 
sequence of 
assessments and bone 
scan at the EOT.
To add clarity
Non-
Substantial
Section 1.3, Schedule of 
Activities, Table 2
Section 8.2.1. Imaging 
Tumor Response 
Assessments
Section 8.2.1.1. Treatment 
Beyond Progression in Both 
Arms
Removed 
recommended PD 
confirmation.
PD confirmation 
not required by 
RECIST v1.1
Non-
substantial
Section 1.3, Schedule of 
Activities, Table 2
Section 6.5 Study 
Intervention Compliance 
Updated text clarifying 
that compliance will 
be assessed prior to the 
dispensing of study 
interventions 
The language 
related to the 
drug compliance 
has been aligned 
with the sponsor 
protocol 
template.
Non-
substantial
Section 1.3, Schedule of 
Activities, Table 2
Section 8.2.1. Imaging 
Tumor Response 
Assessments
The frequency of the 
tumor assessment has 
been clarified to be 
every 8 weeks for the 
first 48 weeks.
To add clarity.
Non-
substantial
Schedule of activities 
(Table 3) and Section 8.3.3. 
Electrocardiograms
Updated timing of PK 
sample collection and 
The timing has 
been restricted to 
5-7 h to align 
Non-
substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
central reading 
requirements
with expected 
Tmax  and central 
reading is not 
required at 
screening 
because ECG is 
only for 
eligibility 
evaluation.
Section 1.3, Schedule of 
Activities, Table 2 & Table 
3
Section 6.1.1.1 ARV-471
Section 6.1.1.2. Fulvestrant
Section 6.2. Preparation, 
Handling, Storage, and 
Accountability 
Section 6.2.1. Preparation 
and Dispensing
Section 6.5. Study 
Intervention Compliance
Section 7.1.1.1. Safety 
Follow-up
Section 8.1.2. Telehealth 
Visits
Section 8.1.3. Home Health 
Visits 
Section 8.5. 
Pharmacokinetics
Section 8.9. Health 
Economics
In case of home health 
visit the participant 
will not return to the 
site. Therefore, the 
paragraphs have been 
updated to 
accommodate home 
health activities. A 
more detailed list of 
assessments to be 
performed during 
home health visit has 
been added. 
The language 
has been slightly 
modified to 
accommodate 
home health 
visits.
Non-
substantial
Table 7 ARV-471 Dose 
Modification in the event of 
QTc Prolongation
The recommended 
dose modifications in 
case of QTc 
prolongation (with no 
reversible cause 
identified) have been 
revised. 
The 
recommended 
dose 
modifications 
have been 
updated for 
consistency with 
the retreatment 
parameters 
reported in the 
Non-
substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Section 6.6.2.5 
ARV-471 Dose 
Delays.
Section 7.1. Discontinuation 
of Study Intervention
Section 8.2.1.1. Treatment 
Beyond Progression in Both 
Arms
Clarified that  
objective disease 
progression is assessed 
by Investigator in case 
of discontinuation and 
for treatment beyond  
progression. Added 
request of participant’s 
consent for treatment 
beyond progression
To add clarity
Non-
substantial
Section 8.1.1 Pre-Screening
Added reference to 
Table 1 and additional 
details related to pre-
screening.
To add clarity
Non-
Substantial
Section 8.2.1.4. Alternative 
Facilities for Tumor 
Assessment
Section 8.3.3.1. Alternative 
Facilities for 
Electrocardiograms
Tumor assessment and 
ECG (unscheduled 
ECGs done as 
clinically indicated) 
can be performed at 
alternative facilities if 
approved upon written 
notification from the 
sponsor.
To align with the 
Section 8.1.5. 
Alternative 
Facilities
Non-
Substantial
Section 8.3.3. 
Electrocardiograms
Clarified that ECG 
interval readings will 
be read and interpreted 
at the site for 
eligibility 
determination and 
safety monitoring and 
clarified that ECG 
tracing should be sent 
to storage/analysis to 
the external vendor.
To add clarity
Non-
Substantial
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Section # and Name
Description of 
Change
Brief Rationale
Substantial or 
Non-
substantial
Throughout the protocol
Typographical errors 
and minor edits were 
made.
For clarification 
and to ensure 
consistency
Non-
Substantial
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10.16. Appendix 16: Abbreviations
Abbreviation
Term
aBC
advanced breast cancer
ADE
adverse device effect
AE
adverse event
AESI
adverse events of special interest
AI 
aromatase inhibitors
AIDS
acquired immunodeficiency syndrome
AKI
acute kidney injury
AKT
protein kinase B
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
ASCO/CAP
American Society of Clinical Oncology/College of 
American Pathologists
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUCinf
area under the plasma concentration-time curve from time 
zero extrapolated to infinity
AUC0-24
area under the concentration-time curve from time 0 to 24 
hours
AUCtau
area under the concentration-time curve during the dosing 
interval (τ)
AV
atrioventricular
AxMP
auxiliary medical products
BC
breast cancer 
BCRP
breast cancer resistance protein
BCS
biopharmaceutics classification system 
BICR
blinded independent central review
BID
twice daily
BOR
best overall response
BP
blood pressure
BPI
brief pain inventory
BPI-SF
brief pain inventory short form
bpm
beats per minute
BUN
blood urea nitrogen
C
cycle 
CAP
chest, abdomen and pelvis; College of American 
Pathologists 
CBR
clinical benefit response
CDK4/6
cyclin dependent kinase 4/6
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Abbreviation
Term
CERAN
complete estrogen receptor antagonist
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical 
Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology collaboration
Cmax
maximum observed concentration
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CR
complete response
CRF
case report form
CRO
contract research organization
CSR
Clinical Study Report
CT
computed tomography; clinical trial; chemotherapy
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTIS
clinical trial information system
CV
cardiovascular
CYP
cytochrome
CYP2B6
cytochrome P450 2B6
CYP3A
cytochrome P450 3A
CYP3A4
cytochrome P450 3A4
D
Day
DCT
data collection tool
DDI
drug-drug interaction
DIDB
drug interaction database
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
DU
dispensable unit
EC
ethics committee; exclusion criteria 
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCrCl
estimated creatine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
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Abbreviation
Term
eGFR
estimated glomerular filtration rate
EORTC QLQ-BR23
European Organization for the Research and Treatment of 
Cancer and Quality of Life Questionnaire-Breast Cancer 
specific 
EORTC QLQ-C30
European Organization for the Research and Treatment of 
Cancer and Quality of Life Questionnaire
EOT
end of treatment 
EQ-5D-5L
European quality of life five-dimension five-level scale
EMA
European Medicines Agency
ER
estrogen receptor
ER
estrogen receptor alpha
ESR1
estrogen receptor 1
ET
endocrine therapy
EU
European Union
EudraCT
European Clinical Trials Database
FAS
full analysis set
FDA
Food and Drug Administration (United States)
FIH
first in human 
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone
FU
follow-up 
g
gram
GCP
Good Clinical Practice
GCSF
granulocyte colony stimulating factor
GGT
gamma-glutamyl transferase
GI
gastrointestinal
GLP
Good Laboratory Practice
GMCSF
granulocyte macrophage colony stimulating factor
H2
histamine receptor 2
HbA1C
hemoglobin A1c
HBV
hepatitis B virus
HCl
Hydrochloride acid
HCP
health care professional
HCV
hepatitis C virus
HDL
high-density lipoprotein
hERG
human ether-a-go-go related gene
HER2
human epidermal growth factor receptor 2
HGRAC
Human Genetics Resources Administration of China
HIV
human immunodeficiency virus
HR
heart rate; hazard ratio 
IA
Interim Analysis
IB
Investigator’s Brochure
IC
Inclusion Criteria
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Abbreviation
Term
IC50
inhibitory concentration 50
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IHC
immuno-histochemistry
ID
identification
IM
intra-muscular
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IoR
Importer of Record
IOTA
investigator overall objective tumor assessment
IPM
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISO
International Organization for Standardization
ITT
Intent -to-treat
IUD
intrauterine device
IV
intravenous
IWR
Interactive Web-based Response
K2 EDTA
dipotassium ethylenediaminetetraacetic acid
kg
kilogram
LBBB
left bundle branch block
LDL
low-density lipoprotein
LFT
liver function test
LHRH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
mBC
metastatic breast cancer
mBPI-SF
modified brief pain inventory short form
MDR
medical device regulation
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MID
minimally important difference
mIU
milli-international unit
ml
milliliter
mm
millimeter
MMRM
mixed model repeated measures
mPFS
median progression free survival
MQI
medically qualified individual
MRI
magnetic resonance imaging
msec
millisecond
mTOR
mammalian target of rapamycin
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Abbreviation
Term
N/A
not applicable or not available depending on the context
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
not evaluable
n  or N  
number
NGS
Next-Generation Sequencing
NIMP
non-investigational medicinal product
OR
objective response
ORR
objective response rate
OS
overall survival
PARP
poly adenosine diphosphate-ribose polymerase
PACL
protocol administrative change letter
PD
pharmacodynamics(s) or progression of disease depending 
on the context
PE
physical examination
PFS
progression-free survival
P-gp
P-glycoprotein
pH
potential of hydrogen
PI
principal investigator
PI3K
phosphoinositide-3-kinase
PIK3CA
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic 
subunit alpha
PLT 
platelet
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PPI
proton pump inhibitors
PR
partial response
PRO 
patient-reported outcomes
PROTAC
PROteolysis Targeting Chimeric
PS
performance status
PSSA
Pfizer's Serious AE Submission Assistant
PT
prothrombin time
PTT
partial thromboplastin time
PVC
premature ventricular contraction
QD
once daily
QoL
quality of life
QTc
corrected QT interval
QTcF 
corrected QT (Fridericia method)
QTcS
corrected QT (Study specific)
QTL
quality tolerance limit
RANKL
receptor activator of nuclear factor kappa-B ligand
rBA
relative bioavailability
RBC
red blood cell
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Abbreviation
Term
RCI
repeated confidence interval
RECIST v1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
ribonucleic acid
RP2D
recommended phase 2 dose
RP3D
recommended phase 3 dose
SABCS
San Antonio Breast Cancer Symposium
SADE
serious adverse device effect
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
safety analysis set
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Screat
serum creatinine
Scys
serum cystatin C
SD
stable disease 
SERCA
selective estrogen receptor covalent antagonist
SERD
selective estrogen receptor degrader 
SERM
selective estrogen receptor modulator
SmPC
Summary of Product Characteristics
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SSID
single subject identifier
SUSAR
suspected unexpected serious adverse reaction
T1/2
terminal elimination half-life
T bili
total bilirubin
Tdp
Torsades de Pointes
TEAE
treatment-emergent adverse events
TGI
tumor growth inhibition
TK
toxicokinetics
Tmax
time to maximum concentration
TOC
table of contents
TRAE
treatment related adverse events
TTD
time to deterioration
ULN
upper limit of normal
US
United States
USADE
unanticipated serious adverse device effect
USPI 
United State Package Insert
UW
University of Washington
VAS
visual analog scale
VE
venous embolism
VS
versus
WBC
white blood cell
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Abbreviation
Term
WOCBP
woman/women of childbearing potential
WT
wild-type
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