Clinical trial NCT03778931
Conditions: Breast Cancer
Sponsor: Stemline Therapeutics, Inc.
Start date: 2019-05-10; Completion date: 2024-08-22
Enrollment: 478 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 clinical study compares the efficacy and safety of elacestrant to the standard of care (SoC) options of fulvestrant or an aromatase inhibitor (AI) in women and men with breast cancer whose disease has advanced on at least one endocrine therapy including a CDK4/6 inhibitor in combination with fulvestrant or an aromatase inhibitor (AI) .

Detailed description:
This is an international, multicenter, randomized, open-label, active-controlled, event-driven, Phase 3 clinical study comparing the efficacy and safety of elacestrant to the SoC options of fulvestrant or an aromatase inhibitor (AI) in postmenopausal women and in men with advanced or metastatic ER+/HER2- breast cancer, either in subjects with tumors that harbor mutations in the ligand binding domain (LBD) of the estrogen receptor 1 (ESR1) gene (ESR1-mut subjects) or in all subjects regardless of ESR1 status (ESR1-mut and ESR1 wild type \[ESR1-WT\]) and whose disease has relapsed or progressed on at least one and no more than two prior lines of endocrine therapy (with documented progression), which must have included prior CDK4/6 inhibitor therapy in combination with fulvestrant or an aromatase inhibitor (AI) and for whom hormonal monotherapy with one of the SoC drugs (fulvestrant, anastrozole, letrozole, exemestane) is an appropriate treatment option.

Arms: arm 1: Subjects in Arm 1 will receive elacestrant arm 2: Subjects in Arm 2 will receive Investigator's choice of one of the Standard of Care drugs (fulvestrant, anastrozole, letrozole, or exemestane)
Interventions: intervention 1: Elacestrant intervention 2: Standard of Care
Intervention descriptions: intervention 1: 400 mg/day once daily oral dosing intervention 2: * Fulvestrant: 500 mg administered intramuscularly (IM) into the buttocks as two 5 mL injections on C1D1, C1D15 and C2D1 and Day 1 of every subsequent 28-day cycle
* Anastrozole 1 mg/day on a continuous dosing schedule
* Letrozole: 2.5 mg/day on a continuous dosing schedule
* Exemestane: 25 mg/day on a continuous dosing schedule

Protocol documents:
SAP_003.pdf: 
      
Sponsor:  
Radius 
Protocol: 
RAD1901-308 
Document Version No.: 
1.1 (Final) 
Document Date: 
10-MAY-2021 
 
 
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TABLE OF CONTENTS  
 
1 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................... 10 
1.1 
INTRODUCTION ............................................................................................................................. 10 
1.2 
OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 10 
1.2.1 
PRIMARY OBJECTIVE OF STATISTICAL ANALYSIS ......................................................... 10 
1.2.2 
KEY SECONDARY OBJECTIVES OF STATISTICAL ANALYSIS ........................................... 10 
1.2.3 
OTHER SECONDARY .................................................................................................... 11 
1.2.4 
EXPLORATORY ............................................................................................................. 11 
2 
STUDY DESIGN ...................................................................................................................... 13 
2.1 
SYNOPSIS OF STUDY DESIGN ........................................................................................................ 13 
2.2 
RANDOMIZATION METHODOLOGY .............................................................................................. 13 
2.3 
STOPPING RULES AND BLINDING .................................................................................................. 13 
2.3.1 
STOPPING RULES ......................................................................................................... 13 
2.3.2 
BLINDING .................................................................................................................... 14 
2.4 
STUDY PROCEDURES ..................................................................................................................... 14 
2.5 
EFFICACY, PHARMACOKINETIC, AND SAFETY VARIABLES ............................................................. 28 
2.5.1 
EFFICACY VARIABLES ................................................................................................... 28 
2.5.2 
PHARMACOKINETIC VARIABLES .................................................................................. 29 
2.5.3 
SAFETY VARIABLES ...................................................................................................... 29 
2.5.4 
EXPLORATORY VARIABLES .......................................................................................... 30 
3 
SUBJECT POPULATIONS ........................................................................................................ 31 
3.1 
POPULATION DEFINITIONS ........................................................................................................... 31 
3.2 
PROTOCOL DEVIATIONS ................................................................................................................ 33 
4 
STATISTICAL METHODS ......................................................................................................... 34 
4.1 
SAMPLE SIZE JUSTIFICATION ......................................................................................................... 34 
4.2 
GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 34 


      
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Protocol: 
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Document Date: 
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4.2.1 
GENERAL METHODS .................................................................................................... 34 
4.2.2 
COMPUTING ENVIRONMENT ...................................................................................... 35 
4.2.3 
REFERENCE START DATE, BASELINE DEFINITIONS, AND STUDY DAY .......................... 35 
4.2.4 
METHODS OF POOLING DATA .................................................................................... 35 
4.2.5 
ADJUSTMENTS FOR COVARIATES ............................................................................... 35 
4.2.6 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 35 
4.2.7 
SUBPOPULATIONS....................................................................................................... 37 
4.2.8 
WITHDRAWALS, DROPOUTS, LOST TO FOLLOW-UP ................................................... 38 
4.2.9 
MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 38 
4.2.10 
VISIT WINDOWS .......................................................................................................... 38 
4.3 
INTERIM ANALYSES ....................................................................................................................... 38 
4.4 
SUBJECT DISPOSITION ................................................................................................................... 39 
4.5 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................... 39 
4.6 
MEDICAL HISTORY, DISEASE HISTORY AND PRIOR THERAPIES ..................................................... 40 
4.7 
EFFICACY EVALUATION ................................................................................................................. 42 
4.7.1 
PRIMARY EFFICACY ENDPOINTS ................................................................................. 42 
4.7.2 
KEY SECONDARY EFFICACY ENDPOINTS ...................................................................... 45 
4.7.3 
OTHER SECONDARY EFFICACY ENDPOINTS ................................................................. 47 
4.7.4 
SUBGROUP ANALYSES ................................................................................................. 50 
4.8 
PATIENT REPORTED OUTCOMES (PROS)....................................................................................... 51 
4.8.1 
EQ-5D-5L ..................................................................................................................... 51 
4.8.2 
EORTC-QLQ-C30 .......................................................................................................... 51 
4.8.3 
PRO-CTCAE .................................................................................................................. 54 
4.8.4 
SENSITIVITY ANALYSES ................................................................................................ 54 
4.8.5 
EXPLORATORY ANALYSES ............................................................................................ 54 
4.9 
PHARMACOKINETIC EVALUATIONS .............................................................................................. 54 
4.10 
EXPLORATORY ANALYSIS .............................................................................................................. 55 
4.11 
INDEPENDENT DATA MONITORING COMMITTEE ......................................................................... 55 


      
Sponsor:  
Radius 
Protocol: 
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Document Version No.: 
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Document Date: 
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4.12 
SAFETY ANALYSES ......................................................................................................................... 55 
4.12.1 
TREATMENT EXPOSURE .............................................................................................. 55 
4.12.2 
ADVERSE EVENTS ........................................................................................................ 57 
4.12.3 
LABORATORY DATA..................................................................................................... 59 
4.12.4 
VITAL SIGNS ................................................................................................................ 60 
4.12.5 
ELECTROCARDIOGRAM ............................................................................................... 61 
4.12.6 
PRIOR AND CONCOMITANT MEDICATIONS ................................................................ 62 
4.12.7 
ECOG PERFORMANCE STATUS .................................................................................... 62 
5 
COVID-19 IMPACT ................................................................................................................ 63 
5.1 
COVID-19 OVERALL IMPACT ON SCHEDULED ASSESSMENTS ....................................................... 63 
5.2 
BY-SUBJECT COVID-19 LISTINGS ................................................................................................... 63 
5.3 
BY-SITE AND BY-COUNTRY COVID-19 IMPACT .............................................................................. 63 
6 
CHANGES TO PLANNED ANALYSES ........................................................................................ 64 
7 
REFERENCES ......................................................................................................................... 65 
8 
CLINICAL STUDY REPORT APPENDICES .................................................................................. 66 
8.1 
MISSING DATE IMPUTATION CONVENTION ................................................................................. 66 
8.1.1 
ADVERSE EVENT (AE) START (ONSET) DATE AND STOP DATE 
IMPUTATION ............................................................................................................... 66 
8.1.2 
CONCOMITANT MEDICATION (CM) START DATE AND STOP DATE 
IMPUTATION ............................................................................................................... 67 
8.1.3 
OTHER DATE IMPUTATIONS ........................................................................................ 67 
8.2 
CRITERIA FOR ABNORMAL VALUES FOR VITAL SIGNS .................................................................. 67 
 
 
 


      
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Document Date: 
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Protocol RAD1901-308 
ELACESTRANT MONOTHERAPY VS. STANDARD OF CARE FOR THE 
TREATMENT OF PATIENTS WITH ER+/HER2- ADVANCED BREAST 
CANCER FOLLOWING CDK4/6 INHIBITOR THERAPY: A PHASE 3 
RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, MULTICENTER 
TRIAL 
(EMERALD) 
Protocol Number: 
(Version Date) 
RAD1901-308 
25 March 2020 
Name of Test Drug: 
Elacestrant (RAD1901) 
Phase: 
3 
Methodology: 
A Randomized, Open-label, Active-control, Multicenter trial 
Sponsor: 
Radius Pharmaceuticals, Inc. 
22 Boston Wharf Road, 7th Floor 
Boston, MA 02201 
  
Tel: 617-551-4000 
Sponsor Representative: 
Maureen Conlan, MD 
Senior Vice President, Head of Oncology 
Document Date: 
10MAY2021 
Document Version: 
1.1 (Final) 
 
 
 


Sponsor: 
Radius
Protocol:
RAD1901-308
Document Version No.:
1.1 (Final)
Document Date:
10-MAY-2021
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SIGNATURE PAGE
Protocol Title:
ELACESTRANT MONOTHERAPY VS. STANDARD OF CARE FOR 
THE TREATMENT OF PATIENTS WITH ER+/HER2- ADVANCED 
BREAST CANCER FOLLOWING CDK4/6 INHIBITOR THERAPY: 
A PHASE 3 RANDOMIZED, OPEN-LABEL, ACTIVE- 
CONTROLLED, MULTICENTER TRIAL (EMERALD)
Sponsor:
Radius Pharmaceuticals, Inc.
22 Boston Wharf Road, 7th Floor
Boston, MA 02201
Waltham, MA 02451
Tel: 617-551-4000
Protocol Number:
RAD1901-308
Document Date/Version:
25 March 2020/6.0
Cytel, Inc. Author:
Cytel, Inc.
675 Massachusetts Avenue
Cambridge, MA 02139
Shubin Liu
Associate Director, Biostatistics
Signature:____________________________________
Date:________________________________________
Sponsor Approval
By signing this document, I acknowledge that I have read the document and approve of the planned 
statistical analyses described herein.  I agree that the planned statistical analyses are appropriate for 
this study, are in accordance with the study objectives, and are consistent with the statistical 
methodology described in the protocol, and all applicable regulatory guidance’s and guidelines.
I have discussed any questions I have regarding the contents of this document with the biostatistical 
author.
I also understand that any subsequent changes to the planned statistical analyses, as described herein, 
may have a regulatory impact and/or result in timeline adjustments.  All changes to the planned 
analyses will be described in the clinical study report (CSR).
________________________________
Signature:_____
Date:________________________________________
__
_


      
Sponsor:  
Radius 
Protocol: 
RAD1901-308 
Document Version No.: 
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Document Date: 
10-MAY-2021 
 
 
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Sponsor Signatory: 
 
Radius Pharmaceuticals, Inc. 
22 Boston Wharf Road, 7th Floor 
Boston, MA 02201 
Maureen Conlan, MD 
Senior Vice President, Head of Oncology 
 
 
 
 
 
 
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 Schedule of Assessments .............................................................................................................. 15 
Table 2 Rules for Deriving Date of Progression or Censor for PFS ......................................................... 43 
Table 3 Best Overall Responses when Confirmation of CR and PR Required ......................................... 48 
Table 4 EORTC QLQ-30 Scales and Items............................................................................................... 52 
Table 5 Criteria for Abnormal Vital Sign Values ...................................................................................... 67 
 


      
Sponsor:  
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Protocol: 
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Document Version No.: 
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Document Date: 
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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AI 
Aromatase inhibitor 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic class 
BOR 
Best overall response 
CBE 
Clinical benefit evaluable 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CM 
Concomitant medication 
CR  
Complete response 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for AEs 
ctDNA 
Circulating tumor DNA 
CV 
Coefficient of variation 
DCO 
Data cut-off 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
EQ-5D-5L 
EuroQoL 5 dimension, 5-level health state utility index 
ER 
Estrogen receptor 
ER+ 
Estrogen receptor positive 
ESMO 
European society for medical oncology 
ESR1 
Estrogen receptor gene 1 


      
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Document Date: 
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Abbreviation 
Definition 
ESR1-mut 
ESR1 mutation 
ESR1-mut-nd 
no ESR1 mutation detected (includes samples where ESR1 mutation 
was not detected and where ESR1 mutation status could not be 
determined) 
EU 
Europe 
HER2- 
Human epidermal growth factor receptor 2 negative 
HR 
Hazard ratio 
HRQOL 
Health-Related Quality of Life  
IDMC 
Independent data monitoring committee 
IHC 
Immunohistochemistry 
IRC 
Imaging review committee 
IRT 
Interactive randomization technology 
ITT 
Intent-to-treat 
KM 
Kaplan Meier 
LFTs 
Liver function tests 
mBC 
Advanced or metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
North America 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PIPS 
Predicted interval plots 
PK 
PP 
Pharmacokinetic(s) 
Per-Protocol Population 
PR 
Partial response 
PRO 
Patient-reported outcome 
PRO-CTCAE 
Patient-reported outcome version of the Common Terminology 
Criteria for Adverse Events 
PT 
Preferred term 


      
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Document Date: 
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Abbreviation 
Definition 
Q1 
First quartile 
Q3 
Third quartile 
QD 
Once daily 
QLQ-C30 
30-item core quality-of-life questionnaire 
RE 
Response Evaluable 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMST 
Restricted Mean Survival Time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SOC 
Standard of Care 
TEAE 
Treatment-emergent adverse event 
TTC 
Time to chemotherapy 
ULN 
Upper limit of normal 


      
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1 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1 
Introduction 
This is an international, multicenter, randomized, open-label, active-controlled, event-driven, Phase 3 
clinical study comparing the efficacy and safety of elacestrant to the standard of care (SOC) options of 
fulvestrant or an aromatase inhibitor (AI) in post-menopausal women and men with estrogen receptor 
(ER)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) advanced or metastatic 
breast cancer ( mBC) whose disease has relapsed or progressed on at least 1 and no more than 2 prior 
lines of endocrine therapy for advanced or metastatic disease, which must have included progression 
on prior CDK4/6 inhibitor therapy in combination with fulvestrant or an AI. Endocrine monotherapy 
with 1 of the SOC drugs (fulvestrant, anastrozole, letrozole, exemestane) must be an appropriate 
treatment option for subjects enrolled in this study. 
1.2 
Objectives of Statistical Analysis 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis of study 
data in order to answer the study objective(s).  Populations for analysis, data handling rules, statistical 
methods, and formats for data presentation are provided.  The statistical analyses and summary 
tabulations described in this SAP will provide the basis for the results sections of the clinical study 
report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative to those 
planned in the study protocol. 
 
1.2.1 
Primary Objective of Statistical Analysis 
x 
To compare progression-free survival (PFS) between elacestrant and SOC options of either 
fulvestrant or an AI based on a blinded Imaging Review Committee (IRC) assessment in post-
menopausal women and men with ER+/HER2- mBC, either in subjects with estrogen receptor 1 
(ESR1) mutation (ESR1-mut subjects) or in all subjects which includes subjects without 
detectable ESR1 mutation (ESR1-mut-nd).  
 
1.2.2 
Key Secondary Objectives of Statistical Analysis 
x 
To compare overall survival (OS) between treatment groups in ESR1-mut subjects 
x 
To compare OS between treatment groups in all subjects (ESR1-mut and ESR1-mut-nd)  
 


      
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Protocol: 
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Document Date: 
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1.2.3 
Other Secondary 
The following secondary objectives will be assessed in ESR1-mut-nd subjects: 
x 
To compare PFS based on blinded IRC assessment between treatment groups 
x 
To compare OS between treatment groups  
 
The following secondary objectives will be assessed in ESR1-mut subjects, ESR1-mut-nd subjects, and all 
subjects (ESR1-mut and ESR1-mut-nd): 
x 
To compare PFS based on local Investigator assessment between treatment groups 
x 
To compare objective response rate (ORR) based on blinded IRC assessment between 
treatment groups 
x 
To compare duration of response (DoR) based on blinded IRC assessment between 
treatment groups 
x 
To compare clinical benefit rate (CBR) based on blinded IRC assessment between 
treatment groups 
x 
To compare ORR based on local Investigator assessment between treatment groups 
x 
To compare DoR based on local Investigator assessment between treatment groups 
x 
To compare CBR based on local Investigator assessment between treatment groups 
 
The following secondary objectives will be assessed in ESR1-mut subjects and all subjects (ESR1-mut 
and ESR1-mut-nd): 
x 
To compare the safety and tolerability between treatment groups 
x 
To assess the pharmacokinetics (PK) of elacestrant 
x 
To describe the changes in Patient Reported Outcomes (PROs) and Health-Related Quality 
of Life (HRQOL) and the changes in PROs/HRQOL between treatment groups  
 
1.2.4 
Exploratory 
The following exploratory objectives will be assessed in ESR1-mut subjects, ESR1-mut-nd subjects, and 
all subjects (ESR1-mut and ESR1-mut-nd): 
x 
To determine the difference in the time to chemotherapy (TTC) between treatment groups 


      
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Radius 
Protocol: 
RAD1901-308 
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Document Date: 
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x 
To evaluate alterations in circulating tumor DNA (ctDNA) relevant to ER+ breast cancer and 
the CDK4/6 pathway and to explore the relationship between these findings and clinical 
response 
x 
To characterize alterations in tumor-specific genes, proteins and RNAs related to oncogenic 
pathways, and proliferation and cell cycle markers in tumor tissue, and to explore the 
relationship between these findings and clinical response 


      
Sponsor:  
Radius 
Protocol: 
RAD1901-308 
Document Version No.: 
1.1 (Final) 
Document Date: 
10-MAY-2021 
 
 
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2 
STUDY DESIGN 
2.1 
Synopsis of Study Design 
This is an international, multicenter, randomized, open-label, active-controlled, event-driven, Phase 3 
study to compare the efficacy and safety of elacestrant to the SOC options of either fulvestrant or an AI 
in post-menopausal women and men with ER+/HER2- mBC whose disease has relapsed or progressed 
on at least 1 and no more than 2 prior lines of endocrine therapy for advanced or metastatic disease, 
which must have included CDK4/6 inhibitor therapy in combination with fulvestrant or an AI.  
2.2 
Randomization Methodology 
The Investigators will randomize eligible subjects by Interactive Randomization Technology (IRT) as 
described in the IRT User Guide. Eligible subjects will be enrolled into the study and randomized in a 1:1 
ratio to receive elacestrant 400 mg tablet once daily (QD) or SOC of either fulvestrant or an AI, stratified 
by  
x 
ESR1 mutational status as detected by ctDNA at central laboratory (ESR1-mut vs ESR1-mut-nd) 
x 
Prior treatment with fulvestrant (yes vs no) 
x 
Presence of visceral metastasis (yes vs no); visceral includes lung, liver, brain, pleural and 
peritoneal involvement   
2.3 
Stopping Rules and Blinding 
2.3.1 
Stopping Rules 
An independent data monitoring committee (IDMC) external to both the Sponsor and clinical research 
organization (CRO) will be responsible for ongoing monitoring of the safety and efficacy according to 
the IDMC Charter.  The IDMC will meet on a regular basis and will make recommendations as to 
whether the trial should continue, be amended, or be discontinued based on ongoing reviews of safety 
and efficacy data. IDMC responsibilities and review schedules are outlined in an IDMC charter.  
The study may be terminated by the sponsor for any of the following reasons: 
x 
Serious safety concern 
x 
Reduced efficacy for elacestrant compared to SOC drugs 
x 
Recommendation of the IDMC 
x 
Administrative decision (eg, termination of product development) 


      
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Radius 
Protocol: 
RAD1901-308 
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Document Date: 
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2.3.2 
Blinding 
This is an open-label study; thus, study subjects and investigators will not be blinded to treatment 
assignment. However, to minimize bias in study conduct, Radius personnel performing statistical 
analyses, including biostatisticians and programmers, will be blinded to treatment assignments and 
aggregated data by treatment assignment until after database lock. CRO study team members and 
select Radius team members will not be blinded to an individual subject’s treatment assignment during 
the conduct of the study but will be blinded to aggregated data by treatment assignment until after 
database lock. The process of managing access to treatment information is documented in a blind 
management plan version final 3.0 dated 01FEB2021.  
 
An independent central IRC, blinded to subjects’ treatment assignment, will review radiographic images 
and clinical information collected on-study to determine the endpoints of disease response and 
progression. 
 
Unblinded safety data, and efficacy data based on local Investigator and IRC assessment and OS, will be 
reviewed at pre-specified intervals by the IDMC. An unblinded statistician at the CRO will perform all 
analyses in preparation for the IDMC evaluations. 
2.4 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
 


      
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Protocol: 
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Document Date: 
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Table 1 Schedule of Assessments 
Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Demography/Informed consentg 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
Medical/Surgical history/Current 
medical conditions 
X 
 
 
 
 
 
 
Breast cancer diagnosis, ER, 
HER2 statush 
X 
 
 
 
 
 
 
 


      
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Protocol: 
RAD1901-308 
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Document Date: 
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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Prior anti-cancer therapyi 
X 
 
 
 
 
 
 
Randomizationj 
 
X 
 
 
 
 
 
Patient Reported Outcomesk 
EQ-5D-5L 
EORTC QLQ-C30 
PRO-CTCAE 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xe 
 
Height 
X 
 
 
 
 
 
 
 


      
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Document Date: 
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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Weight 
X 
X 
 
X 
X 
 
 
Physical examinationl 
X 
X 
 
X 
X 
 
 
Vital signsm 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
X 
X 
 
 
12-lead ECGn 
X 
Xn 
Xn 
Xn 
Xn 
 
 
Estradiol and FSH testing (women 
only)o 
X 
 
 
 
 
 
 
Urinalysisp 
X 
 
 
 
 
 
 


      
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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Hematologyq 
Xr 
X 
X 
X 
X 
 
 
Chemistrys 
Xr 
X 
X 
X 
X 
 
 
Special Chemistryt 
X 
 
 
 
X 
 
 
Coagulationu 
Xr 
X 
X 
X 
X 
 
 
CT of chest, CT/MRI of abdomen, 
pelvis, and clinically indicated sites 
of disease; color photographs with 
measurement markers of 
superficial diseasev 
 
 
Xw 
 
{-------------------- y 
Performed every 8 weeks (± 7 days) from 
the date of randomization) 
 
 
X 
 
 
 
Xf 


      
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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Radionuclide bone scan or whole 
body MRIx 
 
Xw 
{-------------------- y 
Performed every 24 weeks (± 7 days) from 
the date of randomization 
 
Xv 
 
 
Xf 
Evaluation of abnormal bone scan 
or whole body MRIy 
Xw 
X 
Xv 
 
Xf 
Blood sample for PKz 
 
X 
X 
Cycle 2 only 
 
 
 
Blood sample for ctDNA 
(Biomarker testing)aa 
X 
 
 
Cycle 2 and 
Cycle 3 only 
X 
 
 
Tumor biopsybb 
X 
 
 
Xcc 
Xcc 
 
 


      
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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Elacestrant groupdd 
 
{ -------- yOnce Daily 
 
 
 
SOC treatment group -aromatase 
inhibitoree 
 
{ -------- yOnce Daily 
 
 
 
SOC treatment group – 
fulvestrantff 
 
C1D1, C1D15, and Day 1 of every 
subsequent cycle 
 
 
 
Drug compliancegg 
 
{-------------------------------------- y 
 
 
Adverse eventshh 
{-------------------------------------- y 
 
 
 


      
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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Prior/Concomitant 
medications/treatmentsii 
{-------------------------------------- y 
 
Survival follow-up for subjects 
who discontinue treatmentf 
 
 
 
 
 
X 
a. 
All Screening assessments must be completed within 35 days prior to randomization (all imaging must be completed within 28 days prior to 
randomization unless otherwise specified). All surgical procedures related to breast cancer diagnosis must be recorded. 
b. If EOT falls on Day 1 of a cycle and the subject is withdrawing, the EOT assessments are to be completed instead of the Cycle Day 1 
assessments. Assessments completed within the previous 14 days do not have to be repeated at the EOT visit. 


      
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c. 
A Cycle is 28 days. 
d. All assessments are to be performed pre-dose on scheduled visit days unless otherwise indicated. Procedures may be performed ±2 days relative to the  
visit. 
e. 
Onsite visit preferred; if this is not feasible, telephone contact is acceptable. If follow-up assessments are conducted by telephone, the PROs are 
to be omitted. 
f.    For subjects who discontinue study drug due to objective disease progression, survival data and start date and regimen name of the first new anti-
cancer therapy should be collected every 8 weeks (± 7 days) calculated from the last dose of study drug for the duration of the study. For subjects who 
discontinue treatment for reasons other than disease progression, and who do not begin new anti-cancer therapy, tumor assessments will continue 
every 8 weeks (± 7 days, from the date of randomization), and for subjects with bone lesions at baseline radionuclide bone scan or whole body MRI will 
be performed every 24 weeks (± 7 days), as indicated, until disease progression is documented, or new anti-cancer therapy is initiated; at that time, they 
will continue to be monitored every 8 weeks for survival and first new anti-cancer therapy information for the duration of the study. 
 
g.   Informed consent must be obtained prior to any protocol-required assessments (except for certain imaging assessments if they meet the criteria 
defined in Table 20 of the protocol). 
h. ER and HER2 status must be confirmed per local laboratory testing. 
i. 
Prior anti-cancer therapy, including drug names, treatment start/end date, dose, setting (neoadjuvant, adjuvant, or recurrent/metastatic line of 
therapy), best response, date of disease progression, and reason for treatment discontinuation, are to be recorded. 
j. 
Randomization is to occur after eligibility is determined by the study site and confirmed by the Medical Monitor. The planned first dose of C1D1 is to 
start within 1 day after randomization; randomization may occur on D-1 or on D1. Note: there is no Day 0 in this study. C1D1 is the date of first dose 
of study drug. 


      
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k. 
PRO questionnaires are to be completed by the subject using the electronic tablet provided while in clinic (cannot be taken home) at the beginning of 
the study visit and prior to any other assessments or significant interactions with site staff. PRO questionnaires will be performed on C1D1, C1D15, 
C2D1, and D1 of each subsequent cycle through C4, then D1 of every other cycle thereafter starting with C6 (ie, C2, C3, C4, C6, C8, C10, etc), at EOT, 
and at the Safety Follow-Up visit (unless this visit is performed via phone contact). Note: If a certified translation for any PRO questionnaire is not 
available for a subject, that specific PRO assessment can be omitted, but the reason must be documented. 
l. 
Physical examination at Screening to include total body examination of general appearance, skin, neck (including thyroid), ears, eyes, nose, throat, 
lungs, heart, abdomen, back, lymph nodes and extremities and a clinical neurological examination. Post-Screening physical examinations may be 
targeted based on findings present at Screening or subject complaints. Significant findings at Screening should be recorded as medical history or AEs as 
appropriate and clinically significant findings at subsequent visits should be recorded as AEs. 
m. Vital signs (temperature, respiratory rate, sitting blood pressure, and sitting pulse rate) are to be performed prior to phlebotomy at Screening and at 
every visit. On C1D1 and C1D15, all vital signs are to be assessed pre-dose and blood pressure is to be performed 4 hours (± 30 minutes) post-dose 
(all subjects) and prior to phlebotomy for PK assessment (subjects taking elacestrant). On Day 1 of every subsequent cycle, all vital signs 
are to be assessed pre-dose. 
n. 12-lead ECG is to be performed in triplicate, 2 minutes apart, at all time points after the subject has been supine for at least 5 minutes using the 
Sponsor- provided ECG equipment. ECGs will be performed pre-dose and 4 hours (± 30 minutes) post-dose on C1D1 and pre-dose and 4 hours (± 30 
minutes) post- dose on C1D15. ECG will be performed pre-dose on C2D1, and each subsequent cycle through cycle 4, then D1 of every other cycle 
thereafter starting with C6 (ie, C6, C8, C10, etc) and at EOT. See Table 19 of the protocol. 
o. Not required in women who have undergone bilateral surgical oophorectomy. 
p. Urinalysis includes protein, glucose, blood, ketones, nitrites, and leukocyte esterase. Microscopic examination is required only when urinalysis is positive 
for nitrites, leukocyte esterase, protein, or blood. 


      
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q. Hematology includes hemoglobin, hematocrit, white blood cell count with differential (including absolute neutrophil count, lymphocyte, 
monocyte, eosinophil, and basophil counts), and platelet count. 
r. 
If performed > 7 days prior to C1D1, must be repeated and eligibility criteria must still be met. 
s. 
Chemistry includes BUN or urea, creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, magnesium, albumin, total protein, total 
bilirubin (direct and indirect if total is > ULN), alkaline phosphatase, ALT, AST, glucose and lipid panel (total cholesterol, LDL, HDL, and triglycerides). If 
possible, the glucose and lipid panel should be performed with the subject in a fasting state. If performed > 7 days prior to C1D1, must be repeated and 
eligibility criteria must still be met. 
t. 
Hemoglobin A1c is to be measured at Screening and EOT. 
u. Coagulation tests include PT or INR (per the sites’s standards), aPTT (PTT is allowed if aPTT is not available), and fibrinogen. INR is required at Screening. 
If performed > 7 days prior to C1D1, must be repeated and eligibility criteria must still be met. 
v. 
Diagnostic CT for tumor assessment may be used even if acquired during PET/CT hybrid imaging providing the CT images are of sufficient quality. 
Screening tumor assessments must be performed during the Screening period (Day -28 through Day -1) as noted in Table 20 of the protocol. For 
subjects who achieve a CR or PR, a confirmation scan must be repeated at least 4 weeks after the first documented response. Subjects with history of 
stable brain metastases should have brain CT or MRI imaging in parallel with systemic imaging for evaluation of non-target lesions in the brain; brain CT 
or MRI scans are not otherwise required as part of standard imaging. Color photographs must be taken of any skin lesions that will be followed as 
either target or non-target lesions. Tumor evaluation will be performed at EOT unless an evaluation has been performed within the preceding 28 days 
or disease progression has already been documented per RECIST v1.1. See Table 20 of the protocol. For subjects who discontinue treatment for 
reasons other than disease progression (clinical PD or PD  by RECIST criteria), and who do not begin new anti-cancer therapy, tumor assessments will 
continue every 8 weeks from the date of randomization until documentation of progression or start of new anti-cancer treatment; for these subjects, 
additional assessments do not need to be performed at the EOT visit. 


      
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w. To be completed within 28 days prior to randomization. 
x. 
If bone lesions are identified at baseline (ie, during Screening), bone scans or whole body MRI are to be repeated during the active treatment phase 
(using the same modality used during Screening), every 24 weeks (±7 days), and as clinically indicated, from the date of randomization, and at time of 
confirmation of CR. If no bone lesions are identified at baseline, bone scans or whole body MRI are to be repeated during active treatment phase only 
when clinically indicated and are required at time of confirmation of CR. At EOT, bone scans or whole body MRI are required for subjects with bone 
lesions identified at Screening, unless disease progression has been confirmed elsewhere or a scan has been performed within the last 12 weeks. See 
Table 20 of the protocol. 
y. 
Suspicious abnormalities (ie, hotspots) identified on bone scan or whole body MRI at baseline and on subsequent bone scans or whole body MRI 
MUST be confirmed. Diagnostic CT of chest and CT (with bone window settings) or MRI of abdomen and pelvis (or PET CT if CT images are of sufficient 
quality) are sufficient for evaluation of bone lesions involving the axial skeleton. Additional imaging of appendicular skeletal lesions (eg, skull, cervical 
spine, extremities) by bone window settings on CT scan or MRI are required if these sites are the only bone lesions to be followed. If a lesion is not 
confirmed to be metastatic by CT with bone windows or MRI, it should not be followed as a target or non-target lesion and it does not require re-
assessment. The same modality must be used throughout the study for confirmation for a given lesion/subject. Areas that have received palliative 
radiotherapy should be followed as non-target lesions. 
z. 
Blood samples for PK are to be collected at the following time points for subjects randomized to the elacestrant group only: C1D1 and C1D15: 0 h 
(pre- dose) and 4 h (± 30 min) post-dose; C2D1: 0 h (pre-dose). Investigators may obtain additional blood samples for PK analysis at the time(s) that 
significant AE or SAEs occur that are considered potentially related to the study drug. See Table 19 of the protocol. 
aa. Blood sample for ctDNA to be collected at Screening, pre-dose on C2D1, pre-dose on C3D1, and at EOT. Four tubes of blood will be drawn at 
Screening, and 2 tubes will be drawn for all other time points (see Guardant’s Whole Blood Sample Collection, Handling, Shipping and Result 
Instructions for the RAD1901-308 (EMERALD) study for Screening ctDNA samples; see Medpace Laboratory Manual for management of on-
treatment ctDNA samples) 


      
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bb. All subjects with accessible lesions are requested to provide tumor biopsies; however, these biopsies are optional and are not required for eligibility. For 
subjects agreeing to provide biopsies, biopsies will be taken at 3 time points during the study: pre-treatment, on-treatment, and post-treatment. Pre-
treatment biopsies should be obtained after progression on the most recent systemic anticancer therapy and should be performed on a metastatic 
lesion or site of recurrent disease, if accessible. Biopsies obtained for other reasons within 3 months of first dose of study drug that meet these criteria 
may be submitted in lieu of a fresh biopsy. 
cc. On-treatment and post-treatment biopsies are only required if the pre-treatment biopsy was successful (ie, tissue obtained; confirmed to contain 
adequate tumor cells by central laboratory). On-treatment biopsy should be performed between C1D28 and C3D28, as close as feasible to C2D28. 
Post-treatment biopsy should be performed at the time of study drug discontinuation and prior to initiation of new anti-cancer therapy. Biopsies 
should be taken from the same lesion at each time point, when feasible. 
dd. For subjects randomized to elacestrant, elacestrant should be taken at approximately the same time(s) each day on a continuous dosing schedule. 
However, on days of planned clinic visits, subjects should be informed to take their study drug at the study site. Subject is to be instructed to 
complete a daily dosing diary. 
ee. For subjects randomized to SOC, with Investigator selection of AI, AI should be taken at approximately the same time(s) each day on a continuous 
dosing schedule. However, on days of planned clinic visits, subjects should be informed to take their study drug at the study site. Subject is to be 
instructed to complete a daily dosing diary. 
ff. For subjects randomized to SOC, with Investigator selection of fulvestrant, fulvestrant dose (500 mg) is to be administered IM slowly (1-2 minutes 
per injection) divided as two 5-mL injections into gluteal area (one in each buttock) on C1D1, C1D15 and Day 1 of each subsequent cycle. 
 
gg. Elacestrant or AI bottle(s) or blisters, including any unused capsules/tablets, are to be returned to clinic for drug accountability. Drug accountability is to 
be performed on Day 1 of every cycle. Dose, date and time of fulvestrant administration must be documented in both medical record and electronic 
Case Report Form. 


      
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hh. All AEs are to be recorded from time of signed informed consent until 30 days after last dose of study drug. At any time after 30 days from the last 
dose of study drug, the Investigator may report any SAE that he/she believes is related to study drug. 
ii. All prior medications and concomitant medications (including oral, topical, intravaginal, rectal, and inhaled over-the-counter medications, herbal 
treatments, supplements, vitamins, or any substance use) and medical treatments taken from 35 days prior to signing informed consent until 30 days 
after the last dose of study drug are to be recorded. 
AI = aromatase inhibitor; C1D1 = Cycle 1 Day 1; CR = complete response; CT = computed tomography; ctDNA = circulating tumor DNA; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30; EOT = End of Treatment; EQ-5D-5L = EuroQol 5 dimension 5 level; ER = estrogen receptor; FSH = follicle stimulating hormone; 
HER2 = human epidermal growth factor receptor 2; MRI = magnetic resonance image; PK = pharmacokinetics; PR = partial response; PRO = patient- reported 
outcome; PRO-CTCAE = Patient Reported Outcome-Common Terminology Criteria for Adverse Events; PTx = Post-treatment; RECIST = Response Evaluation 
Criteria in Solid Tumors; ULN = upper limit of normal. 


      
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2.5 
Efficacy, Pharmacokinetic, and Safety Variables 
2.5.1 
Efficacy Variables 
2.5.1.1 
Primary Efficacy Variables 
The primary endpoints of this study are as follows: 
x 
IRC-assessed PFS in the ESR1-mut subjects 
x 
IRC-assessed PFS in all subjects (ESR1-mut and ESR1-mut-nd)   
where IRC-assessed PFS is defined as the time from randomization until the date of objective disease 
progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1; Appendix 1 of 
the protocol) as assessed by the blinded IRC, or death from any cause.  
2.5.1.2 
Key Secondary Efficacy Variables 
x 
OS in ESR1-mut subjects 
x 
OS in all subjects (ESR1-mut and ESR1-mut-nd)    
OS is defined as the time from randomization until the date of death from any cause. 
2.5.1.3 
Other Secondary Efficacy Variables 
The following endpoints will be analyzed for ESR1-mut-nd-subjects: 
x 
IRC-assessed PFS  
x 
OS 
The following endpoints will be analyzed for ESR1-mut, ESR1-mut-nd, and all subjects (ESR1-mut and 
ESR1-nd):  
x 
Local Investigator-assessed PFS, defined as the time from randomization until the date of 
objective disease progression per RECIST v1.1 as assessed by local investigators, or death 
from any cause 
x 
IRC-assessed ORR, defined as the percentage of subjects with measurable disease who 
have achieved either confirmed complete response (CR) or partial response (PR), based on 
blinded IRC assessment. To achieve a confirmed CR or PR, the confirmation scan must be 
repeated at least 4 weeks after the first documented response. 
x 
IRC-assessed DoR defined as the duration of time from the date when criteria are met for 
CR or PR (whichever is first recorded) that is subsequently confirmed as assessed by IRC, 
per RECIST v1.1, until the first date of documented recurrent or progressive disease, 


      
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objectively documented based on blinded IRC assessment, or death from any cause, 
whichever occurs first.  
x 
IRC-assessed CBR, defined as the percentage of subjects who have achieved confirmed CR 
}
W Z
v «
] u
] v P
Z
« U
}
o
per RECIST v1.1, based on blinded IRC assessment 
x 
Local Investigator-assessed ORR, defined similarly as IRC-assessed ORR except using local 
Investigator assessment 
x 
Local Investigator-assessed DoR, defined similarly as IRC-assessed DoR except using local 
Investigator assessment 
x 
Local Investigator-assessed CBR, defined similarly as IRC-assessed CBR except using local 
Investigator assessment 
The following endpoints will be analyzed for ESR1-mut and all subjects (ESR1-mut and ESR1-nd):  
x 
PRO endpoints assessed using the health-related quality of life (HRQOL) scales, EuroQOL 5 
Dimension 5 Level (EQ-5D-5L), European Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and PRO Version 
of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). 
 
2.5.2 
Pharmacokinetic Variables 
The following endpoints will be analyzed for ESR1-mut subjects, all subjects (ESR1-mut and ESR1-mut-
nd) and ESR1-mut-nd subjects. 
x 
PK assessed by evaluation of elacestrant plasma concentrations at pre-dose (pretreatment) 
and 4 hours post-dose on Cycle 1 Day 1 (C1D1), pre-dose (Ctrough) and 4 hours post-dose on 
Cycle 1 Day 15 (C1D15) and pre-dose (Ctrough) on Cycle 2 Day 1 (C2D1)   
 
2.5.3 
Safety Variables 
Safety and tolerability are assessed by treatment-emergent adverse events (TEAEs), treatment-
emergent serious adverse events (SAEs), dose modifications due to TEAEs, and clinical laboratory 
data (i.e., hematology, chemistry, and coagulation), electrocardiogram (ECG), ECOG performance 
status, and vital signs. Safety analyses will be performed for ESR1-mut subjects and all subjects 
(ESR1-mut and ESR1-mut-nd). 
 


      
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2.5.4 
Exploratory Variables 
The following exploratory endpoints will be analyzed for ESR1-mut, ESR1-mut-nd, and all subjects 
(ESR1-mut and ESR1-mut-nd): 
x 
Time to chemotherapy (TTC), defined as the time from randomization to initiation of 
chemotherapy 
x 
Alterations in ctDNA relevant to ER+ breast cancer and the CDK4/6 pathway and the 
relationship between these findings and clinical response 
x 
Alterations in genes, proteins, and RNAs related to oncogenic pathways and proliferation 
and cell cycle markers in tumor tissue and the relationship between these findings and 
clinical response 
 


      
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3 
SUBJECT POPULATIONS 
3.1 
Population Definitions 
The following populations will be defined and used for analysis: 
x 
Intent-to-Treat (ITT) Population: The ITT population consists of all randomized subjects. This is the 
primary population for PFS and OS analysis. Subjects will be analyzed according to their randomized 
treatment assignment.  
x 
Per-Protocol (PP) Population: The PP population consists of all randomized subjects who do not 
have any protocol deviations that could confound the interpretation of the primary analyses 
conducted on the ITT population. The PP population will be used to perform sensitivity analysis for 
the primary efficacy endpoint PFS if the primary endpoint is statistically significant. Subjects will be 
analyzed according to their randomized treatment assignment.  
Subjects with protocol deviations for any of the following criteria will be excluded from the PP 
population. 
Eligibility criteria: 
x 
Subject must have a histologically- or cytologically-proven diagnosis of adenocarcinoma of 
the breast with evidence of either locally advanced disease not amenable to resection or 
radiation therapy with curative intent or metastatic disease not amenable to curative 
therapy (Protocol Inclusion Criteria 1) 
x 
Subject must have 1 of the following as defined by RECIST v1.1: (Protocol Inclusion Criteria 
3) 
o Measurable disease 
o Bone only disease with evaluable lesions. Subjects must have at least 1 lytic or 
mixed lytic/blastic bone lesion; blastic lesions only are not evaluable and allowed. 
o Subjects who have had prior radiation to bone must have at least 1 evaluable lesion 
in a nonirradiated area 
x 
Subject must have ER+ and HER2- tumor status confirmed per local laboratory testing 
(Protocol Inclusion Criteria 7) 
x 
Subject must have previously received at least 1 and no more than 2 lines of endocrine 
therapy, either as monotherapy or as a combination therapy with another agent for mBC 
(Protocol Inclusion criteria 8) 
x 
Subject must have progressed during or within 28 days of completion of prior treatment 
with a CDK4/6 inhibitor in combination with either fulvestrant or an AI for mBC (Protocol 
Inclusion Criteria 9) 


      
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x 
Subject must have received no more than 1 line of cytotoxic chemotherapy in the 
advanced/metastatic setting (Protocol Inclusion Criteria 10) 
x 
Subject must have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 
1 (Protocol Inclusion criteria 11) 
x 
Subject must not have received prior treatment with elacestrant or investigational SERD or 
ER antagonist (Protocol Exclusion Criteria 1) 
x 
Subject must not have received prior anti-cancer or investigational drug treatment within 
the protocol defined window period (Protocol Exclusion Criteria 2) 
x 
Subject must not have difficulty in tolerating oral medications (Protocol Exclusion Criteria 
12) 
x 
Subject must not have taken a moderate or strong CYP3A4 inhibitor or inducer 14 days 
prior to study entry or during the study (Protocol Exclusion Criteria 13) 
       Other criteria: 
x 
Subject did not provide main study informed consent 
x 
Subject was randomized but did not receive any study drug 
x 
Subject was treated with study drug they were not randomized to 
x 
Subject received systemic anticancer therapy while on study drug 
x 
Subject received radiation therapy to a target lesion 
x 
Safety Population: The Safety population consists of all subjects who received at least 1 dose of 
study drug. All safety analyses will be performed using the Safety population. Subjects will be 
analyzed according to the treatments they actually received in Cycle 1.   
x 
Response Evaluable (RE) population: The RE population includes all ITT subjects who had 
measurable disease (i.e., at least 1 target lesion) at baseline and at least 1 post-baseline RECIST 
assessment on any (target or non-target) lesions and/or had a new lesion.  IRC-assessed RE 
population will be defined using IRC assessment while Local Investigator-assessed RE population 
will be defined using Local Investigator assessment. 
IRC-assessed ORR and DoR will be analyzed using IRC-assessed RE population. Local Investigator-
assessed ORR and DoR will be analyzed using Local Investigator-assessed RE population. 
x 
Clinical Benefit Evaluable (CBE) population: The CBE population includes all ITT subjects who had 
measurable and/or evaluable disease (i.e., target and/or non-target lesions) at baseline and at least 
1 post-baseline RECIST assessment on any (target or non-target) lesions and/or had a new lesion. 
IRC-assessed CBE population will be defined using IRC assessment while Local Investigator-assessed 
CBE population will be defined using Local Investigator assessment. 


      
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IRC-assessed CBR will be analyzed using IRC-assessed CBE population. Local Investigator-assessed 
CBR will be analyzed using Local Investigator-assessed CBE population. 
x 
Pharmacokinetic (PK) Population: The PK population consists of all subjects who received at least 1 
dose of elacestrant and have plasma elacestrant concentration data for at least 1 scheduled time 
point. PK analyses will be performed using the PK population. 
x 
Biomarker Population: The Biomarker population comprises all safety subjects for whom baseline 
and at least 1 post-baseline result are available for the biomarker of interest. The exploratory 
biomarker analysis will be performed using the Biomarker population. 
3.2 
Protocol Deviations 
A major protocol deviation is defined as a deviation from basic requirements of the study protocol, 
including inclusion and exclusion criteria, concomitant medication restrictions, dosing (i.e., outside of ± 
20% prescribed dose of study drug), or any protocol requirements that result in a significant added risk 
to the study participant or have an impact on the quality of the data collected or the outcome of the 
study. Major protocol deviations will be identified by Radius. The final list of Important Protocol 
Deviations that will exclude subjects from the PP populations will be imported to analysis data via an 
excel file. Major protocol deviations will be summarized by category, if applicable, and by treatment 
group in the ITT population. A by-subject data listing of all protocol deviations will also be provided. 
At the discretion of the sponsor, major and important protocol deviations, as determined by a review of 
the data, may result in the exclusion of a subject’s data from the PP population data set.  The sponsor 
will be responsible for producing the final protocol deviation file (formatted as a Microsoft Excel file); 
this file will include a description of all protocol deviations, and clearly identify whether or not each 
deviation warrants exclusion from the PP population data set.  This file will be finalized prior to 
database lock. 


      
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4 
STATISTICAL METHODS 
4.1 
Sample Size Justification 
Note: This section describes the justification for the sample size used when the study was initiated and 
was based on PFS only. This amendment adds a truncated Hochberg procedure to allow testing of the 
key secondary endpoint of OS while maintaining the family-wise type I error rate at 5% (2-sided). At the 
time of this amendment, the study is fully enrolled (N=478) and the sample size will not be increased.  
Section 4.2.6 describes the testing procedures to be used for OS and the power associated with the OS 
analysis based on the number of OS events expected for the 478 subjects. 
Among the ESR1-mut subjects, the study requires approximately 160 PFS events to have a power of 
80% to detect a hazard ratio of 0.610 at the 2-sided alpha level of 2.5%. Assuming a median PFS of 5.3 
months for the SOC treatment group, this treatment effect represents a median PFS of 8.7 months for 
the elacestrant treatment group, an increase of approximately 3.4 months among the ESR1-mut 
subjects. 
Among all subjects (ESR1-mut and ESR1-mut-nd), a total of approximately 340 PFS events will have 92% 
power to detect a hazard ratio of 0.667 at the 2-sided alpha level of 2.5%.    
The 2-sided alpha level of 2.5% for the sample size calculation is selected to ensure that at least 1 of the 
2 primary efficacy endpoints will pass the Hochberg procedure (Hochberg, 1988) to control the overall 
alpha level at 5.0% (see Section 4.2.6). 
The study will need to randomize approximately 220 ESR1-mut subjects (110/treatment group) and a 
total of approximately 466 subjects of both types (ESR1-mut and ESR1-mut-nd, 233/treatment group) in 
a 1:1 ratio to the two treatment groups.  
To prevent exceeding the target recruitment by more than 10% (i.e., 512 subjects total), if a total of 292 
ESR1-mut-nd subjects is reached before 220 ESR1-mut subjects are enrolled, further enrollment will be 
restricted to ESR1-mut subjects only until the target of 220 is achieved. 
Final analysis of the primary endpoint will be performed at approximately 160 PFS events among the 
ESR1-mut subjects and 340 PFS events among all subjects (ESR1-mut and ESR1-mut-nd), estimated to 
occur at 30-33 months after the first subject is randomized. 
4.2 
General Statistical Methods and Data Handling 
4.2.1 
General Methods 
For continuous variables, descriptive statistics will include the number of subjects, mean, standard 
deviation, median, Q1, Q3, minimum, and maximum. For categorical variables, descriptive statistics will 
include the number of subjects, frequency counts and percentages. Time-to-event endpoints will be 


      
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analyzed by the Kaplan-Meier method. When tabulating categorical data, “missing” will be included as 
a category and the number of subjects with missing data will be presented.  
4.2.2 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4), unless 
otherwise noted.  Medical History and adverse events will be coded using MedDRA version 23.0.  
Concomitant medications will be coded using World Health Organization (WHO) Drug version Sep2018.  
4.2.3 
Reference Start Date, Baseline Definitions, and Study Day 
Baseline is defined as the last non-missing assessment prior to or on the first dose date. For subjects 
who are randomized but not dosed, baseline is defined as the last non-missing assessment prior to or 
on the date of randomization.   
All data listings that contain an evaluation date will contain a relative study day. Study day is defined as 
the number of days relative to the reference start date. The reference start date is designated as Study 
Day 1. Study Day -1 is the day that precedes Study Day 1. There is no Day 0 in this study. Study Day will 
be calculated as follows: 
x 
Before reference start date: Study Day = (Date of assessment – reference start date) 
x 
On or After reference start date: Study Day = (Date of assessment – reference start date) + 1  
x 
For efficacy assessments (tumor assessment, progression, death), the reference start date is date 
of randomization. 
x 
For other assessments, the reference start date is the first dose date. For subjects who did not 
take any study drug, the reference start date is date of randomization. 
4.2.4 
Methods of Pooling Data 
Data from all sites will be pooled for all analyses unless otherwise specified.  
4.2.5 
Adjustments for Covariates 
The primary analysis will include the randomization strata collected from eCRF as the stratification 
factors. For the analyses of all subjects, these stratification factors include ESR1-mutation status (ESR1-
mut vs ESR1-mut-nd), prior treatment with fulvestrant (yes vs no), and presence of visceral metastases 
(yes vs no). For the analyses of ESR1-mut subjects and ESR1-mut-nd subjects, the stratification factors 
include prior treatment with fulvestrant (yes vs no) and presence of visceral metastases (yes vs no).  
4.2.6 
Multiple Comparisons/Multiplicity 
To ensure the family-wide error rate does not exceed 5%, multiplicity adjustments will account for the 
analyses of 2 primary endpoints, 2 key secondary OS endpoints, and the analyses of the key secondary 
OS endpoints at 2 time points.  As described below, a truncated Hochberg procedure will be used to 
test the primary endpoints.  The outcome of the analysis of the 2 PFS primary endpoints will determine 


      
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the amount of alpha that will be passed to the analyses of OS.  A Haybittle-Peto rule will be used to 
adjust the alpha for the analyses of OS at 2 time points.  
The null hypothesis for the primary endpoint in ESR1-mut subjects is that elacestrant does not differ 
from the SOC treatment group in the IRC-assessed PFS for the ESR1-mut subjects; the alternative 
hypothesis is that elacestrant differs from the SOC treatment group in the IRC-assessed PFS for the 
ESR1-mut subjects.   
The null hypothesis for the primary endpoint in all subjects (ESR1-mut and ESR1-mut-nd) is that 
elacestrant does not differ from the SOC treatment group in the IRC-assessed PFS for all subjects (ESR1-
mut and ESR1-mut-nd); the alternative hypothesis is that elacestrant differs from the SOC treatment 
group in the IRC-assessed PFS for all subjects (ESR1-mut and ESR1-mut-nd).    
OS is planned to be analyzed at the following 2 time points: 
x 
At the time of the primary PFS analysis (when approximately 160 and 340 PFS events are 
observed among the ESR1-mut and all subjects (ESR1-mut and ESR1- mut-nd), respectively, and  
x 
At the time of the final OS analysis (when approximately 50% of the subjects have died)  
Although the sample size estimates were based on the conventional Hochberg procedure, a  parallel 
gatekeeping strategy based on the truncated Hochberg procedure (Dmitrienko et al. 2011) will be used 
to control the family-wise type I error rate at 5% (2-sided) and to allow alpha to pass along from the 
analyses of the primary endpoint of PFS to the analyses of the key secondary endpoint of OS. The 
endpoint-specific alpha levels for the conventional Hochberg for this case are 0.05 and 0.05/2, and 
those for the equally weighted Bonferroni method are 0.05/2.  The primary endpoint-specific alpha 
levels for the truncated Hochberg are constructed by combining the endpoint-specific alpha levels of 
the 2 methods with a truncation fraction. The analyses will use a truncation fraction of 0.9:  
r1 = 0.05*0.9 + 0.05/2*(1-0.9) = 0.0475 
r2 = 0.05/2*0.9 + 0.05/2*(1-0.9) = 0.025 
To implement the truncated Hochberg procedure, the p-value for each of the 2 PFS primary endpoints 
will be derived without any adjustment. The larger p-
o
¡ ] o o
} u
1=0.0475.  If the 
larger p-value is not less than 0.0475, the smaller p-
o
¡ ] o o
} u
P
2 = 0.025. 
x If the larger p-value is <0.0475, statistical significance will be claimed for both PFS endpoints. 
An alpha of 0.05 will be passed along to OS. To control for the analyses of OS at the 2 time 
points, the alpha level of 0.05 will be distributed across the 2 time points. A 2-sided alpha level 
of 0.0001 will be allocated at the time of the primary PFS analysis and a 2-sided alpha level of 
0.0499 will be allocated at the time of the final OS analysis. This alpha splitting is according to a 
Haybittle-Peto rule. At each time point, OS will be evaluated using the conventional Hochberg 


      
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procedure and the allocated alpha to control for the multiple testing associated with the 2 
populations. 
x If the larger p-
o
]
H
X
Ò
v
Z
u
o o
-value is <0.025, statistical significance will be 
claimed only for the endpoint associated with the smaller p-value. An alpha of 0.0025 will be 
passed along to OS only in the population in which PFS is significant. To control for the 2 
different times the OS analysis will be conducted, the alpha level of 0.0025 will be distributed 
across the 2 time points. An alpha level of 0.0001 will be allocated at the time of the primary 
PFS analysis and an alpha level of 0.0024 will be allocated at the time of the final OS analysis. 
This adjustment is according to a Haybittle-Peto rule. 
x If the larger p-
o
]
H
X
Ò
v
Z
u
o o
-
o
]
H
X
Ò U
v }
]
be claimed. In this case, no alpha will be passed along to OS. No claim regarding OS will be 
made. 
OS will be evaluated at 2 time points: (1) at the time of the primary analysis of PFS and (2) when 
approximately 50% of all subjects (ESR1-mut and ESR1-mut-nd) have died.  At the time of this 
amendment, the study is fully enrolled (N=478). The second analysis of OS will take place when 
approximately 239 subjects have died.   At the time of the PFS analysis, it is expected that 
approximately 96 subjects will have died.   
Among all subjects (ESR1-mut and ESR1-mut-nd), the study will have 60% power to detect a hazard 
ratio of 0.75 at a 1-sided alpha level of 2.5%.   Assuming a median OS of 25 months for the SOC 
treatment group, this hazard ratio represents a median OS of 33 months for the elacestrant treatment 
group.  This calculation also accounts for 1 interim analysis at an information fraction of 0.4 with an 
alpha spending equal to 0.0001 at the interim analysis. 
The study has enrolled 228 ESR1-mut subjects.  Approximately 114 OS events are expected among the 
ESR1-mut subjects at the time of the second analysis of OS.  With 114 OS events, the study will have 
39% power to detect a hazard ratio of 0.73 at a 1-sided alpha level of 2.5%. Assuming a median OS of 
28 months for the SOC treatment group, this treatment effect represents a median OS of 38 months for 
the elacestrant treatment group, an increase of approximately 10 months among the ESR1-mut 
subjects.  This calculation also accounts for 1 interim analysis at an information fraction of 0.4 with an 
alpha spending equal to 0.0001 at the interim analysis. 
Unless otherwise specified, analyses of all other efficacy endpoints will be performed at the 2-sided 
alpha level of 5% without adjusting the p-values for multiple comparisons.  
4.2.7 
Subpopulations 
Subgroup analyses of IRC-assessed PFS, OS, ORR, DoR, and CBR will be performed in the same manner 
as the analyses using the ITT population for ESR1-mut subjects and for all subjects (ESR1-mut and ESR1- 
mut-nd) for the following stratification factors (based on eCRF):  
- 
Prior treatment with fulvestrant (yes vs no) 


      
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- 
Presence of visceral metastasis (yes vs no) 
Subgroup analyses of IRC-assessed PFS, OS, ORR, DoR and CBR will also be performed in the same 
manner as the analyses using the ITT population for ESR1-mut subjects and all subjects (ESR1-mut and 
ESR1- mut-nd) by categories of  
- 
P
~ D
Ò
«
H
Ò
«
 
- 
P
~ D
Ò
«
H
Ò
«
 
- 
Race (Caucasian vs Asian vs Other)  
- 
Region (Europe [EU], North America [NA], Asia, Other) 
- 
Baseline ECOG Performance Status (0 vs 1)  
- 
Measurable disease at baseline (yes vs no) 
- 
Number of prior lines of endocrine therapy in the advanced/metastatic setting (1 vs 2) 
- 
Number of lines of chemotherapy in the advanced/metastatic setting (0 vs 1) 
4.2.8 
Withdrawals, Dropouts, Lost to Follow-up 
Subjects are free to withdraw from participation in the study for any reason at any time. The reason for 
terminating study participation will be recorded in each subject’s medical records (source documents) 
and entered into the End of Study electronic Case Report Form (eCRF). 
If a subject withdraws from the study, every effort was to be made to complete the end of treatment 
(EOT) assessments; however, if a subject withdraws consent, no further assessments should be 
performed and no additional data should be collected. Radius may retain and continue to use any data 
collected before consent was withdrawn. 
4.2.9 
Missing, Unused, and Spurious Data 
Unless otherwise specified, missing dates for onset of AEs and start dates of concomitant medications 
will be handled according to the Missing Date Imputation Method in Appendix 7.1.   
4.2.10 Visit Windows 
CRF visits will be used for analysis. For the safety analysis, in the case of multiple observations at a 
specific visit, the observation which is the latest will be used. If more than one observation is made on 
the same day, an average value if continuous or the worst value if categorical will be included in the 
analysis.  
4.3 
Interim Analyses 
At about 70% enrollment, an interim futility analysis will be provided to the IDMC. At that time, the 
total number of PFS events is expected to be around 119 (35% of the total events). At this interim data 


      
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look, the IDMC will evaluate the primary endpoint in conjunction with other efficacy endpoints, 
including OS, ORR, DoR and CBR. These additional efficacy data will assist the IDMC to check 
consistency for the totality of the data. The IDMC will make 1 of the following recommendations 
according to the conditional power of the primary efficacy endpoint for all subjects (ESR1-mut and 
ESR1-mut-nd), which will be derived based on the observed data at the interim futility analysis. 
x 
} v
] v
]
o
v u }
] ( ]
] (
Z
} v
]
] } v
o
2.5% 
x 
Terminate enrollment of ESR1-mut-nd subjects due to futility if the conditional power is <20% at 
the alpha level of 2.5% 
x 
Other (specified in IDMC charter) 
If the conditional power is < 20% for all subjects at the alpha level of 2.5%, further enrollment of ESR1-
mut subjects will be evaluated by the IDMC. Study drug administration for ongoing subjects will remain 
unchanged unless otherwise determined by the Investigator. 
The graphical display using predicted interval plots (PIPS) may be used to support the finding from the 
conditional power.  
Details of statistical methods for the interim futility analysis are provided in the interim SAP Version 1.0 
dated 17 August 2020.  
4.4 
Subject Disposition 
Subject disposition will be tabulated by treatment group (elacestrant vs SOC) and by SOC type 
(fulvestrant vs AIs) to include the number screened, the number randomized, the number treated, the 
number in each subject population for data analysis, the number remaining on treatment, the number 
who discontinued study drug and the primary treatment termination reason as recorded in the eCRF, 
and the number who discontinued the study as well as the primary reason for study withdrawal as 
recorded in the eCRF. 
A by-subject data listing of study drug information including the primary reason for treatment 
discontinuation and study withdrawal as recorded in the eCRF, if applicable, will be presented. 
4.5 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group (elacestrant vs SOC) 
and by SOC type (fulvestrant vs AIs) using the ITT, RE, CBE and PP populations for ESR1-mut subjects 
and all subjects (ESR1-mut and ESR1-mut- v
X
P
U
P
P
}
~ ] v
«
H
Ò V
] v
]
] } v U
D
Ò
H
Ò
U
Z
] P Z
U
¡
] Ph
baseline disease characteristics, and ECOG performance status will be summarized using descriptive 
statistics. BMI is calculated as Weight (kg) / Height (m)^2, using baseline weight measurements.  


      
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Baseline ESR1 mutation data per central laboratory results will be summarized by treatment group 
(elacestrant vs SOC) and by SOC type (fulvestrant vs AIs) using the ITT, RE, CBE and PP populations for 
ESR1-mut subjects. Number of subjects with each ESR1 mutation and number of ESR1 mutations per 
subject (0, 1, 2, 3, >3) will be summarized using descriptive statistics. A by-subject listing will be 
provided. 
A summary of stratification factors at randomization in interactive randomization technology (IRT) 
system will be provided, including ESR1 mutation status detected by ctDNA (ESR1-mut vs ESR1-mut-nd), 
prior treatment with fulvestrant (yes vs no), and presence of visceral metastases (yes vs no).  
Stratification factors as recorded in the eCRF will also be summarized. Analysis of primary and 
secondary efficacy endpoints will adjust for the randomization stratification factors obtained from the 
eCRF. 
No formal hypothesis testing will be performed.    
4.6 
Medical History, Disease History and Prior Therapies 
Medical history will be presented by MedDRA (version 23.0) system organ class and preferred term 
(PT), summarizing by treatment group (elacestrant vs SOC) and SOC type (fulvestrant vs AIs) using ITT 
population for ESR1-mut subjects and all subjects (ESR1-mut and ESR1-mut-nd). 
The following summaries will be provided by treatment group and SOC type for the ITT, RE, CBE and PP 
populations for ESR1-mut subjects and all subjects (ESR1-mut and ESR1-mut-nd): 
Summary of breast cancer history and baseline disease characteristics will include years since diagnosis, 
stage at initial diagnosis, TNM staging at initial diagnosis, stage at baseline, TNM staging at baseline, 
sites of disease and number of metastatic sites (0, 1, 2, H3). Sites of disease will be categorized as 
breast, bone, bone only, visceral (any, and brain, liver, lung) and other.  
Data on breast cancer diagnosis, hormone receptor status and HER2 status are based on local historical 
results. Summary of breast cancer histopathology will include source of tissue (original diagnosis, most 
recent biopsy, or interim time point), histology and grade, results for ER status including 
immunohistochemistry (IHC) percentage, results for progesterone receptor status including IHC 
percentage, results for HER2 status including IHC result and in situ hybridization (ISH) HER2/CEP17 
ratio, if performed. Local historical data, including tissue source and results, for ESR1 and PIK3CA 
mutations will be summarized. 
Summary of prior systemic anticancer therapies will include:  
x 
Number of subjects with neoadjuvant therapy 
x 
Number of subjects with adjuvant therapy 
x 
Number of subjects with neoadjuvant and/or adjuvant (neo/adjuvant) endocrine therapy, and each 
type of endocrine therapy in neo/adjuvant setting 
x 
Number of subjects with neo/adjuvant chemotherapy 


      
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x 
Number of subjects with neo/adjuvant targeted therapy  
x 
Total duration of AI therapy in any setting  
x 
In advanced/metastatic setting  
o Number of lines of endocrine therapy (1 or 2) with documented progression  
o Best response to last line of endocrine therapy  
o Number of lines of chemotherapy (0 or 1) 
o Number of lines of targeted therapy  
o Number of subjects with each type of endocrine therapy 
o Number of subjects with each type of targeted therapy 
x 
Time from last prior systemic anticancer therapy to randomization 
x 
Number of subjects with each type of endocrine responsiveness status (primary resistance, 
secondary resistance, endocrine therapy sensitive) 
Endocrine therapy includes fulvestrant, letrozole, anastrozole, exemestane and tamoxifen. AI therapy is 
a subset of endocrine therapy, including letrozole, anastrozole and exemestane. Targeted therapy 
includes mTOR inhibitor, PI3K inhibitor and VEGF inhibitor. Chemotherapy includes cytotoxic 
chemotherapy. Any setting includes neoadjuvant, adjuvant and advanced/metastatic combined. 
According to the European Society for Medical Oncology (ESMO) guidelines, primary endocrine 
resistance is defined as relapse < 24 months while on endocrine therapy in adjuvant setting or 
progression < 6 months while on endocrine therapy in advanced/metastatic setting. Secondary 
v
}
] v
]
v
]
( ] v
o
H
or progression < 12 months after e v
} (
v
}
] v
Z
«
] v
i
months while on endocrine therapy in advanced/metastatic setting. Endocrine sensitive is defined as 
o
H
u } v
Z
(
v
} (
v
}
] v
Z
ths after 
end of endocrine therapy in advanced/metastatic setting. 
If a subject received multiple lines of AI therapy, duration of AI therapy includes the total number of 
calendar days using any AI therapy. Multiple AI therapies given on same day, will be counted as 1 day. 
Summary of prior radiation therapy will include time from last therapy to first dose of study drug, body 
location(s), treatment setting category and primary reason for discontinuation. 
Summary of breast cancer procedures will include time from last procedure to first dose of study drug, 
type of procedure(s) and treatment setting. 
Post-treatment systemic breast cancer therapy will be presented in data listings. Number of subjects 
with post-treatment systemic breast cancer therapy will be summarized.  Time to post-treatment 
systemic breast cancer therapy is defined as the number of days from date of last dose of study drug to 
initiation of systemic breast cancer therapy and will be summarized by category of systemic anticancer 
therapy (e.g., endocrine therapy, targeted therapy, etc.) and treatment group descriptively for the 
subjects who receive systemic breast cancer therapy after study drug discontinuation. 


      
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4.7 
Efficacy Evaluation 
PFS and OS will be analyzed based on ITT population. ORR and CBR will be analyzed using RE 
population, and CBE population, respectively.  
Final analysis of primary endpoints will be performed when approximately 160 events of objective 
disease progression or death based on IRC assessment have occurred among the ESR1-mut subjects 
and 340 events have occurred among all subjects (ESR1-mut and ESR1-mut-nd).  
Analysis of primary and secondary efficacy endpoints will adjust for the randomization stratification 
factors (obtained from eCRF). For the analyses of all subjects, these stratification factors include ESR1-
mutational status (ESR1-mut vs ESR1-mut-nd), prior treatment with fulvestrant (yes vs no), and 
presence of visceral metastases (yes vs no). For the analyses of ESR1-mut subjects, the stratification 
factors include prior treatment with fulvestrant (yes vs no) and presence of visceral metastases (yes vs 
no).  
4.7.1 
Primary Efficacy Endpoints 
4.7.1.1 
Primary Analysis 
The primary efficacy endpoints of this study are  
x 
IRC-assessed PFS in the ESR1-mut subjects 
x 
IRC-assessed PFS in all subjects (ESR1-mut and ESR1-mut-nd)  
which will be analyzed using the ITT population for the ESR1-mut subjects, and all subjects (ESR1-mut 
and ESR1-mut-nd), respectively.     
PFS is defined as the duration (in months) from the date of randomization to the earliest date of 
documented disease progression (RECIST v1.1) as assessed by the blinded IRC, or death due to any 
cause regardless of whether the subject withdraws from randomized therapy (i.e., date of PFS event or 
censoring – date of randomization + 1). Subjects who receive any new systemic anticancer therapy 
before disease progression will be censored at the date of the last adequate tumor assessment before 
initiation of new systemic anticancer therapy. 
Tumor assessment visits are scheduled every 8 weeks ± 7 days. Subjects without documented 
progression or death will be censored at the date of last adequate tumor assessment. Subjects without 
any post-baseline tumor assessments will be censored at the date of randomization (i.e., Day 1); 
however, if the subject dies within 2 visits of baseline without any post-baseline tumor assessments, 
this will be counted as an event. If the subject progresses or dies immediately after 2 or more 
consecutive missed visits, the subject will be censored at the time of the latest evaluable RECIST 1.1 
assessment prior to the 2 missed visits (Note: a visit with a response of NE is not considered as missed 
visit ). Given the scheduled visit assessment scheme (i.e., every 8 weeks ± 7 days), 2 missing visits will 
equate to 18 weeks since the previous RECIST assessment, allowing for early and late visits (i.e., 2 x 8 


      
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weeks + 1 week for an early assessment + 1 week for a late assessment = 18 weeks).  Detailed censoring 
rules are described in Table 2. 
Table 2 Rules for Deriving Date of Progression or Censor for PFS 
Situation 
Date of Progression/Death or 
Censoring 
PFS 
Outcome 
No baseline tumor assessments 
Date of Randomization 
Censored 
No post-baseline assessments and no death 
Date of Randomization 
Censored 
No documented progression and no death 
(with a post-baseline tumor assessment) [1] 
Date of last adequate tumor 
assessment  
Censored 
Subject lost to follow-up (or withdrew 
consent) before documented progression or 
death [1] 
Date of last adequate tumor 
assessment 
Censored 
Documented progression [2] 
Date of documented progression 
Progressed 
Death without documented progression [1] 
Date of death 
Progressed 
Documented progression or death after 
missing 1 post-baseline tumor assessment [2] 
Date of documented progression or 
death   
Progressed 
Documented progression or death after 
u ]
] v P
H
} v
]
}
-baseline tumor 
assessments [2] 
Date of last adequate tumor 
assessment before missed 
assessments or date of randomization, 
whichever is later  
Censored 
Note: If more than 1 situation applies, date of PFS and associated outcome will be determined by the earliest date 
and associated outcome above.  
[1] If a subject received new systemic anticancer therapy, PFS will be censored at the date of last adequate tumor 
assessment before or on initiation of new systemic anticancer therapy. 
[2] If progression occurred after initiation of new systemic anticancer therapy, PFS will be censored at the date of 
last adequate tumor assessment before or on initiation of new systemic anticancer therapy. 
 
Kaplan-Meier method will be used to estimate the survival distribution function of PFS. The following 
summaries by treatment group will be provided: median PFS and 95% CI, 1st and 3rd quartiles and 95% 
CI, PFS rates and 95% CI at months 3, 6, 12 (and every 6 months thereafter until the end of follow-up or 
no more subjects are at risk).  Confidence interval will be constructed using Brookmeyer and Crowley 
method (1982) via linear transformation.  


      
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The difference in the primary endpoints between the 2 treatment groups will be analyzed using the 
stratified log-rank test, with the randomization stratification factors (as described in section 4.7) for 
generation of the p-value. 
The hazard ratio (HR) and 95% CI for the treatment effect will be estimated using the stratified Cox 
proportional hazards regression model with Effron method of handling ties, stratified by randomization 
stratification factors (as described in section 4.7). Confidence interval will be constructed using the 
profile likelihood method. 
The Kaplan–Meier curve of PFS of the 2 treatment groups will be displayed graphically, along with 
median event times and 95% CIs, for 2 sets of study subjects, ESR1-mut subjects and all subjects. 
4.7.1.2 
Assumptions of Proportionality 
The assumption of proportional hazards will be tested first by examining Kaplan–Meier curves and plots 
of the log of negative log of estimated survival probability versus log (time) and, if these raise concerns, 
by fitting a time dependent covariate (adding a treatment-by-time or treatment-by-ln(time) interaction 
term) to assess the extent to which this represents random variation. 
If a lack of proportionality is evident, the HR from the primary analysis can still be meaningfully 
interpreted as an average HR over time unless there is extensive intersection of the survival curves.   
In addition, the Restricted Mean Survival Time (RMST) method (Royston and Parmar 2013) permits 
inference over a specified time period, with an area-under-the-curve type approach, in situations with 
non-proportional hazards. Details for RMST are described in the section of sensitivity and supplemental 
analysis below.  
4.7.1.3 
Sensitivity Analyses 
The following sensitivity analyses will be performed. 
Sensitivity Analysis 1 (Actual event PFS analysis): In this analysis, PFS events recorded after missing 2 or 
more consecutive tumor assessments will be included as events, with the PFS event date defined as the 
actual event date after the 2 missed tumor assessments. 
Sensitivity Analysis 2 (Backdating PFS analysis): In this analysis, PFS events recorded after missing 2 or 
more consecutive tumor assessments will be included as events, with the PFS event date defined as the 
date of the next scheduled tumor assessment after the last adequate tumor assessment.  
For example, suppose a subject had the last adequate tumor assessment in January, missed tumor 
assessments in March and May, and then had a PFS event in July. In Sensitivity Analysis 1, the subject 
will have the actual PFS event date in July as the event date; in Sensitivity Analysis 2, this subject will 
have the next scheduled tumor assessment date (after the last adequate tumor assessment in January) 
in March as the event date.      
The above 2 sensitivity analyses will be performed in the same manner as the primary efficacy analyses. 


      
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Sensitivity Analysis 3 (Unstratified analysis): As a sensitivity analysis to assess the impact of 
stratification (obtained from eCRF), the 2 treatment groups will be compared using the unstratified log-
rank test. The HR together with the associated 95% confidence interval obtained using the unstratified 
Cox regression model will also be presented. 
Sensitivity Analysis 4 (COVID-19 analysis): To assess potential COVID-19 impact, if subjects died due to 
COVID-19 infection without PD, PFS date will be censored at the death date. Analysis of PFS will be 
performed in the same manner as the primary efficacy analyses if at least 5% of deaths are due to 
COVID-19 infection. 
Sensitivity Analysis 5 (Per-Protocol Population analysis): This analysis will be performed based on PP 
population in the same manner as the primary efficacy analyses if the primary endpoints are 
statistically significant. 
4.7.1.4 
Restricted Mean Survival Time Analysis 
The RMST methodology is independent of the proportional hazards assumption and can be used as a 
supplemental analysis to explore the robustness of the primary analysis results. The restricted mean 
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Z
v
Z
]
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}
Z
}
should not exceed the minimum of the largest follow-up time for both treatment groups so that the 
RMST of both treatment groups being evaluated can be adequately estimated and comparison 
¡
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tudy 
follow-up so that the majority of survival outcomes will be covered by the time interval. The RMST up 
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-up 
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The RMST analysis of the primary efficacy endpoints will be performed with the randomization 
stratification factors (as described in section 4.7) as covariates.  
RMST estimate of the IRC-assessed PFS with the 95% CI will be provided for each treatment group. The 
treatment effect will be assessed based on the difference of RMST in IRC-assessed PFS between the 
treatment groups. The associated 95% CI for the difference in means and a p-value will be generated. 
4.7.2 
Key Secondary Efficacy Endpoints 
4.7.2.1 
Key Secondary Analysis 
Key secondary efficacy endpoints include the following: 
x 
OS in ESR1-mut subjects  
x 
OS in all subjects (ESR1-mut and ESR1- mut-nd) 
Overall survival is defined as the time from the date of randomization until death due to any cause 
regardless of whether the subject withdraws from randomized treatment or receives another 
anticancer therapy (i.e., date of death or censoring – date of randomization + 1). Any subject not known 


      
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to have died at the time of analysis will be censored based on the last recorded date on which the 
subject was known to be alive. The last known alive date is the date subject last confirmed to be alive 
from eCRF Survival Status page. 
 
Analyses of OS in ESR1-mut subjects and in all subjects (ESR1-nut and ESR1- mut-nd) will be performed 
using the ITT population. 
For each of the 2 sets of study subjects, OS will be analyzed at the following 2 time points 
x 
At the time of the primary PFS analysis (when approximately 160 and 340 PFS events are 
observed among the ESR1-mut and all subjects (ESR1-mut and ESR1- mut-nd), respectively, and  
x 
At the time of the final OS analysis (when approximately 50% of the subjects have died)  
At each time point, analyses of OS will be conducted in a similar manner as the primary analysis of PFS.  
Number and percentage of subjects with event and subjects censored will be tabulated by treatment 
group.  
Kaplan-Meier method will be used to estimate the survival distribution function of OS. The following 
summaries by treatment group will be provided: median OS and 95% CI, 1st and 3rd quartiles and 95% 
CI, overall survival rates and 95% CI at months 6, 12, and 18 (and every 6 months thereafter until the 
end of follow-up or no more subjects are at risk).  
The difference in the key secondary endpoints between the 2 treatment groups will be analyzed using 
the stratified log-rank test, with the randomization stratification factors (as described in section 4.7) for 
generation of the p-value.  
The HR and 95% CI for the treatment effect will be estimated using the stratified Cox proportional 
hazards regression model with Efron method of handling ties, stratified by randomization stratification 
factors (as described in section 4.7). Confidence interval will be constructed using the profile likelihood 
method.  
The Kaplan–Meier curve of OS of the 2 treatment groups will be displayed graphically, along with 
median event times and 95% CIs, for 2 sets of study subjects, ESR1-mut subjects and all subjects (ESR1-
mut and ESR1-mut-nd). 
4.7.2.2 
Sensitivity Analyses 
A sensitivity analysis for OS will examine the censoring patterns to rule out attrition bias with regard to 
the treatment comparisons, achieved by a Kaplan-Meier plot of time to censoring where the censoring 
indicator of OS is reversed. 
The number of subjects prematurely censored will be summarized by treatment group. A subject 
would be defined as prematurely censored if their survival status was not defined at the data cut-off 
(DCO). 


      
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In addition, duration of follow-up will be summarized using medians: 
x 
In all subjects: Time from randomization to the date of death (i.e. overall survival) or to the 
date of censoring (date last known to be alive) for censored subjects regardless of treatment 
group. 
x 
By treatment group: Time from randomization to the date of death (i.e. overall survival) or to 
the date of censoring (date last known to be alive) for censored subjects 
To assess potential COVID-19 impact, if subjects died due to COVID-19 infection, OS date will be 
censored at the death date. Analysis of OS will be performed in the same manner as the primary key 
secondary analysis if at least 5% of deaths are due to COVID-19 infection. 
4.7.2.3 
Restricted Mean Survival Time Analyses 
Restricted mean survival time analysis will be provided for the key secondary efficacy endpoints in a 
similar manner as IRC-assessed PFS as described in Section 4.7.1.4 as a supportive analysis. 
4.7.3 
Other Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed in ESR1- mut-nd subjects 
x 
IRC-assessed PFS 
x 
OS  
The following secondary efficacy endpoints will be assessed for ESR1-mut subjects, ESR1- mut-nd 
subjects, and All (ESR1-mut and ESR1- mut-nd) subjects: 
x 
Local Investigator-assessed PFS 
x 
IRC-assessed ORR and DoR 
x 
IRC-assessed CBR 
x 
Local Investigator-assessed ORR and DoR 
x 
Local Investigator-assessed CBR 
Analyses of IRC-assessed PFS in ESR1- mut-nd subjects will be performed using the ITT population for 
the ESR1- mut-nd subjects, in the same manner as the analyses of the primary efficacy endpoints. 
Analyses of OS in ESR1- mut-nd subjects will be performed using the ITT population for the ESR1- mut-
nd subjects, in the same manner as the analyses of OS in ESR1-mut subjects and all subjects (ESR1-mut 
and ESR1- mut-nd).   


      
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4.7.3.1 
Local Investigator-assessed PFS 
 PFS will also be derived based on local investigator assessment, in the same way as the derivation of 
the primary endpoints and will be analyzed using the ITT population for ESR1-mut subjects, ESR1- mut-
nd subjects, and all subjects (ESR1-mut and ESR1- mut-nd), in the same manner as the primary and 
secondary analyses. 
4.7.3.2 
IRC-assessed Objective Response Rate (ORR) 
Independent Review Committee-assessed ORR is defined as the percentage of subjects whose best 
overall response (BOR) was either complete response (CR) or partial response (PR), where BOR will be 
derived using blinded IRC assessment following the RECIST (version 1.1) criteria. For each subject, BOR 
can be 1 and only 1 of the following: CR, PR, stable disease (SD), progressive disease (PD) and not 
evaluable (NE), with derivation using the order of CR > PR > SD > PD > NE. Additionally, the response of 
CR or PR will require confirmation at least 4 weeks after the initial documentation of the response. 
When confirmation is required, BOR is derived according to Table 3 below. Responses recorded after 
initiation of new systemic anti-cancer therapy will be excluded from BOR derivation. 
Table 3 Best Overall Responses when Confirmation of CR and PR Required 
Overall response 
First time point 
Overall response 
Subsequent time point 
Best overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD provided wise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not evaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response 
would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may have been claimed when 
subsequent scans suggest small lesions were likely still present and in fact the subject had PR, not CR at the first timepoint. 
Under these circumstances, the original CR should be changed to PR and the best response is PR.    


      
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Independent Review Committee-assessed ORR derived as above, will be summarized using the RE 
population (defined based on IRC assessment) for ESR1-mut subjects, ESR1- mut-nd subjects, and all 
subjects (ESR1-mut and ESR1- mut-nd). The ORR will be summarized as a binomial response rate with 
95% CIs based on Clopper-Pearson method. Comparison between treatment groups will be performed 
using Cochran-Mantel-Haenszel (CMH) test adjusting for randomization stratification factors (as 
described in section 4.7). The Mantel-Fleiss criterion will be checked to verify the suitability of CMH 
test. If Mantel- & o
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test (Proc Logistic) will be used instead with adjustment for the same set of randomization stratification 
factors. 
Difference between treatment groups in the ORR along with 95% stratified Newcombe confidence 
limits for CI will also be provided.      
A waterfall plot will be produced to present percentage change from baseline in sum of the diameters 
and BOR for each subject by treatment group. 
4.7.3.3 
IRC-assessed Duration of Response (DoR) 
Independent Review Committee-assessed DoR will be summarized using the RE population (based on 
IRC assessment)  who achieved confirmed CR or PR based on the blinded IRC review for ESR1-mut 
subjects, ESR1- mut-nd subjects, and all subjects (ESR1-mut and ESR1- mut-nd).  
Duration of Response is defined as the duration from the first response until disease progression or 
death from any cause.  DoR will be censored at the last assessment if the subject did not have disease 
progression. If subjects receive new systemic anti-cancer therapy before progression, DoR will be 
censored at the last assessment before or on the date of initiation of new systemic anti-cancer therapy. 
/ v
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last tumor assessments prior to the missed visits. 
Duration of Response will be analyzed by treatment group using the Kaplan-Meier method, with the 
median, 25th and 75th percentiles reported along with the 95% CIs. The Kaplan–Meier curve will also 
be plotted by treatment group. 
4.7.3.4 
IRC-assessed Clinical Benefit Rate (CBR) 
Independent Review Committee-assessed CBR will be summarized using the CBE population (based on 
IRC assessment) for ESR1-mut subjects, ESR1- mut-nd subjects, and all subjects (ESR1-mut and ESR1- 
mut-nd). CBR is defined as the proportion of subjects who had confirmed CR or PR any time during the 
study, or SD that lasted at least 24 weeks (including disease assessments performed up to a week 
earlier than the scheduled date). The IRC-assessed CBR will be derived based on the blinded IRC 
assessment and will be analyzed in the same manner as the analysis of ORR.  
4.7.3.5 
Local Investigator-assessed ORR and DoR 
Objective Response Rate will be derived from tumor assessments performed by Local Investigators 
using the RECIST criteria and analyzed in the same manner as the analysis of IRC-assessed ORR.  


      
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Local Investigator-assessed DoR will be derived and analyzed in the same manner as the IRC-assessed 
DoR.  
Analyses of local Investigator-assessed ORR and DoR will be provided for the RE population (based on 
Local Investigator assessment) for ESR1-mut subjects, ESR1- mut-nd subjects, and all subjects (ESR1-
mut and ESR1- mut-nd). 
4.7.3.6 
Local Investigator-assessed CBR 
The Local Investigator-assessed CBR will be derived based on Local Investigator assessment, similar to 
the derivation of the IRC-assessed CBR and analyzed in the same manner for CBE population (based on 
Local Investigator assessment) for ESR1-mut subjects, ESR1- mut-nd subjects, and all subjects (ESR1-
mut and ESR1- mut-nd). 
4.7.4 
Subgroup Analyses 
Subgroup analyses of IRC-assessed PFS, OS, ORR, DoR, and CBR will be performed in the same manner 
as the analyses using the ITT population for ESR1-mut subjects and all subjects (ESR1-mut and ESR1- 
mut-nd) for the following stratification factors (based on eCRF):  
- 
Prior treatment with fulvestrant (yes vs no) 
- 
Presence of visceral metastasis (yes vs no)  
Subgroup analyses of IRC-assessed PFS, OS, ORR, DoR and CBR will be performed in the same manner 
as the analyses using the ITT population for ESR1-mut subjects and all subjects (ESR1-mut and ESR1- 
mut-nd) for the following subgroups:  
- 
P
~ D
Ò
«
H
Ò
«
 
- 
P
~ D
Ò
«
H
Ò
«
 
- 
Race (Caucasian vs Asian vs Other)  
- 
Region (Europe [EU], North America [NA], Asia, Other) 
- 
Baseline ECOG Performance Status (0 vs 1)  
- 
Measurable disease at baseline (yes vs no) 
- 
Number of prior lines of endocrine therapy in the advanced/metastatic setting (1 vs 2) 
- 
Number of lines of chemotherapy in the advanced/metastatic setting (0 vs 1) 
A subgroup analysis may not be performed if the number of subjects in the subgroup in each treatment 
group is not sufficiently large (e.g., <5%). In the case of the subgroup variable with more than 2 levels, 
pooling may be considered when there is insufficient sample size within the level. 


      
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4.8 
Patient Reported Outcomes (PROs) 
PRO endpoints are secondary endpoints and will be summarized by treatment group using the ITT 
population for ESR1-mut subjects and all subjects (ESR1-mut and ESR1- mut-nd).   
4.8.1 
EQ-5D-5L 
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health state utility.  
The EQ-5D-5L, developed by the EuroQol Group, is a generic questionnaire that provides a simple 
descriptive profile of health and a single index value for health status for economic appraisal. The EQ-
5D-5L questionnaire comprises 6 questions that cover 5 dimensions of health (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression). For each dimension, respondents select which 
statement best describes their health on that day from a possible 5 options of increasing levels of 
severity (no problems, slight problems, moderate problems, severe problems and unable to/extreme 
problems). A unique EQ-5D health state, termed the EQ-5D-5L profile, is reported as a 5-digit code with 
a possible 3,125 health states. For example, state 11111 indicates no problems on any of the 5 
dimensions.  Respondents also assess their health on that day using the EQ-VAS, which ranges from 0 
(worst imaginable health) to 100 (best imaginable health). 
The EQ-5D profile will be converted into a weighted health state utility value, termed the EQ-5D index, 
by applying a country-specific equation to the EQ-5D-5L profile that represents the comparative value 
of health states.  This equation is based on national valuation sets elicited from the general population 
and the base case will be the UK perspective.  Where a valuation set has not been published, the EQ-
5D-5L profile will be converted to the EQ-5D index using a crosswalk algorithm (van Hout et al. 2012).  
The EQ-VAS is reported separately. 
Descriptive statistics will be calculated for each scheduled visit/time point in the study, for each study 
drug, and as a total. This will report the number of subjects, the number of EQ-5D questionnaires 
completed for each visit, and the number and proportion of subjects responding to each dimension of 
the EQ-5D-5L. Additionally, summary statistics (eg, n, mean, median, SD, min, and max) will be reported 
for the EQ-5D index score and the EQ-VAS score, and the change from baseline will be reported for the 
EQ-5D index score and the EQ-VAS score.  
Graphical plots of the mean (+/- standard deviation) EQ-5D index score and EQ-VAS score, including 
change from baseline by scheduled visits/time points in the study may be produced. 
4.8.2 
EORTC-QLQ-C30 
The EORTC QLQ-C30 consists of 30 questions that can be combined to produce 5 functional scales 
(physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), 
and global health status/QoL scale. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 
Scoring Manual (Fayers et al. 2001). An outcome variable consisting of a score from 0 to 100 will be 
derived for each of the symptom scales, each of the functional scales, and the global measure of health 
status scale in the EORTC QLQ-C30 according to the EORTC QLQ-C30 Scoring Manual. Higher scores on 


      
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the global measure of health status and functional scales indicate better health status/function, but 
higher scores on symptom scales represent greater symptom severity.  
 Patient-reported outcome (PRO), based on scales from the QLQ-C30 questionnaires, will be 
summarized at Cycle 1 Day 1 (i.e., baseline) and each time it is measured according to the protocol 
schedule, along with change from baseline (CFB). Line graph presentation of arithmetic mean 
(±standard deviation) plots of scores and change from baseline versus time point will be produced. 
The following scores will be calculated: 5 functional scales, 3 symptom scales, a global health 
status/quality of life (QoL) scale, and 6 single items, Table 4. 
Table 4 EORTC QLQ-30 Scales and Items 
Scale/Item 
Label 
Items (Questions) 
included 
Range of response for 
items 
Global Health Status / QOL 
QL2 
29, 30 
6 
Functional Scales 
 
 
 
Physical functioning 
PF2 
1 - 5 
3 
Role functioning 
RF2 
6, 7 
3 
Emotional functioning 
EF 
21 - 24 
3 
Cognitive functioning 
CF 
20, 25 
3 
Social functioning 
SF 
26, 27 
3 
Symptom Scales/Items 
 
 
 
Fatigue 
FA 
10, 12, 18 
3 
Nausea and vomiting 
NV 
14, 15 
3 
Pain 
PA 
9, 19 
3 
Dyspnea 
DY 
8 
3 
Insomnia 
SL 
11 
3 


      
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Scale/Item 
Label 
Items (Questions) 
included 
Range of response for 
items 
Appetite loss 
AP 
13 
3 
Constipation 
CO 
16 
3 
Diarrhea 
DI 
17 
3 
Financial difficulties 
FI 
28 
3 
 
All of the scales and single-item measures range in score from 0 to 100. For global health status and 
functional scales, 100 is associated with a high performance while for symptoms scales, 100 is 
associated with high burden related to the symptoms. The calculation for each score is derived as 
follows. 
1. A raw score is calculated as the average of the items of the scale 
2. A linear transformation is applied to standardize the raw score so that the score ranges from 0 
to 100. 
For example, the below algorithm demonstrates how various QLQ-C30 scales are computed:  
 
Functional scales/items: Score = {1-(RS-1)/range}×100 
 
Symptom scales/items: Score = {(RS-1)/range}×100 
 
Global health status/QoL:  Score = {(RS-1)/range}×100 
For all scales, the Raw Score, RS, is the mean of the component items. 
In case of missing items, the following rules will be applied: 
1. If at least half of the items from the scale are not missing, missing items will be ignored. RS will 
be calculated as the mean of the non-missing items. 
2. If not, the scale will be set to missing. For single item measures, the score is set to missing. 


      
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QoL endpoints will be summarized by treatment at baseline and each study visit, along with CFB. Line 
graph presentation of arithmetic mean (±standard deviation) plots of scores and CFB versus time point 
will be produced. 
Summaries of absolute and change from baseline values of each EORTC QLQ-C30 scale/item and 
associated 95% CI will be reported by scheduled visit for each treatment group. Line graph presentation 
of least square mean plots of scores versus time point will be produced. 
4.8.3 
PRO-CTCAE 
The patient reported outcomes version of the common criteria for adverse events (PRO-CTCAE), a PRO 
version of the CTCAE system developed by the National Cancer Institute (NCI), is included to assess 
tolerability from the patient’s perspective. It was developed in recognition that collecting symptom 
data directly from patients can improve the accuracy and efficiency of symptomatic AE data collection. 
Symptoms have been converted to patient terms (e.g., CTCAE term “myalgia” converted to “aching 
muscles”). It characterizes the frequency, severity and interference of symptomatic treatment 
toxicities, such as pain, fatigue, nausea, and cutaneous side effects, reported from the subject’s 
perspective. 
PRO-CTCAE data at baseline will be presented as the number (%) of subjects with each level of attribute 
item for each PRO-CTCAE symptom term. Change from baseline at all visits will be presented in 3 
categories: improved, no change or worsened from baseline for each PRO-CTCAE symptom term. A bar 
chart of the incidence by visit will be presented for each symptom term. 
4.8.4 
 Sensitivity Analyses 
Sensitivity analyses will be performed for all PRO endpoints by excluding subjects who had at least 1 
missing visit due to COVID-19. Sensitivity analyses will be performed in the same manner as the primary 
PRO analyses. 
4.8.5 
Exploratory Analyses 
A mixed model repeated measures (MMRM) model may be developed to analyze the CFB of QoL over 
study visits through Cycle 6. Subjects in the ITT population having at least a baseline value and one 
value after randomization should be included in this analysis. The model may consider CFB as the 
dependent variable and include the following variables: treatment, visit, stratification factors, baseline 
value, interaction of visit and baseline, interaction of treatment and visit. Subject will be a random 
effect. Least square means and their 95% confidence intervals may be computed. Line graph 
presentation of least square mean plots of scores versus time point may be produced. 
4.9 
Pharmacokinetic Evaluations 
Elacestrant plasma concentrations will be summarized descriptively (with n, mean, standard deviation, 
CV, median, minimum, maximum, geometric mean and its associated CV) by visit and nominal 


      
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timepoint (pre-dose or 4 hours post-dose) for ESR1-mut subjects, all subjects (ESR1-mut and ESR1-mut-
nd) and ESR1-mut-nd subjects. Plot of geometric mean of the elacestrant concentrations by nominal 
time point will also be presented.   
4.10 Exploratory Analysis 
Time to Chemotherapy (TTC) is defined as the number of days from randomization to initiation of 
chemotherapy and will be summarized by treatment group descriptively for the subjects who receive 
chemotherapy as first systemic anticancer therapy after treatment discontinuation.  
Listings will be provided for tumor biopsies obtained at pre-treatment, on-treatment and post-
treatment periods. 
Biomarker analyses may be conducted when study is closed. 
4.11 Independent Data Monitoring Committee 
An independent IDMC external to both the Sponsor and clinical research organization CRO will be 
responsible for ongoing monitoring of the safety and efficacy according to the IDMC Charter.  The IDMC 
will meet on a regular basis and will make recommendations as to whether the trial should continue, be 
amended, or be discontinued based on ongoing reviews of safety and efficacy data. IDMC 
responsibilities and review schedules are outlined in an IDMC charter.  
4.12 Safety Analyses 
Unless otherwise specified, safety analyses will be conducted using the Safety population for ESR1-mut 
subjects and all subjects (ESR1-mut and ESR1- mut-nd).  Safety evaluations will be based on the 
incidence, relationship, severity grade, and seriousness of treatment emergent adverse events (TEAEs), 
ECOG performance status, vital signs, ECGs, and laboratory tests of chemistry, hematology, and 
coagulation parameters, as well as dose modifications (interruptions/reductions) due to TEAEs, and 
treatment discontinuations due to TEAEs. In addition, study drug exposure and usage of concomitant 
medications will be summarized. 
4.12.1 Treatment Exposure 
Treatment exposure will be summarized descriptively by treatment group and SOC type (fulvestrant vs 
AIs) as duration on treatment and extent of exposure to study drug.  
Duration on Treatment will be defined as follows: 
Treatment duration (days) for elacestrant and AIs will be calculated as (Last dose date – First dose date 
+ 1). 


      
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Treatment duration (days) for fulvestrant will be calculated as (End date of last cycle – First dose date + 
1). End date of last cycle is the earliest of the following dates: the expected end date of last cycle, date 
of death, date of last known alive, date of subject withdrawal from the study, or the analysis cut-off 
date if subject is known to be alive after analysis cut-off date. Expected end date of last fulvestrant 
cycle is calculated as: 
x 
If last dose of fulvestrant was administered in cycle 1, expected end date of last cycle is the last 
dose date + 13 days 
x 
If last dose of fulvestrant was administered beyond cycle 1, expected end date of last cycle is the 
last dose date + 27 days 
Measures of extent of exposure include the Total Number of Doses per Subject, Absolute Dose 
Intensity, Relative Dose Intensity (%) and compliance (%).  
Duration on Treatment, Total Number of Doses, Absolute Dose Intensity, Relative Dose Intensity and 
Compliance will be summarized by treatment and SOC type (fulvestrant vs AIs), as well as presented in 
a by-subject data listing. 
 
4.12.1.1 Elacestrant/AIs 
For subjects assigned to take the oral drugs of elacestrant and the AIs, the study drug is to be taken 
every day during treatment. The start and stop date will be recorded for each un-interrupted dosing 
period, where the same dose is taken every day. In case of a dose change, such as dose level change, or 
missing doses, etc, a new period will be recorded.  
The number of doses in a period is the number of days in the period calculated as (end date – start date 
+ 1), assuming one dose per day. The Total Number of Doses is then calculated by taking the sum of the 
number of doses in all the periods. Study drug Compliance is defined as Total Number of Doses divided 
by Duration on Treatment.  
The dose intensity of a period is the sum of doses in the period divided by the number of days in the 
period calculated as (end date – start date + 1), assuming one dose per day. The ‘Absolute Dose 
Intensity (mg/day)’ is then calculated by taking the sum of doses in all the periods divided by the sum 
of the number of days in each period. The ‘Planned dose intensity (mg/day)’ for a subject is their initial 
dose. The ‘Relative Dose Intensity (%)’ is Absolute Dose Intensity divided by planned dose intensity 
*100.  
Dose Reductions 
Frequency tables on number of subjects with at least 1 dose reduction of any study drug will be 
provided.  
Dose reductions due to AE for subjects receiving elacestrant will be summarized as follows: 


      
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Number of subjects with at least 1 dose reduction  
 
Time to first dose reduction  
 
Number of dose reductions (0 vs 1 vs 2) 
A listing with visit (cycle) dates, drug administration start and end dates and times, and end of study 
status will be provided. Subjects with missing or delayed doses will be listed. 
4.12.1.2 Fulvestrant 
For subjects assigned to take fulvestrant, the study drug is to be taken via intramuscular injection on 
Days 1, 15, 29, and every 28 days thereafter.  
For these subjects, the Total Number of Doses is derived by taking the sum of the number of doses 
recorded during treatment.    
Total Number of Intended Dose = 1, if Duration of treatment < 15 
                                                    = 2, if 15 G
] } v
} (
d
u
v
D
29
 
                                                    = round ([Duration of Treatment-28] / 28, 1) + 2 
Compliance is defined as Total Number of Doses divided by the Total Number of Intended Doses.  
Dose Reductions 
Dose reductions due to AE for subjects receiving fulvestrant will be summarized as follows: 
 
Number of subjects with 1 dose reduction  
 
Time to first dose reduction  
Number of missing doses due to COVID-19 will be summarized using descriptive statistics. 
Administration details due to COVID-19 will be presented in a by-subject listing. 
4.12.2 Adverse Events 
All AEs will be coded to preferred term (PT) and system organ class and using the MedDRA (version 
23.0) coding dictionary.   
Analyses of AEs will be performed for those events that are considered to be treatment-emergent 
adverse events (TEAEs), where TEAE is defined as: 
x 
Any AE that was absent (i.e., had not occurred) or had resolved prior to the start of study drug, 
and which occurred on or after the date of the first dose of study drug and within 30 days of 
the last dose of study drug; or  
x 
Any AE that started prior to the first dose of study drug, was ongoing after treatment started, 
and increased in severity after the start of study drug and within 30 days of the last dose of 
study drug 


      
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Adverse events will be summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given system organ class or PT. Preferred terms for a similar 
medical concept (i.e., synonym terms) will be grouped across different system organ classes in all AE 
summary tables except as otherwise noted. All listings will present PTs by original PT term.  
For summaries by severity/toxicity grade, a subject with multiple occurrences under the same PT or 
system organ class will be represented under the most severe occurrence. For summaries by 
relationship to study drug, a subject with multiple occurrences under the same PT or system organ class 
will be represented under the most related occurrence. A TEAE is considered treatment-related if its 
causality was related on the AE eCRF page. 
The worst toxicity grade per subject, by system organ class, or per PT will be used in the CTCAE grade 
summary. Missing grade will be not imputed. Missing relationship to study drug will not be imputed. 
An overall summary of AEs will include the number of subjects in the following categories:  
x 
Any TEAE 
x 
Any treatment-related TEAE 
x 
Any CTCAE Grade 3 and Grade 4 TEAE 
x 
Any treatment-related CTCAE Grade 3 and Grade 4 TEAE 
x 
Any fatal (Grade 5) TEAE  
x 
Any treatment-related fatal (Grade 5) TEAE 
x 
Any SAE 
x 
Any treatment-related SAE 
x 
Any TEAE leading to dose interruption  
x 
Any treatment-related TEAE leading to dose interruption 
x 
Any TEAE leading to dose reduction 
x 
Any treatment-related TEAE leading to dose reduction 
x 
Any TEAE leading to discontinuation of study drug  
x 
Any treatment-related TEAE leading to discontinuation of study drug 
TEAEs will also be summarized by system organ class, PT, treatment group and SOC type (fulvestrant vs 
AIs) for the following: 
x 
All TEAEs 
x 
Treatment-related TEAE 
x 
CTCAE Grade 3 and Grade 4 TEAEs 
x 
Treatment-related CTCAE Grade 3 and Grade 4 TEAEs 
x 
Fatal (Grade 5) TEAEs  


      
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x 
Treatment-related fatal (Grade 5) TEAEs 
x 
SAEs 
x 
Treatment-related SAEs 
x 
TEAEs leading to dose interruption  
x 
Treatment-related TEAEs leading to dose interruption 
x 
TEAEs leading to dose reduction 
x 
Treatment-related TEAEs leading to dose reduction 
x 
TEAEs leading to discontinuation of study drug  
x 
Any treatment-related TEAE leading to discontinuation of study drug 
Summary TEAE tables described above (except SAEs) will be presented using grouped PTs as well. AE 
grouping will be provided in a supplementary document.  
All AEs with outcome of death, all serious TEAEs and TEAEs leading to treatment discontinuation will be 
listed. 
TEAEs will also be summarized by PT, treatment group and SOC type (fulvestrant vs AIs), by descending 
order of overall frequency in the elacestrant group. 
A by-subject data listing of all the AEs will be provided by treatment group and SOC type (fulvestrant vs 
AIs). The listing will include subject, verbatim term, original PT, and system organ class, TEAE flag 
(yes/no), SAE flag (yes/no), the AE start and stop dates and study days, AE severity grade, relationship 
to study drug, actions taken, and outcome. The listing will also be provided for subjects <65 years and 
i
H
Ò
«
o « X
 
In addition, summary of primary cause of death will be provided by treatment group and SOC type 
(fulvestrant vs AIs). A listing of all deaths will be provided, including primary cause of death. 
4.12.3 Laboratory Data 
Summaries of laboratory data using descriptive statistics by study visit will be presented by treatment 
and SOC type (fulvestrant vs AIs), including absolute results and changes from baseline. This includes 
chemistry, hematology, and coagulation.  Results from unscheduled visits will not be included in this 
summary. 
Laboratory values will be graded by NCI CTCAE v5.0, where applicable.  
Shift analyses of chemistry, hematology, and coagulation laboratory data from baseline to the worst 
post-baseline value in CTCAE grade (when applicable) will be performed by treatment group and SOC 
type (fulvestrant vs AIs), where the baseline category and post-baseline category will be tabulated.  In 
the shift tables, percentages will only be calculated based on the number of subjects that have valid 
data for both baseline and at least 1 post-baseline assessment; subjects who are missing either 


      
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assessment will not be included in the percentage calculation (numerator or denominator). Results 
from both scheduled and unscheduled visits will be included in the shift analyses, as applicable. 
A summary of subjects with abnormal liver function tests (LFTs) during treatment will be presented by 
maximum elevation of LFTs. Abnormal LFT criteria are summarized as follows: 
•  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x upper limit of normal (ULN) 
and 3x baseline (CTCAE Grade 2 or above) 
•  ALT or AST > 5x ULN and 5x baseline (CTCAE Grade 3 or 4) 
•  ALT or AST > 20x ULN and 20x baseline (CTCAE Grade 4) 
•  ALT > 3x ULN and 3x baseline (CTCAE Grade 2 or above) 
•  ALT > 5x ULN and 5x baseline (CTCAE Grade 3 or 4) 
•  ALT > 20x ULN and 20x baseline (CTCAE Grade 4) 
•  AST > 3x ULN and 3x baseline (CTCAE Grade 2 or above) 
•  AST > 5x ULN and 5x baseline (CTCAE Grade 3 or 4) 
•  AST > 20x ULN and 20x baseline (CTCAE Grade 4) 
•  Serum total bilirubin >1.5x ULN and 1.5x baseline (CTCAE Grade 2 or above) 
•  Serum total bilirubin >2x ULN and 2x baseline 
•  Serum total bilirubin >3x ULN and 3x baseline (CTCAE Grade 3 or 4) 
•  Alkaline phosphatase >1.5x ULN and 1.5x baseline 
•  Alkaline phosphatase >3x ULN and 3x baseline 
•  ALT or AST >3x ULN and total bilirubin >2x ULN 
•  ALT or AST >3x ULN and total bilirubin >2x ULN, plus alkaline phosphatase <2x ULN 
All laboratory data including results from unscheduled visits will be provided in data listings with 
indication of higher or lower than the associated normal range of each laboratory test. 
4.12.4 Vital Signs 
Vital sign data will be summarized by treatment group and SOC type (fulvestrant vs AIs) for each 
visit/time point. For vital signs, descriptive statistics will be provided for the observed values and for the 
corresponding change from baseline values.  Results from unscheduled visits will not be included in this 
summary. However, vital sign data from all post-baseline assessment visits (scheduled and 
unscheduled) will be used for the abnormal value determination. 
Vital sign data will also be presented for each subject in a data listing. 


      
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Abnormal vital sign values 
Values of vital signs are considered abnormal if they meet the selected criteria listed in Table 5 
Appendix 8.2. The number (and percentage) of subjects with post-baseline abnormal values who did 
not have abnormal values at baseline will be analyzed by treatment group and SOC type (fulvestrant vs 
AIs) using the Safety population. For calculation of the percentages for each vital sign parameter, the 
denominator is based on the number of subjects who had no abnormal values at baseline and had at 
least 1 post-baseline assessment for the vital sign parameter being analyzed. The numerator is based 
on subjects from the denominator who had at least 1 abnormal value post baseline for the vital sign 
parameter being analyzed. A supportive listing of subjects with any abnormal values will also be 
provided. 
4.12.5 Electrocardiogram 
All ECGs will be performed in triplicate using central vendor ECG machine. On Cycle 1 Day 1 and Cycle 1 
Day 15, ECGs will be performed pre-dose and 4 hours post-dose. Electrocardiograms at all other visits 
will be performed pre-dose only. Electrocardiogram parameters collected are Ventricular Rate (VR), PR-
interval, QRS-duration, QT-interval, QTcF-interval (QT corrected by Fridericia’s method, ie, QT/RR0.33) 
and the Central Reader’s assessment of the ECG profile. 
The actual value and change from baseline will be summarized descriptively by treatment group and 
SOC type (fulvestrant vs AIs) for the quantitative ECG results by time point. Results from unscheduled 
visits will not be included in this summary. Overall ECG impression will be assessed by the Central 
Reader in 3 categories: normal, not clinically significant abnormal, or clinically significant abnormal. A 
listing of ECG interpretation will be provided. 
The number and percentage of subjects with change from baseline >30 msec and >60 msec and the 
number and percentage of subjects with newly occurring value H
Ò
u
 in QT and QTcF will be 
presented by treatment group and SOC type (fulvestrant vs AIs).  Shift tables from baseline to worst 
post-baseline value will be provided by treatment group and SOC type (fulvestrant vs AIs) for QT and 
Y d
&
o
] v
Z
( } o o } ¡ ] v P
P }
]
W
D
Ò
500 msec.  
o ]
] v P
} (
i
¡ Z }
∆
]
v
Y d
&
H
Ò
increase from baseline at any time will be provided. 
Sensitivity analyses will be performed for ECGs by excluding subjects who had at least 1 missing visit 
due to COVID-19. Sensitivity analyses will be performed in the same manner as the primary ECG 
analyses. 
All ECG data for each subject will be provided in a data listing. 


      
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4.12.6 Prior and Concomitant Medications 
Concomitant medications will be coded using the WHO Drug Dictionary (version Sep2018). Results will 
be tabulated by anatomic therapeutic class (ATC), preferred term (PT), treatment and SOC type 
(fulvestrant vs AIs).  Any medications that did not end prior to first dose of study drug will be included 
in the tabulation of concomitant medications. In addition, concomitant medications used to treat bone 
metastases (e.g., bisphosphonates, RANKL inhibitors) will be tabulated in the same manner. 
Prior medications (i.e., those used prior to the initiation of study drug and ended prior to the first dose 
of study drug) will be summarized descriptively by ATC, PT, treatment group and SOC type (fulvestrant 
vs AIs). 
All medications recorded on the concomitant medications log will be presented in a by-subject data 
listing. 
Number and percentage of subjects with prohibited concomitant medications of moderate or strong 
CYP3A4 inhibitors or inducers will be summarized by treatment group and SOC type (fulvestrant vs AIs). 
A by-subject data listing will be provided. 
Number and percentage of subjects who received any on-treatment palliative radiotherapy will be 
summarized by treatment group and SOC type (fulvestrant vs AIs), and will include indication, body site 
of radiation, AE resulting in need for radiotherapy, and number of subjects who had radiation therapy 
to target lesions and number of subjects who had radiation therapy non-target lesions. A by-subject 
listing will be provided. 
All prior and concomitant therapies/procedures will be provided in a listing. Prior and concomitant 
transfusions will be summarized by transfusion type and by treatment group and SOC type (fulvestrant 
vs AIs). All prior and concomitant transfusions will be provided in a listing. 
4.12.7 ECOG Performance Status 
ECOG performance status is assessed at baseline, every cycle post baseline and at the End of Treatment 
(EOT) visit. ECOG performance status will be summarized over time by treatment group and SOC type 
(fulvestrant vs AIs) until the last cycle. Change from baseline to last cycle or EOT in ECOG performance 
will be summarized by treatment and SOC type (fulvestrant vs AIs) in a shift table.  
 


      
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5 
COVID-19 IMPACT 
The COVID-19 worldwide pandemic has impacted the conduct of this study. Challenges led to issues 
such as quarantines, site closures, travel limitations, or interruptions to the supply chain of 
investigational products.  These challenges may have led to difficulties in sites adhering to protocol-
specified visits and/or procedures, including administration of investigational products. 
Regulatory authorities in the EU and the US have provided guidance on how to handle the potential 
impacts of the COVID-19 pandemic when conducting clinical studies.  In the US, the Food and Drug 
Administration (FDA) published “FDA Guidance on Conduct of Clinical Trials of Medical Products during 
the COVID-19 Public Health Emergency”, and in the EU, the European Medicines Agency (EMA) 
published “Guidance on the Management of Clinical Trials during the COVID-19 (coronavirus) 
pandemic.” 
5.1 
COVID-19 Overall Impact on Scheduled Assessments 
Analyses of COVID-19 impact will be based on the “COVID-19 Impact on Visits,” “COVID-19 Impacted 
visit assessments” and “COVID-19 Study/Treatment Discontinuation” eCRF pages. 
COVID-19 overall visit impact will be tabulated for the ITT population. The number and percentage of 
subjects in the categories defined by COVID-19 impact on visit and COVID-19 reasons for impacted visit 
will be tabulated. Alternative methods of partially executed visits will be summarized. The number and 
percentage of subjects will be presented by alternative method and treatment group. 
5.2 
By-subject COVID-19 Listings 
A by-subject listing of COVID-19 impacted visit assessments will be provided. Details of impacted visits 
will be listed. 
5.3 
By-Site and By-country COVID-19 Impact  
COVID-19 impact will be tabulated for each site. The number and percentage of subjects who had at 
least 1 impacted visit due to COVID-19 will be presented by site and treatment group. COVID-19 impact 
will be also tabulated for each country in the same manner. 


      
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6 
CHANGES TO PLANNED ANALYSES 
The following changes were made from RAD1901-308 Protocol Version 6.0 dated 25 March 2020 in this 
SAP dated 04MAY2021 Version final 1.1: 
x The definitions of the analysis populations of Response Evaluable (RE) and Clinical Benefit 
Evaluable (CBE) have been updated in Section 3. 
x The “the length of time from randomization until…” has been updated to “the time from 
randomization until…” in definition of OS and PFS in Section 1.2 to avoid redundancy. 
x The protocol specified that “ORR and CBR will be summarized as a binomial response rate 
and compared between treatment groups using stratified Fisher’s exact test.” As there is no 
SAS procedure supporting stratified Fisher’s exact test, the analysis method for ORR and 
CBR has been updated to CMH test and exact test (Proc Logistic) in Section 4.7.3. 
x The protocol specified that “PK analyses will be performed using the PK population.” One of 
the secondary objectives is to assess the PK of elacestrant. As there are only 2 PK time 
points, it is not possible to perform noncompartmental PK analyses. Instead, elacestrant 
plasma concentrations will be summarized as described in Section 4.9. 
x The exploratory biomarker analyses will not be conducted. 
x Per-protocol population has been added. It will be used in sensitivity analyses for PFS if 
primary endpoints are statistically significant. 
The following change was made from SAP dated 05MAR2021 Version final 1.0 in this SAP dated 
04MAY2021 Version final 1.1: 
x The conventional Hochberg procedure was specified in the protocol to control the overall 
Type I error rate for the testing of PFS in 2 populations. To ensure that OS can be tested in 
the event that PFS is statistically significant in only 1 of the populations, a parallel 
gatekeeping strategy based on the truncated Hochberg will be used to control the family-
wise type I error rate at 5% (2-sided) and to determine how much alpha will pass along 
from the primary endpoint PFS to the key secondary endpoint OS. 


      
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7 
REFERENCES 
FDA Guidance for Industry 2007, Toxicity Grading Scale for Health Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials 
Hochberg Y. A Sharper Bonferroni Procedure for Multiple Tests of Significance. Biometrika 1988. 74: 
800-802 
Royston P, Parmar MKB 2013 Restricted mean survival time:an alternative to hazard ratio for the design 
and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol.:13(1):152 
Fayers et al. 2001, EORTC QLQ-C30 Scoring Manual 
van Hout et al. 2012, Interim Scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L Value Sets. 
Value in Health 15 (2012) 708 –715 
Dmitrienko, A., Kordzakhia, G., Tamhane, A. C. (2011). Multistage and Mixture Parallel Gatekeeping 
Procedures in Clinical trial. Journal of Biopharmaceutical Statistics, 21: 726–747. 


     Statistical Analysis Plan Template 
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8 
CLINICAL STUDY REPORT APPENDICES 
8.1 
Missing Date Imputation Convention 
8.1.1 
Adverse Event (AE) Start (Onset) Date and Stop Date Imputation 
AE start (onset) date and stop date are separated into 3 different data fields, including day, month and 
year. Completely missing AE date (ie, missing day, missing month and missing year) will not be imputed. 
Partial AE start date will be imputed according to the rules as follows in a sequential fashion. 
In the imputation of missing or partial dates, if the imputed date is after min (death date, cutoff date), 
min (death date, cutoff date) will be used as the imputed date. 
AE Stop Date 
x 
If month and year are present, then impute as the last day of that month 
x 
If only the year is present, impute as December 31 of that year 
x 
If the stop date is entirely missing, assume the event is ongoing 
AE Start Date 
x 
If month and year are present, and are not equal to the month and year of the first dose, then 
imputed as the first day of the month 
x 
If month and year are present, and are equal to the month and year of first dose 
o If stop date is complete and earlier than the date of first dose, then impute as the first 
day of the month 
o Else impute as the date of first dose 
x 
If only the year is present, and the year is not equal to the year of the first dose, then impute as 
January 1 of the year 
x 
If only the year is present, and the year is equal to the year of the first dose 
o If stop date is complete and earlier than the date of first dose, then impute as January 1 
of the year 
o If stop date is partially missing and the month and year of stop date are earlier than the 
month and year of first dose, then impute as January 1 of the year 
o Else impute as the date of first dose 


      
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x 
If the start date is entirely missing 
o If the stop date is complete and earlier than the date of first dose, then impute as 
January 1 of the stop year 
o If the day of stop date is missing, and the month and year are earlier than the month 
and year of first dose, then impute as January 1 of the stop year 
o If the day and month of stop date are missing, and the year is earlier than the year of 
first dose, then impute as January 1 of the stop year 
o Else impute as the date of first dose 
8.1.2 
Concomitant Medication (CM) Start Date and Stop Date Imputation 
The imputation rules for CM are the same as the rules for AE. 
8.1.3 
Other Date Imputations 
In the case of partial start date of post treatment systemic anti-cancer therapy, the date will be 
imputed as the first day of the month but not earlier than the last dose date. A month and year must be 
present or the date will remain missing. 
8.2 
Criteria for Abnormal Values for Vital Signs 
Table 5 Criteria for Abnormal Vital Sign Values 
Vital Signs Parameter 
Low 
High 
Pulse rate (bpm) 
<45 
>130 
Systolic blood pressure (mmHg) 
<80  
>155 
Diastolic blood pressure (mmHg) 
 
>100 
Respiratory Rate (breaths per minute)  
 
> 25  
d
u
~ ∏
 
G
Ò
 
H  
Source: FDA Guidance for Industry 2007, Toxicity Grading Scale for Health Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials 
 
 

Prot_000.pdf: 
Clinical Study Protocol 
RAD1901-308 
 
1 
 
 
  
 
 
 
TITLE PAGE 
 
ELACESTRANT MONOTHERAPY VS. STANDARD OF CARE FOR THE 
TREATMENT OF PATIENTS WITH ER+/HER2- ADVANCED BREAST 
CANCER FOLLOWING CDK4/6 INHIBITOR THERAPY: A PHASE 3 
RANDOMIZED, OPEN-LABEL, ACTIVE-CONTROLLED, MULTICENTER 
TRIAL 
(EMERALD) 
 
 
 
Protocol Number: 
RAD1901-308 
Study Drug: 
Elacestrant (RAD1901) 
Version Number: 
6.0 
Version Date: 
25 March 2020 
IND Number: 
124748 
EudraCT Number: 
2018-002990-24 
Developmental Phase: 
3 
Study Site: 
Multicenter; international 
 
Sponsor: 
 
Radius Pharmaceuticals, Inc. 
 
 
 
 
 
950 Winter Street 
 
 
 
 
 
Waltham, MA 02451 
 
 
 
 
 
Tel: 617-551-4000 
Fax: 617-551-4701 
 
Protocol Amendment History 
Version number 
Version date 
1.0 (Original) 
06AUG2018 
2.0 
17AUG2018 
3.0 
22AUG2018 
4.0 
22AUG2018 
5.0 
28MAR2019 
6.0 
25MAR2020 


Clinical Study Protocol 
RAD1901-308 
 
2 
 
 
  
 
 
PROCEDURES IN CASE OF EMERGENCY 
Emergency contact information can be found on the subject identification card. 


Clinical Study Protocol 
RAD1901-308 
 
3 
 
 
  
 
 
1. 
SYNOPSIS 
Name of Sponsor/Company: 
Radius Pharmaceuticals, Inc. (RADIUS) 
Name of Investigational Product: 
Elacestrant (RAD1901) 
Name of Active Ingredient: 
Elacestrant 
Title of Study: 
Elacestrant Monotherapy vs. Standard of Care for the Treatment of Patients with ER+/HER2- 
Advanced Breast Cancer Following CDK4/6 Inhibitor Therapy: A Phase 3 Randomized, 
Open-Label, Active-Controlled, Multicenter Trial 
Study Center(s): 
Approximately 230 sites worldwide, including, but not limited to, Europe, North America, 
Middle East, Asia-Pacific, and South America 
Objectives: 
Primary Objective: 
To demonstrate that elacestrant compared with the standard of care (SOC) options of either 
fulvestrant or an aromatase inhibitor (AI) is superior in prolonging progression-free survival 
(PFS) based on a blinded Imaging Review Committee (IRC) assessment in post-menopausal 
women and men with estrogen receptor positive (ER+)/human epidermal growth factor 
receptor 2 negative (HER2-) advanced/metastatic breast cancer (mBC), either in subjects 
with mutations of the estrogen receptor 1 (ESR1) gene (ESR1-mut subjects) or in all subjects 
which includes subjects without detectable ESR1 mutations (ESR1-mut-nd) 
Key Secondary Objectives: 
 To compare overall survival (OS) between treatment groups in ESR1-mut 
subjects  
 To compare OS between treatment groups in all subjects (ESR1-mut and 
ESR1-mut-nd) 
Other Secondary Objectives: 
The following secondary objectives will be assessed for ESR1-mut-nd subjects: 
 To compare PFS based on blinded IRC assessment between treatment groups 
 To compare OS between treatment groups  
The following secondary objectives will be assessed for ESR1-mut subjects, ESR1-mut-nd 
subjects, and all subjects (ESR1-mut and ESR1-mut-nd): 


Clinical Study Protocol 
RAD1901-308 
 
4 
 
 
  
 
 
 To compare PFS based on local Investigator assessment between treatment 
groups 
 To compare objective response rate (ORR) based on blinded IRC assessment 
between treatment groups 
 To compare duration of response (DoR) based on blinded IRC assessment 
between treatment groups 
 To compare clinical benefit rate (CBR) based on blinded IRC assessment between 
treatment groups 
 To compare ORR based on local Investigator assessment between treatment 
groups 
 To compare DoR based on local Investigator assessment between treatment 
groups 
 To compare CBR based on local Investigator assessment between treatment 
groups 
The following secondary objectives will be assessed for ESR1-mut subjects and all subjects 
(ESR1-mut and ESR1-mut-nd): 
 To compare the safety and tolerability between treatment groups 
 To assess the pharmacokinetics (PK) of elacestrant 
 To describe the changes in Patient Reported Outcomes (PROs) and 
Health-Related Quality of Life (HRQOL) and the changes in PROs/HRQOL 
between treatment groups 
Exploratory Objectives: 
The following exploratory objectives will be assessed in ESR1-mut subjects, ESR1-mut-nd 
subjects, and all subjects (ESR1-mut and ESR1-mut-nd): 
 To determine the difference in the time to chemotherapy (TTC) between 
treatment groups 
 To evaluate alterations in circulating tumor deoxyribonucleic acid (ctDNA) 
relevant to ER+ breast cancer and the cyclin-dependent kinase (CDK) 4/6 
pathway and to explore the relationship between these findings and clinical 
response 
 To characterize alterations in tumor-specific genes, proteins, and RNAs related to 
oncogenic pathways and proliferation and cell cycle markers in tumor tissue and 
to explore the relationship between these findings and clinical response 
Endpoints: 
Primary Endpoints: 
The primary endpoints of this study are as follows: 


Clinical Study Protocol 
RAD1901-308 
 
5 
 
 
  
 
 
 IRC-assessed PFS in ESR1-mut subjects 
 IRC-assessed PFS in all subjects (ESR1-mut and ESR1-mut-nd) 
Key Secondary Endpoints: 
The key secondary endpoints are as follows: 
 OS in ESR1-mut subjects 
 OS in all subjects (ESR1-mut and ESR1-mut-nd) 
Other Secondary Endpoints: 
The following endpoints will be analyzed for ESR1-mut-nd subjects: 
 IRC-assessed PFS 
 OS 
The following endpoints will be analyzed for ESR1-mut, ESR1-mut-nd, and all subjects 
(ESR1-mut and ESR1-mut-nd): 
 Local Investigator-assessed PFS 
 IRC-assessed ORR 
 IRC-assessed DoR 
 IRC-assessed CBR 
 Local Investigator-assessed ORR 
 Local Investigator-assessed DoR 
 Local Investigator-assessed CBR 
The following endpoints will be assessed for ESR1-mut subjects and all subjects (ESR1-mut 
and ESR1-mut-nd): 
 Safety and tolerability, assessed by adverse events (AEs), serious adverse events 
(SAEs), dose modifications, clinical laboratory parameters (ie, hematology, 
chemistry, and coagulation), electrocardiograms (ECGs), performance status, and 
vital signs 
 PK, assessed by evaluation of elacestrant concentrations at pre-dose 
(pre-treatment) and 4 hours post-dose on Cycle 1 Day 1 (C1D1), pre-dose (trough 
concentration [Ctrough]) and 4 hours post-dose on C1D15, and pre-dose (Ctrough) on 
C2D1 
 PRO endpoints, assessed using the HRQOL scales, EuroQoL 5 Dimension 5 
Level (EQ-5D-5L), European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and Patient Reported 
Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE) 
 


Clinical Study Protocol 
RAD1901-308 
 
6 
 
 
  
 
 
Exploratory Endpoints: 
The following exploratory endpoints will be assessed in ESR1-mut subjects, ESR1 mut-nd 
subjects, and all subjects (ESR1-mut and ESR1-mut-nd): 
 TTC 
 Alterations in ctDNA relevant to ER+ breast cancer and the CDK4/6 pathway and 
the relationship between these findings and clinical response 
 Alterations in tumor-specific genes, proteins, and RNAs related to oncogenic 
pathways and proliferation and cell cycle markers in tumor tissue and the 
relationship between these findings and clinical response 
Methodology: 
This is an international, multicenter, randomized, open-label, active-controlled, event-driven, 
Phase 3 clinical study comparing the efficacy and safety of elacestrant to the SOC options of 
fulvestrant or an AI in post-menopausal women and men with ER+/HER2- mBC whose 
disease has relapsed or progressed on at least 1 and no more than 2 prior lines of endocrine 
therapy for advanced or metastatic disease, which must have included progression on prior 
CDK4/6 inhibitor therapy in combination with fulvestrant or an AI. Endocrine monotherapy 
with 1 of the SOC drugs (fulvestrant, anastrozole, letrozole, exemestane) must be an 
appropriate treatment option for subjects enrolled in this study. 
Subjects will be randomized in a 1:1 ratio to receive either elacestrant or the Investigator’s 
choice of endocrine monotherapy with 1 of the following SOC drugs: fulvestrant, 
anastrozole, letrozole, or exemestane. 
Note: During SOC treatment, the Investigator will follow any warnings or precautions for 
use as detailed in each Product Insert (PI) or Summary of Product Characteristics (SmPC). 
Randomization will be stratified based on the following criteria: 
 ESR1 mutation(s) detected in ctDNA (ESR1-mut vs ESR1-mut-nd) 
 Prior treatment with fulvestrant (yes vs no) 
 Presence of visceral metastases (yes vs no); visceral includes lung, liver, brain, 
pleural, and peritoneal involvement 
The ctDNA ESR1 mutation status must be centrally determined during Screening prior to 
randomization. 
Study Committees: 
IRC 
A blinded, independent IRC will review radiographic images and clinical information 
collected on study to determine the protocol-defined endpoints of disease response and 
progression. Further information on the independent review process will be provided in the 
IRC Charter. 
 


Clinical Study Protocol 
RAD1901-308 
 
7 
 
 
  
 
 
Independent Data Monitoring Committee (IDMC) 
An IDMC external to both RADIUS and the clinical research organization (CRO) will be 
responsible for ongoing monitoring of the safety and efficacy according to the IDMC 
Charter. The IDMC will meet on a regular basis and will make recommendations as to 
whether the trial should continue, be amended, or be discontinued based on ongoing reviews 
of safety and efficacy data. 
Study Steering Committee (SSC) 
A SSC composed of international physicians with expertise in management of ER+ mBC 
will be convened by RADIUS. The remit of the SSC is to provide guidance to RADIUS on 
protocol development and implementation, Investigator selection, and recruitment strategies. 
The SSC will also apprise RADIUS on advances in the field that could impact the trial. The 
SSC will not be provided with any efficacy or safety data during the trial. 
Number of Subjects (planned): 
This study is event-driven and is planned for a total of approximately 160 PFS events 
(objective disease progression assessed by the blinded IRC or death) among the ESR1-mut 
subjects and 340 PFS events among all subjects (ESR1-mut and ESR1-mut-nd). It is 
estimated that approximately 466 subjects (220 ESR1-mut; 246 ESR1-mut-nd) will need to 
be enrolled in the study in a 1:1 randomization at approximately 230 clinical study sites 
experienced in conducting oncology clinical trials in Europe, North America, Middle East, 
Asia-Pacific, and South America. Additional or fewer subjects and regions may be required 
to achieve the planned total number of events. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria: 
1. Must have a histologically- or cytologically-proven diagnosis of adenocarcinoma of 
the breast with evidence of either locally advanced disease not amenable to resection 
or radiation therapy with curative intent or metastatic disease not amenable to 
curative therapy 
2. Must be appropriate candidates for endocrine monotherapy 
3. Must have 1 of the following as defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1: 
a. Measurable disease 
b. Bone only disease with evaluable lesions. Subjects must have at least 1 lytic 
or mixed lytic/blastic bone lesion; blastic lesions only are not evaluable and 
allowed. Subjects who have had prior radiation to bone must have at least 1 
evaluable lesion in a nonirradiated area 
4. Female or male ≥ 18 years of age 
5. Female subjects must be post-menopausal women, defined by 1 of the following 
criteria: 


Clinical Study Protocol 
RAD1901-308 
 
8 
 
 
  
 
 
a. Documented bilateral surgical oophorectomy 
b. Age ≥ 60 years with amenorrhea ≥ 1 year since last menses 
c. Age < 60 years with amenorrhea ≥ 1 year since last menses with no alternative 
pathological or physiological cause (including ongoing or recent 
chemotherapy, treatment with tamoxifen or toremifene, or a gonadotropin 
releasing hormone agonist), and serum estradiol and follicle stimulating 
hormone (FSH) levels within the laboratory reference range for post-
menopausal women 
d. Age < 60 years with tamoxifen or toremifene therapy within the last 
12 months, with documentation of 12 months of amenorrhea prior to 
tamoxifen or toremifene therapy and serum estradiol and FSH levels within 
the laboratory reference range for post-menopausal women 
e. Females with hormonally-induced menopause (ie, requiring ongoing hormone 
suppression) are not eligible 
6. Male subjects must, even if surgically sterilized (ie, status post-vasectomy): 
a. Agree to practice highly effective barrier contraception (use condoms) during 
the entire study treatment period and through 120 days after the last dose of 
study drug. For subjects (who have not undergone vasectomy) with female 
partners of childbearing potential, the subject and his partner must, in addition 
to condoms, use highly effective contraceptive measures when engaging in 
sexual intercourse throughout the treatment period and for at least 120 days 
after the last dose of study drug (ie, oral contraceptive and condoms; 
intrauterine device and condoms; diaphragm with spermicide and condoms; 
other forms of contraception must be approved by the medical monitor) 
OR 
Agree to practice true abstinence during the entire study treatment period and 
through 120 days after the last dose of study drug 
Note: Abstinence should only be used as a contraceptive method if it is in line 
with the subject’s usual and preferred lifestyle. Periodic abstinence (calendar 
symptothermal, post-ovulation methods) is not an acceptable method of 
contraception. 
b. Agree not to donate sperm during the course of treatment period of this study 
or within 120 days after receiving the last dose of the study drug 
7. Must have ER+ and HER2- tumor status confirmed per local laboratory testing. 
Status may be confirmed on original diagnosis tissue samples or post-treatment 
samples (most recent biopsy preferred, if testing available). ER and HER2 testing 
must be performed in the following manner: 
a. Documentation of ER+ tumor with ≥ 1% staining by immunohistochemistry 
(IHC) as defined in the 2010 American Society for Clinical Oncology (ASCO) 
recommendations for ER testing (Hammond et al, 2010), with or without 
progesterone receptor (PGR) positivity 


Clinical Study Protocol 
RAD1901-308 
 
9 
 
 
  
 
 
AND 
b. Documentation of HER2- tumor with an IHC result of 0 or 1+ for cellular 
membrane protein expression or an in situ hybridization negative result as 
defined in the 2013 or 2018 ASCO recommendations for HER2 testing 
(Wolff et al, 2013; Wolff et al, 2018) 
8. Must have previously received at least 1 and no more than 2 lines of endocrine 
therapy, either as monotherapy or as a combination therapy with another agent (eg, 
PI3K inhibitor), for mBC 
a. Must have progressed during or within 28 days of completion of each line of 
endocrine therapy; ie, if a subject was discontinued due to toxicity without 
progression, this would not count as a line of prior therapy 
b. For subjects who progress during or within 12 months of adjuvant endocrine 
therapy, this will count as 1 line of endocrine therapy for mBC. In the absence 
of such progression, adjuvant therapy does not count as 1 of the required lines 
of endocrine therapy 
9. Must have progressed during or within 28 days of completion of prior treatment with 
a CDK4/6 inhibitor in combination with either fulvestrant or an AI (this counts as a 
line of prior endocrine therapy) for mBC 
a. Prior treatment with a CDK4/6 inhibitor not in combination with fulvestrant 
or an AI will not fulfill this criterion 
b. Discontinuation of prior CDK4/6 inhibitor due to toxicity, in the absence of 
progression, will not fulfill this criterion 
10. Must have received no more than 1 line of cytotoxic chemotherapy in the 
advanced/metastatic setting  
a. Cytotoxic chemotherapy does not include: CDK4/6 inhibitors, mechanistic target 
of rapamycin (mTOR) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, or 
immunotherapy. There are no restrictions on prior use of these agents 
b. There is no requirement for documentation of progressive disease to prior 
chemotherapy 
c. Chemotherapy given in combination with endocrine therapy counts as both a 
line of endocrine therapy and a line of chemotherapy 
d. Chemotherapy administered for less than 1 cycle will not be counted as a prior 
line of chemotherapy 
e. For subjects who progress within 12 months of neoadjuvant or adjuvant 
chemotherapy, this will count as 1 prior line of therapy for 
advanced/metastatic disease 
11. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
12. Resolution of all toxic effects of prior therapies or surgical procedures to Grade ≤ 1 
(except alopecia and peripheral neuropathy) 
13. Adequate organ function as defined below: 


Clinical Study Protocol 
RAD1901-308 
 
10 
 
 
  
 
 
a. Hematologic function (in the absence of transfusion of red blood cells or 
platelets or the use of growth factors within the preceding 4 weeks) 
 Absolute neutrophil count ≥ 1.0 x 109/L 
 Platelet count ≥ 75 x 109/L 
 Hemoglobin ≥ 9.0 g/dL 
b. Renal function 
 Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or creatinine 
clearance calculated by Cockcroft-Gault equation ≥ 30 mL/min 
(Appendix 4) 
c. Hepatic function 
 Alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN) 
 Aspartate aminotransferase (AST) ≤ 3x ULN 
 Total bilirubin ≤ ULN or total bilirubin ≤ 1.5x ULN with direct bilirubin 
≤ ULN of the laboratory in subjects with documented Gilbert’s Syndrome 
d. Chemistry 
 Potassium, sodium, calcium (corrected for albumin), magnesium, and 
phosphorus National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0 Grade ≤ 1. If Screening assessments 
are abnormal, chemistry assessments may be repeated up to 2 times; 
subjects may receive appropriate supplementation or treatment (eg, for 
hypercalcemia) prior to re-assessment 
e. Coagulation 
 International normalized ratio (INR) ≤ 1.5 
Note: Subjects who are receiving anticoagulation treatment which is 
monitored by international normalized ratio (INR) (eg, warfarin) may be 
allowed to participate if they have a stable INR (ie, within therapeutic range) 
for at least 28 days prior to the first dose of study drug, in the absence of any 
exclusionary medical conditions, and provided that an AI would be 
appropriate therapy for the subject 
14. Ability to understand the protocol and provide informed consent 
Exclusion Criteria 
Subjects must meet none of the following exclusion criteria: 
1. Prior treatment with elacestrant or investigational selective estrogen receptor degrader 
(SERD) or ER antagonist (eg, D-0502, GDC-0810, GDC-0927, GDC-9545, G1T-48, 
LSZ102, AZD9496, SAR439859, ZN-c5, H3B-6545, bazedoxifene, lasofoxifene) 
2. Prior anti-cancer or investigational drug treatment within the following windows: 


Clinical Study Protocol 
RAD1901-308 
 
11 
 
 
  
 
 
a. Fulvestrant treatment (last injection) < 42 days before first dose of study drug 
b. Any other endocrine therapy < 14 days before first dose of study drug 
c. Chemotherapy or other anti-cancer therapy < 21 days before first dose of study 
drug 
d. Any investigational anti-cancer drug therapy < 28 days or 5 half-lives (whichever 
is shorter) before the first dose of study drug. Enrollment of subjects whose most 
recent therapy was an investigational agent should be discussed with RADIUS 
e. Bisphosphonates or RANKL inhibitors initiated or dose changed < 3 months prior 
to first dose of study drug 
3. Radiation therapy within 14 days (28 days for brain lesions per Exclusion Criterion 4) 
before the first dose of study drug 
4. Presence of symptomatic metastatic visceral disease, including but not limited to, 
extensive hepatic involvement, untreated or progressive central nervous system 
(CNS) metastases, or symptomatic pulmonary lymphangitic spread. Subjects with 
discrete pulmonary parenchymal metastases are eligible provided their respiratory 
function is not significantly compromised as a result of disease in the opinion of the 
Investigator. Subjects with previously treated CNS metastases are eligible provided 
that all known lesions were previously treated, they have completed radiotherapy at 
least 28 days prior to first dose of study drug, and are clinically stable. If 
anticonvulsant medication is required, subjects must be stable on a non-enzyme 
inducing anticonvulsant regimen 
5. Intact uterus with a history of endometrial intraepithelial neoplasia (atypical 
endometrial hyperplasia or higher-grade lesion) 
6. Diagnosis of any other malignancy within 5 years before enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the 
cervix, or second primary breast cancer 
7. Any of the following within 6 months before enrollment: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v5.0 
Grade ≥ 2, prolonged QTcF ≥ Grade 2 (ie, > 480 msec), uncontrolled atrial 
fibrillation of any grade, coronary/peripheral artery bypass graft, heart failure ≥ Class 
II as defined by the New York Heart Association guidelines, or cerebrovascular 
accident including transient ischemic attack 
8. Child-Pugh Score greater than Class A (ie, score >6) 
9. Coagulopathy or any history of coagulopathy within the past 6 months, including 
history of deep vein thrombosis or pulmonary embolism. However, subjects with the 
following conditions will be allowed to participate: 
a. Adequately treated catheter-related venous thrombosis occurring >28 days prior 
to the first dose of study drug 
b. Treatment with an anticoagulant, eg, warfarin or heparin, for a thrombotic event 
occurring > 6 months before enrollment, or for an otherwise stable and allowed 
medical condition (eg, well controlled atrial fibrillation), provided dose and 
coagulation parameters (as defined by local standard of care) are stable for at least 


Clinical Study Protocol 
RAD1901-308 
 
12 
 
 
  
 
 
28 days prior to the first dose of study drug and provided that an AI would be an 
appropriate therapy for the subject 
10. Known bleeding disorder which, in the opinion of the Investigator, would prohibit 
administration of fulvestrant if that would be SOC choice for the subject 
11. Known difficulty in tolerating oral medications or conditions which would impair 
absorption of oral medications such as: uncontrolled nausea or vomiting (ie, CTCAE 
≥ Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility 
disorder, malabsorption syndrome, or prior gastric bypass 
12. Unable or unwilling to avoid prescription medications, over-the-counter medications, 
dietary/herbal supplements (eg, St. John’s wort), and/or foods (eg, grapefruit, 
pomelos, star fruit, Seville oranges and their juices) that are moderate/strong 
inhibitors or inducers of CYP3A4 activity. Participation will be allowed if the 
medication, supplements, and/or foods are discontinued for at least 5 half-lives or 14 
days (whichever is longer) prior to study entry and for the duration of the study 
13. Major surgery < 28 days before the first dose of study drug 
14. Any concurrent severe, acute, or chronic medical or psychiatric condition or 
laboratory abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with compliance with study 
procedures or the interpretation of study results and, in the judgment of the 
Investigator, would make the subject inappropriate for entry into this study 
15. Known hypersensitivity reaction to drugs chemically related to elacestrant or their 
excipients 
16. Known hypersensitivity to fulvestrant, anastrozole, letrozole, or exemestane (or to 
any of their excipients), unless treatment with 1 of the other 3 of these 4 treatment 
options would be appropriate therapy 
17. Subjects who meet any contraindication, according to the respective PI or SmPC, for 
any SOC drug that the Investigator would choose for that subject should the subject 
be randomized to the SOC group 
Investigational Product, Dosage and Mode of Administration: 
Elacestrant will be provided as 100 mg and/or 400 mg tablets to be taken orally once per day 
on a continuous dosing schedule. Protocol-defined dose reductions will be permitted. 
Reference Therapy, Dosage and Mode of Administration: 
SOC monotherapy of either fulvestrant or an AI (letrozole, anastrozole, exemestane) is to be 
administered as follows: fulvestrant 500 mg administered intramuscularly (IM) into the 
buttocks as 2 - 5 mL injections on C1D1, C1D15 and C2D1, and Day 1 of every subsequent 
28-day cycle or an AI taken orally on a continuous dosing schedule (anastrozole 1 mg/day; 
letrozole 2.5 mg/day; or exemestane 25 mg/day). 
 


Clinical Study Protocol 
RAD1901-308 
 
13 
 
 
  
 
 
Duration of Treatment: 
Subjects will continue to receive treatment until disease progression, clinically significant 
AE, significant study noncompliance, unable to receive study treatment for > 14 consecutive 
days, treatment discontinuation in the best interest of the subject, or subject refuses 
treatment. Based on median duration of treatment of 3.8 months in Study RAD1901-005 for 
all subjects treated with 400 mg elacestrant, subjects randomized to elacestrant are expected 
to remain on treatment for approximately 4 months. Subjects exhibiting a response would be 
expected to have longer treatment duration. 
Criteria for Evaluation: 
Efficacy: 
Efficacy analyses will be performed using tumor assessments made by the blinded IRC as the 
primary data source. Analyses of endpoints based on local Investigator assessment will also 
be performed as supportive analyses. 
Safety: 
Assessment of safety and tolerability will be based on incidence of AEs, SAEs, dose 
modifications, review of clinical laboratory data (ie, hematology, chemistry, and 
coagulation), ECG monitoring, physical examinations, performance status, and vital signs. 
Statistical Methods: 
Sample Size Assumptions: 
Among the ESR1-mut subjects, the study requires approximately 160 PFS events to have a 
power of 80% to detect a hazard ratio of 0.610 at the 2-sided alpha level of 2.5%. Assuming 
a median PFS of 5.3 months for the SOC treatment group, this treatment effect represents a 
median PFS of 8.7 months for the elacestrant treatment group, an increase of approximately 
3.4 months among the ESR1-mut subjects. 
Among all subjects (ESR1-mut and ESR1-mut-nd), a total of approximately 340 PFS events 
will have 92% power to detect a hazard ratio of 0.667 at the 2-sided alpha level of 2.5%. 
The 2-sided alpha level of 2.5% for the sample size calculation was selected to ensure that at 
least 1 of the 2 primary endpoints will pass the Hochberg procedure to control the overall 
alpha level at 5.0%. 
The study will need to randomize approximately 220 ESR1-mut subjects (110/treatment 
group) and a total of approximately 466 subjects of both types (ESR1-mut and ESR1-mut-nd; 
233/treatment group) in a 1:1 ratio to the 2 treatment groups. To prevent exceeding the target 
recruitment by more than 10% (ie, 512 subjects total), if a total of 292 ESR1-mut-nd subjects 
is reached before 220 ESR1-mut subjects are enrolled, further enrollment will be restricted to 
ESR1-mut subjects only until the target of 220 is achieved. 
Final analysis of the primary endpoints will be performed at approximately 160 PFS events 
among the ESR1-mut subjects and 340 PFS events among all subjects (ESR1-mut and 
ESR1-mut-nd), estimated to occur 30-33 months after the first subject is randomized. 


Clinical Study Protocol 
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14 
 
 
  
 
 
Analysis Populations: 
The following populations will be defined and used for analysis: 
 The Intention-to-Treat (ITT) Population consists of all randomized subjects. This 
is the primary population for PFS and OS analyses. Subjects will be analyzed 
according to their randomized treatment assignments. 
 The Safety Population consists of all subjects who received at least 1 dose of 
study medication. All safety analyses will be performed using the Safety 
population. Subjects will be analyzed according to the treatments they actually 
received in Cycle 1. 
 The Response Evaluable (RE) population includes all ITT subjects who had 
measurable disease (ie, at least 1 target lesion) at baseline and at least 1 post-
baseline RECIST assessment on any (target or non-target) lesions and/or had a new 
lesion. The RE population is used for the analyses of best overall response and 
ORR. 
 The Clinical Benefit Evaluable (CBE) population includes all ITT subjects who had 
measurable and/or evaluable disease (ie, target and/or non-target lesions) at 
baseline and at least 1 post-baseline RECIST assessment on any (target or non-
target) lesions and/or had a new lesion.  The CBE population is used for the 
analyses of CBR. 
 The PK population consists of all subjects who received at least 1 dose of 
elacestrant and have PK concentration data for at least 1 scheduled time point. PK 
analyses will be performed using the PK population. 
 The Biomarker population consists of all subjects in the Safety population for 
whom adequate quality and volume of biomarker samples are available for 
analysis. The exploratory biomarker analysis will be performed using the 
Biomarker population. 
Subject Characteristics: 
Subject characteristics will be summarized by treatment group using the ITT population for 
2 sets of study subjects: ESR1-mut subjects and all subjects (ESR1-mut and ESR1-mut-nd). 
Standard descriptive statistics for continuous and categorical variables will be provided for 
subject demographics, baseline disease characteristics, prior anti-cancer therapies, and other 
baseline characteristics. No hypothesis testing will be conducted. 
Efficacy Analysis 
Type I Error Control 
The 2 primary endpoints will be evaluated using the Hochberg procedure in order to maintain 
the overall alpha level at 2-sided 5.0%: 
 The p-value for each of the 2 primary endpoints will be derived without any 
adjustment. These 2 p-values will be sorted in a numerical order so that 1 p-value is 
larger than the other 


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 If the larger p-value is <0.05, statistical significance will be claimed for both 
endpoints 
 If the larger p-value is ≥0.05 and the smaller p-value is <0.025, statistical significance 
will be claimed only for the endpoint associated with the smaller p-value 
 If the larger p-value is ≥0.05 and the smaller p-value is ≥0.025, no statistical 
significance will be claimed for either of the 2 primary endpoints 
Primary Endpoints 
Analyses of IRC-assessed PFS in ESR1-mut subjects and all subjects (ESR1-mut and ESR1-
mut-nd) will be performed using the ITT population for the ESR1-mut subjects and the entire 
ITT population, respectively. PFS will be analyzed using Kaplan-Meier (KM) methods and 
displayed graphically, with median event times and 95% confidence intervals (CIs). The 
differences in the primary endpoints between treatment groups will be analyzed using the 
stratified log-rank test with the stratification factors of prior treatment with fulvestrant (yes 
vs no) and presence of visceral metastases (yes vs no) as the primary analyses. The 
unstratified log-rank test will be performed as a sensitivity analysis. The Cox regression 
model, including treatment and the stratification factors as above, will be used to estimate the 
hazard ratio and 95% CI. 
Key Secondary Endpoints 
Analyses of OS in ESR1-mut subjects and in all subjects (ESR1-mut and ESR1-mut-nd) will 
be performed using the ITT population for the ESR1-mut subjects and the entire ITT 
population, respectively. 
For each of the 2 sets of study subjects, OS will be analyzed at the following 2 time points: 
 At the time of the final PFS analysis (when approximately 160 and 340 PFS events 
are observed among the ESR1-mut and all subjects [ESR1-mut and ESR1-mut-nd], 
respectively) 
 At the time of the final OS analysis (when 50% of the subjects have died) 
At each time point, OS for the treatment groups will be analyzed using KM methods and 
displayed graphically, with median event times and 95% CIs displayed only for analysis at 
the final OS time. The Cox regression model that includes treatment and stratification factors 
(as in the primary analyses of the primary endpoints) will be used to estimate the hazard ratio 
and 95% CI. In addition, the difference between treatment groups will be analyzed using the 
stratified log-rank test at the final OS time. A 2-sided alpha level of 0.01% will be allocated 
at the final PFS analysis time point and a 2-sided alpha level of 4.99% will be allocated at the 
final OS analysis time point. 
Other Secondary Endpoints 
Analyses of IRC-assessed PFS in ESR1-mut-nd subjects will be performed using the ITT 
population for ESR1-mut-nd subjects in the same manner as the analyses of the primary 
endpoints. 


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Analyses of OS in ESR1-mut-nd subjects will be performed using the ITT population for the 
ESR1-mut-nd subjects in the same manner as the analyses of OS in ESR1-mut subjects and 
in all subjects (ESR1-mut and ESR1-mut-nd). 
Local Investigator-assessed PFS will be analyzed in the same manner as IRC-assessed PFS. 
ORR and CBR will be summarized as binomial response rates and compared between 
treatment groups using stratified Fisher’s exact test. 
DoR will be summarized for subjects who achieve either a confirmed complete response or 
partial response using the KM method. Estimated median values of DoR along with 95% CI 
will be provided. 
Results of the efficacy analyses in the 3 sets of study subjects, ESR1-mut subjects, 
ESR1-mut-nd subjects, and all subjects (ESR1-mut and ESR1-mut-nd) will be presented 
using Forest plots. 
Subgroup analyses of PFS, OS, ORR, and CBR based on prior treatment with fulvestrant and 
presence of visceral metastases will be performed in the same manner as the analyses in the 
overall populations. 
Safety Analyses 
Safety analyses will be performed using the Safety population for 2 sets of study subjects: 
ESR1-mut subjects and all subjects (ESR1-mut and ESR1-mut-nd). 
For each set of study subjects, safety analyses will be performed by treatment group and 
include summaries of the following: 
 AEs, including NCI CTCAE v5.0 severity grade and relationship to study drug 
 Deaths, SAEs, and AEs leading to study drug withdrawal 
 Dose interruptions and reductions due to AEs 
 Laboratory values over time and shifts in laboratory measurements by NCI 
CTCAE v5.0 grade 
 ECG values over time and change from baseline 
 ECOG performance status over time and shifts in ECOG performance status  
 Vital sign values over time and incidence of potentially clinically significant 
values 
Interim Analysis 
An interim futility analysis will be performed at about 70% enrollment. Recommendations 
for further enrollment in the study will be made by the IDMC. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................3 
ABBREVIATIONS AND DEFINITIONS OF TERMS ...............................................................24 
2. 
INTRODUCTION ......................................................................................................27 
2.1. 
Breast Cancer ..............................................................................................................27 
2.2. 
Elacestrant ...................................................................................................................29 
2.2.1. 
Nonclinical Studies .....................................................................................................29 
2.2.2. 
Clinical Studies ...........................................................................................................32 
2.2.2.1. 
Pharmacokinetic Data .................................................................................................34 
2.2.2.2. 
Safety and Tolerability in Healthy Volunteers Studies ..............................................34 
2.2.2.3. 
Clinical Pharmacology in Healthy Volunteer Studies ................................................35 
2.2.2.4. 
Vasomotor Symptoms Studies ....................................................................................36 
2.2.2.5. 
Metastatic Breast Cancer Studies ...............................................................................36 
2.3. 
Study Rationale ...........................................................................................................42 
2.4. 
Rationale for Study Dose ............................................................................................43 
3. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................44 
3.1. 
Objectives ...................................................................................................................44 
3.1.1. 
Primary and Key Secondary Objectives .....................................................................44 
3.1.2. 
Other Secondary Objectives .......................................................................................44 
3.1.3. 
Exploratory Objectives ...............................................................................................45 
3.2. 
Endpoints ....................................................................................................................45 
3.2.1. 
Primary and Key Secondary Endpoints ......................................................................45 
3.2.1.1. 
Primary Endpoints ......................................................................................................45 
3.2.1.2. 
Key Secondary Endpoints ...........................................................................................45 
3.2.2. 
Other Secondary Endpoints ........................................................................................45 
3.2.3. 
Exploratory Endpoints ................................................................................................46 
4. 
INVESTIGATIONAL PLAN .....................................................................................47 
4.1. 
Overall Study Design ..................................................................................................47 
4.2. 
Number of Subjects ....................................................................................................49 
4.3. 
Treatment Assignment ................................................................................................49 
4.4. 
Disease Progression and Tumor Assessments ............................................................49 


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4.5. 
Dose Adjustment, Interruption, or Discontinuation Criteria ......................................50 
4.5.1. 
Criteria for Elacestrant ................................................................................................50 
4.5.2. 
Criteria for Standard of Care ......................................................................................51 
4.5.3. 
Criteria for QTcF Prolongation ..................................................................................52 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................52 
5.1. 
Subject Inclusion Criteria ...........................................................................................52 
5.2. 
Subject Exclusion Criteria ..........................................................................................55 
5.3. 
Subject Withdrawal Criteria .......................................................................................57 
5.3.1. 
Subject Withdrawal from Active Treatment Phase ....................................................57 
5.3.2. 
Subject Withdrawal from the Study ...........................................................................58 
6. 
STUDY TERMINATION ..........................................................................................59 
7. 
STUDY PROCEDURES ............................................................................................59 
7.1. 
Demographic, Medical History, Prior and Concomitant Medication .........................59 
7.2. 
Physical Examination and Vital Signs ........................................................................59 
7.3. 
Electrocardiograms and Prolonged QTcF Guidelines ................................................59 
7.4. 
Tumor Assessments ....................................................................................................60 
7.4.1. 
Overview .....................................................................................................................60 
7.4.2. 
CT or MRI Tumor Assessment...................................................................................60 
7.4.3. 
Radionuclide Bone Scan or Whole Body MRI Tumor Assessment of Bone 
Lesions and Follow-up Assessments of Bone Lesions ...............................................61 
7.4.4. 
Clinical Lesions ..........................................................................................................62 
7.5. 
Laboratory Assessments .............................................................................................62 
7.5.1. 
Estradiol and Follicle Stimulating Hormone ..............................................................62 
7.5.2. 
Urinalysis ....................................................................................................................62 
7.5.3. 
Chemistry ....................................................................................................................62 
7.5.4. 
Special Chemistry .......................................................................................................62 
7.5.5. 
Coagulation .................................................................................................................63 
7.5.6. 
Hematology .................................................................................................................63 
7.6. 
Tumor Biomarkers ......................................................................................................63 
7.6.1. 
Tumor Biopsy .............................................................................................................63 
7.6.2. 
Circulating Tumor DNA .............................................................................................63 
7.6.3. 
Residual Samples for Exploratory Biomarker Analysis .............................................64 
7.6.4. 
Disposal of Samples ...................................................................................................64 


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7.7. 
Patient Performance Status and Patient Reported Outcomes .....................................65 
7.7.1. 
ECOG Performance Status .........................................................................................65 
7.7.2. 
Patient Reported Outcomes ........................................................................................65 
7.8. 
Pharmacokinetic Samples ...........................................................................................65 
7.9. 
Adverse and Serious Adverse Events .........................................................................66 
7.9.1. 
Definition of Adverse Events .....................................................................................66 
7.9.1.1. 
Adverse Event .............................................................................................................66 
7.9.1.2. 
Serious Adverse Event ................................................................................................66 
7.9.2. 
Relationship to Study Drug ........................................................................................67 
7.9.3. 
Study Drug Action Taken ...........................................................................................68 
7.10. 
Adverse Event Outcome .............................................................................................68 
7.10.1. 
Treatment Given .........................................................................................................68 
7.10.2. 
Follow-up of Adverse Events .....................................................................................69 
7.10.3. 
Overdose and Medication Error ..................................................................................69 
7.10.3.1. 
Elacestrant ...................................................................................................................69 
7.10.3.2. 
Standard of Care .........................................................................................................69 
7.11. 
Recording Adverse Events .........................................................................................69 
7.12. 
Reporting Adverse Events ..........................................................................................71 
7.13. 
Partner Pregnancy .......................................................................................................71 
8. 
SCHEDULE OF PROCEDURES AND OBSERVATIONS .....................................71 
8.1. 
Screening and Randomization ....................................................................................71 
8.2. 
Assessments during Treatment ...................................................................................72 
8.3. 
Assessments at End of Treatment ...............................................................................72 
8.4. 
Post-Treatment Safety Follow-Up ..............................................................................72 
8.5. 
Post-Treatment Follow-Up .........................................................................................72 
8.6. 
Study Completion .......................................................................................................72 
9. 
TREATMENT OF SUBJECTS ..................................................................................73 
9.1.1. 
Description of Study Drugs ........................................................................................73 
9.1.1.1. 
Elacestrant (Investigational Product) ..........................................................................73 
9.1.1.2. 
Standard of Care Options ............................................................................................73 
9.1.2. 
Prior and Concomitant Medications ...........................................................................74 
9.1.3. 
Prohibited Medications ...............................................................................................74 


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9.1.4. 
Compliance .................................................................................................................75 
9.1.5. 
Randomization and Blinding ......................................................................................75 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................76 
10.1. 
Study Drug ..................................................................................................................76 
10.1.1. 
Elacestrant ...................................................................................................................76 
10.1.2. 
Standard of Care .........................................................................................................76 
10.1.2.1. 
Fulvestrant ..................................................................................................................76 
10.1.2.2. 
Anastrozole .................................................................................................................76 
10.1.2.3. 
Letrozole .....................................................................................................................76 
10.1.2.4. 
Exemestane .................................................................................................................76 
10.1.3. 
Elacestrant Packaging and Labeling ...........................................................................76 
10.1.4. 
Storage, Handling, and Accountability .......................................................................76 
10.1.4.1. 
Elacestrant Storage .....................................................................................................77 
10.1.4.2. 
Standard of Care Storage ............................................................................................77 
10.1.5. 
Administration ............................................................................................................77 
10.1.5.1. 
Elacestrant ...................................................................................................................77 
10.1.5.2. 
Standard of Care .........................................................................................................78 
10.1.5.3. 
Unused Study Drug .....................................................................................................79 
11. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................80 
11.1. 
Statistical Hypotheses and Type I Error Control ........................................................80 
11.1.1. 
Statistical Hypotheses .................................................................................................80 
11.1.2. 
Type I Error Control ...................................................................................................80 
11.2. 
Analysis Populations ..................................................................................................80 
11.3. 
Description of Statistical Methods ..............................................................................81 
11.3.1. 
General Approach .......................................................................................................81 
11.3.2. 
Procedures for Handling Missing, Unused, and Spurious Data .................................81 
11.3.3. 
Demographics and Baseline Subject Characteristics ..................................................81 
11.3.4. 
Treatment Exposure ....................................................................................................82 
11.3.5. 
Analysis of the Primary Endpoints .............................................................................82 
11.3.6. 
Analyses of Secondary Endpoints ..............................................................................83 
11.3.7. 
Patient Reported Outcomes ........................................................................................84 
11.3.8. 
Pharmacokinetic Analysis ..........................................................................................84 


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11.3.9. 
Safety Analyses ..........................................................................................................84 
11.3.10. 
Exploratory Analyses ..................................................................................................85 
11.4. 
Interim Analysis ..........................................................................................................85 
11.5. 
Sample Size Assumptions...........................................................................................86 
11.6. 
Study Committees .......................................................................................................86 
11.6.1. 
Independent Data Monitoring Committee ..................................................................86 
11.6.2. 
Study Steering Committee ..........................................................................................86 
11.6.3. 
Imaging Review Committee .......................................................................................86 
12. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ...............................87 
12.1. 
Study Monitoring ........................................................................................................87 
12.2. 
Audits and Inspections ................................................................................................87 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................87 
14. 
ETHICS ......................................................................................................................87 
14.1. 
Ethics Review .............................................................................................................87 
14.2. 
Ethical Conduct of the Study ......................................................................................88 
14.3. 
Written Informed Consent ..........................................................................................88 
14.4. 
Subject Confidentiality and Privacy ...........................................................................88 
15. 
DATA HANDLING AND RECORD KEEPING ......................................................89 
15.1. 
Inspection of Records .................................................................................................89 
15.2. 
Retention of Records ..................................................................................................89 
16. 
PUBLICATION POLICY ..........................................................................................89 
17. 
LIST OF REFERENCES ............................................................................................90 
18. 
APPENDICES ............................................................................................................93 
APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) V1.1 ...........................................................................................................94 
APPENDIX 2. SCHEDULE OF EVENTS ...............................................................................101 
APPENDIX 3. ECOG PERFORMANCE STATUS.................................................................112 
APPENDIX 4. COCKCROFT-GAULT FORMULA ...............................................................113 
APPENDIX 5. NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS NCI-CTCAE V 5.0 ...................................114 
APPENDIX 6. NEW YORK HEART ASSOCIATION GUIDELINES ..................................115 
APPENDIX 7. CHILD-PUGH ASSESSMENT OF HEPATIC FUNCTION ..........................116 


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APPENDIX 8. MEDICATIONS AND FOODS THAT ARE MODERATE OR 
STRONG INDUCERS OR INHIBITORS OF CYP3A4/5 ......................................117 
 
LIST OF TABLES 
Table 1: 
Summary of Elacestrant Clinical Studies ...................................................................33 
Table 2: 
Study RAD1901-106 Summary Table of Efficacy Endpoints ...................................37 
Table 3: 
Study RAD1901-005 Summary Table of Efficacy Endpoints ...................................38 
Table 4: 
Progression-Free Survival by ESR1 Mutational Status for All Subjects and 
for Subjects Previously Treated with CDK4/6 Inhibitors in Elacestrant 
Studies RAD1901-106 and RAD1901-005 ................................................................39 
Table 5: 
Overall Summary of Adverse Events in Subjects with Breast Cancer using 
Combined Data from RAD1901-106 and RAD1901-005 (ITT Population) ..............40 
Table 6: 
Most Common (>10%) Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term Synonyma in Subjects with Breast Cancer 
using Combined Data from RAD1901-005 and RAD1901-106 (ITT 
Population) ..................................................................................................................41 
Table 7: 
Dose Modification Guidelines for AEs Related to Elacestrant ..................................51 
Table 8: 
Elacestrant Dose Reduction Guidelines ......................................................................51 
Table 9: 
Mandatory Dose Interruptions and Dose Reductions for Prolonged QTcF ...............52 
Table 10: Classification for Study Drug Action Taken with Regard to an Adverse 
Event ...........................................................................................................................68 
Table 11: Classifications for Outcome of an Adverse Event ......................................................68 
Table 12: Grading of Adverse Events .........................................................................................70 
Table 13: Investigational Product ...............................................................................................73 
Table 14: Rules for Deriving Date of Progression or Censor for IRC-Assessed PFS ................82 
Table 15: Target and Non-Target Lesion Response ...................................................................97 
Table 16: Time Point Response: Subjects with Non-Target Disease Only ................................98 
Table 17: Best Overall Response when Confirmation of CR or PR is Required .......................98 
Table 18: Schedule of Events ...................................................................................................101 
Table 19: Pharmacokinetics, Vital Signs, and ECG Schedule of Events Relative to 
Elacestrant and SOC Dosing ....................................................................................108 
Table 20: Tumor Assessment Requirements Flowchart ...........................................................109 
 
 
 


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LIST OF FIGURES 
Figure 1: 
Elacestrant Inhibits the Tumor Growth of PDX Models that Harbor 
Frequently Detected ESR1 Mutations, Y537S and D538G ........................................30 
Figure 2: 
Anti-Tumor Activity of Elacestrant in a Post-Fulvestrant Setting .............................31 
Figure 3: 
Elacestrant Anti-Tumor Activity in a Palbociclib-Resistant PDX Model 
(WHIM43) ..................................................................................................................32 
Figure 4: 
Study Design ...............................................................................................................48 
 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AI 
Aromatase inhibitor 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
C1D1……. CxDx 
Cycle 1 Day 1…… Cycle x Day x 
CBE 
Clinical Benefit Evaluable 
CBR 
Clinical benefit rate 
CDK 
Cyclin-dependent kinase  
CDK4/6i 
Cyclin-dependent kinase 4/6 inhibitor 
CI 
Confidence intervals 
CNS 
Central nervous system 
CR 
Complete response 
CRA 
Clinical research associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
ctDNA 
Circulating tumor deoxyribonucleic acid 
Ctrough 
Trough concentration 
CV 
Coefficient of variation  
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire-Core 30 
ER 
Estrogen receptor 
ERα 
Estrogen receptor-alpha 
ER+ 
Estrogen receptor positive 
EOT 
End of treatment 
ESR1 
Estrogen receptor 1 gene 


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Abbreviation 
Definition 
ESR1-mut 
ESR1 mutation 
ESR1-mut-nd 
no ESR1 mutation detected (includes samples where ESR1 mutation was not 
detected and where ESR1 mutation status could not be determined) 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
FES 
16a-18F-fluoro-17β-estradiol 
FES-PET 
Fluoroestradiol-positron emission tomography 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GnRH 
Gonadotropin releasing hormone 
HDPE 
High density polyethylene 
HER2 
Human epidermal growth factor receptor 2 
HER2+ 
Human epidermal growth factor receptor 2 positive 
HER2- 
Human epidermal growth factor receptor 2 negative 
HR 
Heart rate 
HRQOL 
Health-Related Quality of Life 
HV 
Healthy volunteer 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IM 
Intramuscular(ly) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRC 
Imaging Review Committee 
IRT 
Interactive randomization technology 
ITT 
Intention-to-treat 
KM 
Kaplan-Meier 
LBD 
Ligand-binding domain 
LH 
Luteinizing hormone 
mBC 
Advanced/metastatic breast cancer 
MRI 
Magnetic resonance imaging 
mTOR 
Mechanistic target of rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 


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Abbreviation 
Definition 
PDX 
Patient-derived xenograft 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PGR 
Progesterone receptor 
PI 
Product Insert 
PI3K 
Phosphoinositide 3-kinase 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PRO 
Patient reported outcomes  
PRO-CTCAE 
Patient Reported Outcome-Common Terminology Criteria for Adverse 
Events 
PT 
Prothrombin time 
PTx 
Post-treatment 
Q1 
1st quartile 
Q3 
3rd quartile 
QD 
Once daily 
QTcF 
QT corrected by Fridericia's formula 
RNA 
Ribonucleic acid 
RP2D 
recommended Phase 2 dose  
RADIUS 
Radius Pharmaceuticals, Inc 
RE 
Response Evaluable 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SERD 
Selective estrogen receptor degrader 
SERM 
Selective estrogen receptor modulator 
SmPC 
Summary of Product Characteristics 
SOC 
Standard of care 
SSC 
Study Steering Committee 
t½ 
Half-life 
TEAE 
Treatment emergent adverse event 
tmax 
Time to maximum concentration 
TTC 
Time to chemotherapy 
ULN 
Upper limit of normal 
U.S. 
United States 
WT 
Wild-type 


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2. 
INTRODUCTION 
2.1. 
Breast Cancer 
Breast cancer is the leading type of cancer in women and the second leading cause of all new 
cancers worldwide when genders are combined (Ferlay et al, 2015). In women, it is the fifth 
leading cause of death (Ferlay et al, 2015) and the leading cause of cancer-related deaths 
(DeSantis et al, 2015). For European women, there were ~464,000 new cases and, 
concurrently, ~131,000 deaths from breast cancer in 2012 (Ferlay et al, 2015). In the United 
States (U.S.), approximately 330,000 (~ 266,120 invasive and ~63,960 non-invasive or in 
situ) new cases are expected for 2018 while an estimated 40,920 American women will die 
from the disease during this same period (breastcancer.org). In comparison, breast cancer in 
men is very rare; less than 1% of the total number of cancer cases. Nevertheless, the 
American Cancer Society estimates there will be 2,550 new cases of invasive breast cancer 
in men and nearly 500 men will die from breast cancer in 2018 (breastcancer.org). 
In the U.S. and Europe, improved treatments for many breast cancer patients are prolonging 
survival and improving quality of life, but the death rate for breast cancer is second only to 
lung cancer for women in the U.S. Furthermore, preventive methods are not abolishing new 
cases; breast cancers account for ~30% of all newly diagnosed cancers among U.S. women 
and the incidence rate of male breast cancer has not changed over the last 30 years 
(breastcancer.org). Thus, even in developed regions of the world, there is an unmet medical 
need for improving the care and treatment of patients diagnosed with this disease. 
Breast cancer is subdivided into categories based on tumor receptor status and is considered 
hormone receptor positive (+) if the tumor expresses the estrogen receptor (ER) or the 
progesterone receptor (PGR) and human epidermal growth factor receptor 2 positive 
(HER2+) if the tumor expresses the HER2 receptor. Alternatively, a tumor may not express 
any of these receptors and is considered receptor negative (-). Approximately 60-75% of 
breast cancers express the ER at the time of diagnosis (Hawkins, 1987). Given that the ER 
drives the growth and survival of these hormone-positive tumors, the National 
Comprehensive Cancer Network (NCCN, 2018) guidelines recommend endocrine treatment 
for estrogen receptor positive (ER+) breast cancer patients. Available endocrine treatments 
act as antiestrogens either by 1) decreasing ligand levels (ovarian ablation, gonadotropin 
releasing hormone (GnRH) agonists, aromatase inhibitors [AIs]) or 2) antagonizing the 
receptor (selective estrogen receptor modulators [SERMs]; eg, tamoxifen, toremifene), or 3) 
acting as selective estrogen receptor degraders (SERDs; eg, fulvestrant). 
While ER+ status has proven to be a positive prognostic factor and adjuvant endocrine 
therapy for primary ER+ disease can lead to long-term clinical benefit, there is currently no 
cure for advanced or metastatic ER+ breast cancer. Interestingly, even after treatment 
progression on multiple endocrine therapies, ER expression is often maintained in the 
metastatic setting, allowing physicians to cycle through available endocrine therapies in an 
attempt to control disease progression and reduce or delay the need for chemotherapeutic 
intervention (McDonnell and Wardell, 2010; Oesterreich and Davidson, 2013). Despite the 
availability of several approved endocrine therapies, there remains a large unmet need for 
improved treatment options, particularly in the setting of recurrent metastatic disease 
(Glück, 2014). 


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Fulvestrant (Faslodex® AstraZeneca) is currently the only approved SERD for the treatment 
of patients who have ER+ advanced or metastatic breast cancer (mBC). Fulvestrant 
effectively degrades the ER and has demonstrated clinical benefit in ER+ mBC patients. In 
the first-line metastatic setting, fulvestrant was associated with a median progression-free 
survival (PFS) of 6.5 months at 500 mg monthly dose in patients with ER+ metastatic or 
locally advanced breast cancer who failed previous hormonal therapy (DiLeo et al, 2010). 
While fulvestrant has demonstrated clinical benefit and is currently the only approved SERD 
for use in breast cancer patients, it has been described as being limited by its 
pharmacokinetic (PK) properties and its intramuscular (IM) route of administration, 
underscoring the need for novel ER antagonists (Wardell et al, 2015; Bihani et al, 2017). 
A sizable proportion of ER+ patients are de novo resistant to first-line endocrine therapy in 
the metastatic setting and the majority of those who initially respond ultimately become 
resistant to all available endocrine agents (Osborne and Schiff, 2011). These treatment 
failures have fueled the development of novel endocrine agents or targeted therapies that can 
be combined with endocrine therapies to increase clinical efficacy. The combination of 
cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) with AIs or fulvestrant in the first and 
second-line metastatic setting, respectively, has resulted in significant increases in PFS 
(Cristofanilli et al, 2016; Finn, et al 2016). However, patients receiving combination 
regimens that include a CDK4/6 inhibitor are rarely cancer free and unfortunately, the 
disease will inevitably progress. For patients who have disease progression on first- and 
second-line monotherapy and combination hormonal therapies, there is a need for well-
tolerated and efficacious therapeutic options.  
Point mutations in the ligand-binding domain (LBD) of ER have been described as a 
potential mechanism of treatment resistance and as a poor prognostic factor in metastatic 
ER+ disease (Chandarlapaty et al, 2016; Fanning et al, 2016). Two of the most frequently 
found estrogen receptor 1 gene (ESR1) mutations in patients, Y537S and D538G, have been 
shown to result in estradiol-independence and constitutive activation of ER in nonclinical 
models (Li et al, 2013; Toy et al, 2013; Jeselsohn et al, 2014). Furthermore, nonclinical 
studies have suggested that mutations in ER can cause decreased binding of ER antagonists 
to the receptor and a corresponding decrease in activity (Fanning et al, 2016). Recent clinical 
reports have demonstrated that some patients who have received AI therapy had detectable 
point mutations in ER (Chandarlapaty et al, 2016; Fribbens et al, 2016). While the detection 
of ESR1-mut post-AI has been demonstrated clinically, the efficacy of AIs or fulvestrant in 
tumors harboring ESR1-mut has not been evaluated in a prospective clinical study where 
patients were stratified based on ESR1 status. The limited available clinical data are based 
on retrospective study designs with relatively small data sets, making it difficult to 
accurately predict hormonal agent activity against specific ESR1-mut or against tumors that 
harbor multiple ESR1-mut. Prospective studies stratified by ESR1-mut status will be critical 
in identifying the optimal therapeutic approach for subjects with tumors bearing ESR1-mut.  
Next-generation, orally-bioavailable SERDs with improved PK properties have garnered 
significant interest as potential therapies for metastatic ER+ breast cancer in an effort to 
produce more durable clinical responses with a more favorable route of administration 
(Bentzon et al, 2008; McDonnell and Wardell, 2010; Osborne and Schiff, 2011; 
Glück, 2014). Herein, the rationale for the proposed evaluation of elacestrant, a novel, 


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orally-bioavailable SERD for the treatment of ER+ breast cancer in a post-endocrine, post-
CDK4/6 inhibitor setting, including patients who have tumors harboring ESR1 mutations, is 
described. 
2.2. 
Elacestrant 
Elacestrant is a tetrahydronaphthalene compound with a favorable tissue selective ER 
profile. Elacestrant is intended for once daily (QD) oral administration in tablet form. 
Elacestrant acts as a SERD at higher doses and, therefore, is being developed for the 
treatment of ER+ mBC. At lower doses, elacestrant was evaluated as a treatment for 
menopause-related vasomotor symptoms in women experiencing natural or 
surgically-induced menopause. 
2.2.1. 
Nonclinical Studies 
Elacestrant has been evaluated in a series of general pharmacology and toxicology studies. Data 
relevant to this protocol are described below with additional details provided in the Investigator’s 
Brochure (IB). 
Elacestrant binds with high affinity and selectivity for estrogen receptor-alpha (ERα) in vitro, 
causes a dose-dependent degradation of the ER, and has good oral bioavailability. Elacestrant 
has a low risk for adverse cardiac safety events and no effect on mortality in rats and monkeys. 
Slight increases in clotting time were observed, but clotting times were less than those observed 
in warfarin-treated rats. No adverse effects were observed on the respiratory system, the central 
nervous system, wound healing, or animal behavior and social interactions. To date, nonclinical 
studies of elacestrant in rats have shown no evidence of uterine stimulation (a known risk factor 
for endometrial cancer) or an increase in bone loss. Elacestrant showed a favorable profile when 
assessed for genetic toxicology and did not demonstrate mutagenic, clastogenic, aneuploidy, or 
genotoxic effects. Fertility, reproductive, and developmental toxicity studies have not been 
performed. Nonclinical data suggest elacestrant also has a favorable tissue selectivity profile, 
with an antagonist effect on ER in the breast and uterine tissue, while having agonist effects on 
bone (Garner et al, 2015). 
Studies using in vivo xenografts and in vitro cancer cell lines have been used to demonstrate 
elacestrant-induced growth inhibition of a variety of breast cancer models. In the presence of 
estradiol, elacestrant showed dose-dependent antagonism of estradiol-mediated proliferation of 
MCF-7 and T47D breast cancer cells. In the in vivo setting, elacestrant also inhibited the 
estrogen-dependent growth of MCF-7 breast cancer tumors. Furthermore, elacestrant has 
anti-tumor activity in multiple patient-derived xenograft (PDX) models of ER+ breast cancer, 
including those that are estrogen-independent, insensitive to fulvestrant, and/or harbor mutations 
in the ESR1 gene (Figure 1, Figure 2, and Figure 3). Anti-tumor activity of elacestrant was 
demonstrated in PDX models harboring either Y537S or D538G mutations in the ER, 2 of which 
came from patients treated with AIs, tamoxifen, and fulvestrant (Figure 1 and Figure 2). 
Additionally, 1 of these PDX models, WHIM43, was also resistant to the CDK4/6 inhibitor, 
palbociclib. In that model, elacestrant treatment resulted in significant growth inhibition 
compared to vehicle-treated tumors. Fulvestrant produced some growth inhibition; however, this 
effect was not statistically significantly different from vehicle-treated tumors (Figure 3). 


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Figure 1: 
Elacestrant Inhibits the Tumor Growth of PDX Models that Harbor 
Frequently Detected ESR1 Mutations, Y537S and D538G 
 
ESR1 mut = estrogen receptor 1 gene mutation. 
 
 


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Figure 2: 
Anti-Tumor Activity of Elacestrant in a Post-Fulvestrant Setting  
 
Fulvestrant resistance was generated in the MAXF-713 PDX model by exposing mice to 4 rounds of fulvestrant 
treatment. This derivative model was supplemented with estradiol and treated with a vehicle control, fulvestrant 
(subcutaneous, weekly), or elacestrant (oral, daily) as shown and tumor growth measured. Tumor growth was also 
evaluated in this model in the absence of estradiol supplementation as a method of mimicking aromatase inhibitor 
treatment. 
AI = aromatase inhibitor; PDX = patient-derived xenograft; SEM = standard error of the mean. 
 
 


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Figure 3: 
Elacestrant Anti-Tumor Activity in a Palbociclib-Resistant PDX Model 
(WHIM43) 
 
WHIM43 is a PDX model derived from a patient previously treated with multiple endocrine therapies (tamoxifen, 
fulvestrant, AIs). The WHIM43 model harbors a D538G mutation in the ESR1 gene and demonstrates treatment 
resistance to CDK4/6 inhibitor palbociclib. PDX models are derived from patients that have received hormonal 
therapies. PDX mice were treated with vehicle, elacestrant (oral, daily), palbociclib (oral, daily) or fulvestrant 
(subcutaneous, weekly). 
AI = aromatase inhibitor; ESR1 = estrogen receptor gene 1; fulv = fulvestrant; PDX = patient-derived xenograft; 
tam = tamoxifen. 
2.2.2. 
Clinical Studies 
As of 27 December 2019, a total of 585 subjects have been enrolled in the elacestrant 
development program, with 451 subjects having received elacestrant: 431 post-menopausal 
women and 20 men. The clinical development program includes 9 clinical studies: 2 dose-
finding studies in healthy volunteers, 2 Phase 2 safety and efficacy studies in post-menopausal 
women with vasomotor symptoms, 2 Phase 1 clinical pharmacology studies in healthy 
volunteers, 2 Phase 1 studies and the ongoing Phase 3 study in post-menopausal women (and 
men in study RAD1901-308) with mBC (Table 1). Safety data from these studies is provided in 
more detail in Section 2.2.2.5.4 and in the IB. 


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Table 1: 
Summary of Elacestrant Clinical Studies 
Study 
Number 
Phase 
Population 
N 
Primary 
Objective 
Elacestrant 
Doses/formulations 
Status 
RAD1901-001 
1 
Postmenopausal 
women HVs 
80 
(62 
elacestrant 
capsulea /18 
placebo) 
Safety, 
tolerability, 
single and 
multiple dose PK 
of elacestrant, 
bioavailability 
and food effect 
1, 10, 25, 50, 100,  
200 mg QD capsule 
and 1 mg IV 
Completed 
RAD1901-002 
2 
Postmenopausal 
women with 
vasomotor 
symptoms 
100  
(81 
elacestrant 
capsule/ 19 
placebo) 
Safety and 
efficacy of 
elacestrant on 
vasomotor 
symptoms 
10, 25, 50, 100 mg 
QD; capsule 
Completed 
RAD1901-004 
1 
Postmenopausal 
women HVs 
52  
(44 
elacestrant /  
8 placebo 
Safety, 
tolerability, and 
PK of elacestrant 
200, 500, 750, 1000 
mg QD; capsule 
Completed 
RAD1901-005 
1 
Postmenopausal 
women with 
mBC 
57 (33 
capsule and 
27 tabletb) 
Safety, PK, and 
MTD and/or 
RP2D of 
elacestrant 
200, 400, 600 mg 
QD; capsule and 
tablet 
Enrollment 
completed 
RAD1901-106 
1 
Postmenopausal 
women with 
mBC 
16 (16 
capsule and 
2 tabletc) 
Effect of 
elacestrant on the 
availability of ER 
binding sites 
using FES-PET 
imaging 
200 mg QD x 14 
days then escalated 
to 400 mg QD; and 
400 mg QD; 
capsule and tablet 
Completed 
RAD1901-109 
1 
Postmenopausal 
women and 
men HVs 
18 
elacestrant  
(9F and 9M) 
Effect of food on 
elacestrant PK 
400 mg QD; tablet 
Enrollment 
completed 
RAD1901-110 
1 
Postmenopausal 
women and 
men HVs 
18 
elacestrant  
(9F and 9M) 
Effect of strong 
CYP3A4 
inhibitor 
itraconazole on 
elacestrant PK 
200 mg QD; tablet 
Enrollment 
completed 
VMRAD1901-
203 
2 
Postmenopausal 
women with 
vasomotor 
symptoms 
139  
(101 
elacestrant/  
38 placebo) 
Safety and 
efficacy of 
elacestrant on 
vasomotor 
symptoms 
5, 10, 20 mg QD; 
capsule 
Completed 
RAD1901-308 
3 
Postmenopausal 
women and 
men with mBC 
466 
(planned) 
Efficacy (PFS) of 
elacestrant vs 
active 
comparatorsd 
400 mg QD; tablet 
Enrollment 
ongoing 
F = female; FES-PET = 16α-18F-fluoro-17β-estradiol positron emission tomography; HV = health 
volunteer; IV = intravenous; M = male; mBC = advanced/metastatic breast cancer; MTD = maximum-tolerated 
dose; PFS = progression-free survival; PK = pharmacokinetics; RP2D = recommended Phase 2 dose; QD = once 
daily 
aFive subjects in Study RAD1901-001 received both IV and capsules. 
bThree subjects in Study RAD1901-005 received both capsules and tablets. 
cTwo subjects in Study RAD1901-106 received both capsules and tablets. 
dActive comparators includes Standard of Care - Fulvestrant, Anastrozole, Letrozole, Exemestane. 


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2.2.2.1. 
Pharmacokinetic Data 
PK data have been evaluated in all of the clinical studies, including studies in healthy post-
menopausal women, post-menopausal women with vasomotor symptoms, and women with 
mBC. Key PK findings are as follows: 
 Following oral administration, elacestrant is absorbed rapidly, reaching maximum 
plasma concentrations (tmax) within approximately 1 to 4 hours after multiple daily 
ascending doses (10 to 1000 mg for 7 days). Steady-state plasma concentrations of 
elacestrant were reached at approximately Day 6 following QD dosing, which is 
consistent with the observed half-life (t1/2) of approximately 30 to 50 hours. Human 
plasma protein binding was high (essentially 100%). 
 Exposure to elacestrant increased in a dose-dependent manner. 
 Preliminary results from the food-effect study with elacestrant tablets (study 
RAD1901-109) indicate that administration with a light, low-fat meal or a heavy, 
high-fat meal increased the geometric mean elacestrant Cmax by 32% and 36%, 
respectively, and increased the geometric mean elacestrant AUC0-∞ by 16% and 26%, 
respectively. 
 The PK of elacestrant is similar between healthy post-menopausal women and post-
menopausal women with ER+/HER2- mBC. 
 In vitro studies indicate that elacestrant is a CYP3A4 substrate.  The preliminary 
results from the drug-drug interaction study RAD1901-110 indicate that 
coadministration of the potent CYP3A4 inhibitor, itraconazole 200 mg QD, with 
elacestrant 200 mg QD increased the geometric mean elacestrant Cmax by 4.37-fold 
(from 45.6 ng/mL to 199.3 ng/mL) and increased the geometric mean elacestrant 
AUC0-∞ by 5.27-fold (from 720 ng·h/mL to 3710 ng·h/mL). Therefore, elacestrant 
should not be coadministered with other drugs that alter (inhibit or induce) CYP3A4. 
 Preliminary data from exposure-response analyses support the proposed elacestrant 
QD dose of 400 mg for treatment of ER+/HER2- mBC. 
2.2.2.2. 
Safety and Tolerability in Healthy Volunteers Studies 
Study RAD1901-001 is a Phase 1, randomized, double-blind, placebo-controlled study 
evaluating safety, tolerability, single and multiple dose PK, bioavailability and food effect 
in healthy volunteers. Overall, 80 subjects were enrolled, with 62 treated with elacestrant 
(capsule formulation) and 18 with placebo. Single oral doses ranged from 1 to 200 mg and 
multiple oral doses (QD for 7 days) ranged from 10 to 200 mg. This study showed food effects 
via differences in PK under fasting and fed conditions. There were no clinically-relevant changes 
in laboratory parameters, vital signs, physical examinations, or 12-lead electrocardiograms 
(ECGs). There were no deaths, no serious adverse events (SAEs), and no subject withdrawals 
due to adverse events (AEs). Overall, the drug was well-tolerated. The most frequently reported 
(>5%) AEs in subjects receiving elacestrant were headache, nausea, dyspepsia, myalgia, 
diarrhea, and dizziness; all were mild in intensity and transient. Tolerability was similar under 
fed and fasting conditions and the AE profiles were similar for both the single- and multiple-dose 
parts of the study. There were no clinically relevant changes in laboratory parameters, vital signs 


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(blood pressure [BP], pulse rate, body temperature), physical examination or ECG over the 
course of the study. ECG parameters (heart rate [HR], PR interval, QT interval, QTcB-interval) 
showed no changes of clinical relevance. 
Study RAD1901-004 is a Phase 1, randomized, double-blind, placebo-controlled, multiple-
ascending-dose study in healthy post-menopausal women. The study primarily evaluated 
safety, tolerability, and PK of elacestrant (capsule formulation) administered orally QD for 7 
consecutive days at doses of 200 mg to 1000 mg QD. The secondary objectives were to 
determine the occupancy of ERα in peripheral tissues and to determine if elacestrant crossed 
the blood-brain barrier. Overall, 52 subjects were enrolled with 44 treated with elacestrant 
and 8 with placebo. Static positron emission tomography (PET) scans of the uterus showed a 
mean ERα occupancy of 83% in the 200 mg dose group and a mean ERα occupancy of 92% 
in the 500 mg dose group. Minimal levels of elacestrant were detected in cerebrospinal fluid 
(CSF; CSF/plasma concentration ratios <0.2%), suggesting a small amount of elacestrant 
penetrated the blood-brain barrier. Elacestrant was well tolerated by the majority of subjects. 
There were no deaths or SAEs reported. A total of 9 subjects were withdrawn from 
elacestrant treatment due to 1 or more AEs. The majority of AEs leading to withdrawal were 
gastrointestinal AEs. The maximum intensity of these AEs was Grade 3 for 3 of the 9 
withdrawn subjects, Grade 2 for 5 of these subjects and Grade 1 for 1 subject. The most 
frequently reported AEs for elacestrant vs placebo were nausea (43% vs 25%, respectively), 
dyspepsia (36% vs 13%, respectively), headache (34% vs 25%, respectively), and vomiting 
(32% vs 0%, respectively). 
2.2.2.3. 
Clinical Pharmacology in Healthy Volunteer Studies 
Study RAD1901-109 is a Phase 1, randomized, open-label, 3-period, crossover food-effect study 
comparing the PK profile of elacestrant 400 mg tablets administered in the fasted, fed (light, 
low-fat meal), and fed (heavy, high-fat meal) states in 18 healthy men and post-menopausal 
women. Preliminary results indicate that administration of the elacestrant 400 mg tablet with a 
light, low-fat meal or a heavy, high-fat meal increased the geometric mean elacestrant Cmax by 
32% and 36%, respectively, and increased geometric mean elacestrant AUC0-∞ by 16% and 26%, 
respectively, compared to fasted administration. These effects were smaller than the food-effect 
observed with the original elacestrant capsule formulation that exhibited a 106% increase in 
elacestrant Cmax and a 57% increase in elacestrant AUC0-∞ for administration with a heavy, high-
fat meal. It is recommended to administer elacestrant after a light meal to improve the 
gastrointestinal tolerability effects associated with fasted administration. 
Study RA1901-110 is a Phase 1, nonrandomized, open-label, drug-drug interaction study 
evaluating the effect of a potent CYP3A4 inhibitor, itraconazole, on the steady-state PK profile 
of elacestrant in 18 healthy men and post-menopausal women. Preliminary results indicate that 
coadministration of the potent CYP3A4 inhibitor, itraconazole 200 mg QD, with elacestrant 200 
mg QD increased the geometric mean elacestrant Cmax by 4.37-fold (from 45.6 ng/mL to 199.3 
ng/mL) and increased the geometric mean elacestrant AUC0-∞ by 5.27-fold (from 720 ng·h/mL 
to 3710 ng·h/mL). Therefore, elacestrant should not be coadministered with other drugs that alter 
(inhibit or induce) CYP3A4. 


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2.2.2.4. 
Vasomotor Symptoms Studies 
The efficacy of elacestrant in reducing the frequency or severity of vasomotor symptoms in 
post-menopausal women with moderate to severe vasomotor symptoms was studied in 2 Phase 2 
clinical studies: RAD1901-002 and VMRAD1901-203. The efficacy of elacestrant in reducing 
vasomotor symptoms was not clearly demonstrated. No further trials in subjects with vasomotor 
symptoms are planned. 
2.2.2.5. 
Metastatic Breast Cancer Studies 
The safety, tolerability, and efficacy of elacestrant in post-menopausal women with ER+/HER2- 
mBC have been studied in 2 Phase 1 clinical studies: RAD1901-005 and RAD1901-106, and is 
currently being evaluated in the ongoing Phase 3 study RAD1901-308. Efficacy results for each 
of the Phase 1 studies is provided in Section 2.2.2.5.1 Section 2.2.2.5.1 , respectively. Safety data 
for subjects receiving 400 mg elacestrant QD from Studies RAD1901-005 and RAD1901-106 
have been pooled and are shown separately for subjects receiving capsules or tablets in 
Section 2.2.2.5.4. 
2.2.2.5.1. Study RAD1901-106 
Study RAD1901-106 is a Phase 1b study in post-menopausal women with ER+/HER2- mBC to 
evaluate the effect of elacestrant on the availability of ER binding sites using fluoroestradiol-
positron emission tomography (FES-PET) imaging. Overall, 16 subjects were enrolled; 8 
received 200 mg QD of elacestrant which was increased to 400 mg QD after 14 days (200/400 
mg group), and 8 subjects received 400 mg QD of elacestrant. The primary study endpoint was 
the percentage difference in FES uptake in tumor lesions (up to a maximum of 20 lesions) after 
14 days of treatment with elacestrant compared with baseline. 
At baseline, over half (56.3%) of the subjects had at least 1 ESR1 mutation based on circulating 
tumor deoxyribonucleic acid (ctDNA). Subjects had received a median of 3.0 lines of prior 
anticancer therapies (inclusive of all types of therapy, regardless of setting), and a median of 1.0 
line of prior chemotherapy. Six (37.5%) subjects received prior therapy with fulvestrant and 6 
(37.5%) subjects received prior therapy with an mechanistic target of rapamycin (mTOR) 
inhibitor; no subject received a prior CDK4/6 inhibitor. 
Van Kruchten (2015) previously reported on the relationship between ER reduction and response 
to the SERD fulvestrant by using FES-PET imaging at baseline and after fulvestrant treatment. 
The study defined subjects with a <75% reduction in FES uptake as having “residual ER 
availability.” Based on this cut-off, 38% (6/16) of subjects had significant residual ER 
availability after 4 weeks of fulvestrant treatment and this residual ER availability was associated 
with early progression. In study RAD1901-106, elacestrant greatly reduced FES uptake from 
baseline to Day 14. All but 1 subject in the 400 mg cohort (7/8; 87.5%) and 57% of subjects 
(4/7) in the 200/400 mg cohort had a greater than 75% reduction in FES uptake. The overall 
median reduction in FES uptake was 88.0%. This reduction in FES uptake was similar in 
subjects with and without mutations in ESR1. 
For subjects receiving the recommended Phase 2 dose (RP2D) of elacestrant of 400 mg QD, with 
or without a 14-day lead-in at 200 mg QD, and having Response Evaluation Criteria in Solid 
Tumors (RECIST) measurable disease at baseline and with at least 1 post-baseline measurement, 


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the objective response rate (ORR) was 11.1% (N=1/9), clinical benefit rate (CBR) at 24 weeks 
was 30.8% (N=4/13), duration of response (DoR) was 22.00 weeks, and median PFS was 5.3 
months (Table 2). No significant correlation was found between FES uptake and best overall 
response, using Spearman’s rank correlation coefficient. 
Table 2: 
Study RAD1901-106 Summary Table of Efficacy Endpoints 
 
Elacestrant  
Parameter 
200/400 mg 
400 mg 
Overall 
ORRa  % (n/N) 
0 (0/4) 
20.0 (1/5) 
11.1 (1/9) 
DoR (weeks) 
 
22.00 
22.0 
Time to Response (weeks) 
 
7.86 
7.86 
CBRb at 24 weeks  % (n/N) 
16.7 (1/6) 
42.9 (3/7) 
30.8 (4/13) 
Median PFS (months) 
3.6 
6.9 
5.3 
DoR = Duration of Response; PFS = Progression Free Survival. 
aORR = Objective Response (CR+PR) Rate, CR = Complete Response, PR = Partial Response. 
The ORR is calculated as the proportion of RE subjects who had objective response. RE 
population: all ITT subjects who had target lesion at baseline and at least 1 post-baseline 
RECIST assessment on any (target or non-target) lesions and/or had a new lesion. 
bThe CBR at 24 weeks is calculated as the proportion of CBE subjects who had confirmed 
CR or PR any time during the study, or SD that lasts at least 24 weeks. CBE population: all ITT 
subjects who had measurable and/or evaluable disease (ie, target or non-target lesions) at 
baseline and at least 1 post-baseline RECIST assessment on any (target or non-target) lesions 
and/or had a new lesion. 
Database lock date for study RAD1901-106: November 27, 2018. 
Source:  Section 14.2, Table 14.2.1.2, Table 14.2.1.5, Table 14.2.1.3.1, Table 14.2.1.4 
2.2.2.5.2. Study RAD1901-005 
Study RAD1901-005 is a Phase 1 study to determine the safety, PK, and maximum tolerated 
dose and/or RP2D of elacestrant in post-menopausal women with ER+/HER2- mBC. The study 
consisted of 4 parts: dose escalation (Part A), safety expansion (Part B), tablet introduction (Part 
C), and dose expansion (Part D). Part A used a 3+3 design with planned escalating oral capsule 
QD doses of 200, 400, 600, 800, and 1000 mg. Part B enrolled subjects to further study 400 mg 
QD, the RP2D identified from Part A. Part C evaluated the safety, tolerability, and PK of the 
elacestrant tablet dosage formulation at 400 mg QD. Part D enrolled additional subjects to 
evaluate the safety and preliminary efficacy of elacestrant tablet 400 mg oral QD dose in a 
subject population with different eligibility requirements from Parts A, B, and C. Although the 
study planned to enroll 36 subjects in Part D, due to a change in corporate strategy, enrollment 
was terminated after only 10 subjects were enrolled, limiting the conclusions that can be drawn 
from this cohort of subjects. 
At baseline 50.9% (29/57) of subjects had at least one ESR1 mutation based on ctDNA. Subjects 
received a median of 3.0 lines of prior anticancer therapies (inclusive of all types of therapies, 
regardless of setting); approximately half of the subjects had prior treatment with a CDK4/6 
inhibitor and/or SERD; approximately one-third had prior treatment with an mTOR inhibitor. 
Subjects enrolled in Part D had to meet different eligibility criteria than subjects enrolled in 


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Parts A, B, and C and received a greater number of prior lines of therapy than subjects enrolled 
in other parts of the study (median of 4.0 vs 3.0); therefore, antitumor activity for subjects in Part 
D cannot be directly compared to activity in Parts A, B, and C. 
Preliminary efficacy results are summarized in Table 3. Regardless of which study part they 
were enrolled in, all subjects treated at the RP2D of elacestrant 400 mg QD, the confirmed ORR 
with RECIST measurable disease at baseline and with at least 1 post-baseline measurement was 
19.4% (N=6/31); CBR at 24 weeks was 42.6% (N=20/47), median DoR was 24.86 weeks, and 
median PFS was 4.5 months (Table 3). 
Table 3: 
Study RAD1901-005 Summary Table of Efficacy Endpoints 
 
Elacestrant  
Parameter 
Part A+B+C 
400 mg 
Part D 
400 mg 
All 
400 mg 
ORRa % (n/N) 
27.3 (6/22) 
 0 (0/9) 
19.4 (6/31) 
Median DoR (weeks) 
24.86 
 
24.86 
Median Time to Response (weeks) 
8.21 
 
8.21 
CBRb at 24 weeks % (n/N) 
47.4 (18/38) 
22.2 (2/9) 
42.6 (20/47) 
Median PFS (months) 
5.4 
1.9 
4.5 
Part A = Dose Escalation, Part B = Safety Expansion, Part C = Tablet Introduction, and Part D = 
Dose Expansion. 
DoR = Duration of Response; PFS = Progression Free Survival. 
aORR = Objective Response (CR+PR) Rate, CR = Complete Response, PR = Partial Response. 
aThe ORR is calculated as the proportion of RE subjects who had objective response. RE population: 
all ITT subjects who had measurable disease (ie, at least 1 target lesion at baseline and at least 1 
post-baseline RECIST assessment on any (target or non-target) lesions and/or had a new lesion. 
bThe CBR at 24 weeks is calculated as the proportion of CBE subjects who had confirmed CR or 
PR any time during the study, or SD that lasts at least 24 weeks. 
bCBE population: all ITT subjects who had measurable and/or evaluable disease (ie, target or non-
target lesions) at baseline and at least 1post-baseline RECIST assessment on any (target or non-
target) lesions and/or had a new lesion. 
Database lock date for study RAD1901-005: December 20, 2019. 
Source: Section 14.2, Table 14.2.1.1a, Table 14.2.1.4a, Table 14.2.1.2.1a, Table 14.2.1.3a 
2.2.2.5.3. Exploration of Anti-Tumor Activity based on ESR1 Mutational Status in Studies 
RAD1901-106 and RAD1901-005 
To understand potential biomarkers for identification of patient populations who may derive 
preferential benefit from elacestrant, ctDNA from subjects enrolled in studies RAD1901-005 and 
RAD1901-106 were analyzed to determine ESR1 mutational status at baseline. A subset analysis 
was then conducted to determine PFS for subjects by baseline ESR1 mutational status (Table 4). 
A trend showing increased PFS in the subjects whose tumors harbored ESR1 mutations was 
observed; median PFS for subjects with ESR1 mutations compared with subjects without ESR1 
mutations was 7.4 and 2.8 months, respectively, in Study RAD1901-005 and 3.9 and 5.3 months, 
respectively, in Study RAD1901-106. Notably, in Study RAD1901-005, of the 6 subjects who 
achieved partial response (PR) by RECIST criteria, 5 had ESR1 mutations at baseline. 


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PFS was also calculated for subjects who had previously been treated with CDK4/6 inhibitors in 
Study RAD1901-005 (Table 4). While the number of subjects is small, the trend toward an 
increased PFS in CDK4/6 pre-treated subjects whose tumors harbor ESR1 mutations persisted. 
Table 4: 
Progression-Free Survival by ESR1 Mutational Status for All Subjects and 
for Subjects Previously Treated with CDK4/6 Inhibitors in Elacestrant 
Studies RAD1901-106 and RAD1901-005 
 
Median PFS (months)  
Prior Anti-Cancer Therapy 
ESR1-mut 
ESR1-mut-nd 
Overall 
RAD1901-005 + RAD1901-106 
 
 
 
 All Prior Therapies 
7.4 (n=34) 
3.7 (n=32) 
5.3 (n=66) 
 Prior CDK4/6 inhibitor 
4.9 (n=13) 
1.9 (n=13) 
3.8 (n=26) 
RAD1901-005 
 
 
 
 All Prior Therapies 
7.4 (n=25) 
2.8 (n=25) 
4.5 (n=50) 
 Prior CDK4/6 inhibitor 
4.9 (n=13) 
1.9 (n=13) 
3.8 (n=26) 
RAD1901-106 
 
 
 
 All Prior Therapies 
3.9 (n=9) 
5.3 (n=7) 
5.3 (n=16) 
 Prior CDK4/6 inhibitor 
NAa 
NAa 
NAa 
CDK = cyclin-depedent kinase; ESR1 = estrogen receptor gene; ESR1-mut = ESR1 mutation; 
ESR1-mut-nd = no ESR1 mutation detected (includes samples with no mutation detected and 
samples where ESR1 mutational status could not be determined). 
Study RAD1901-106 ESR1 mutation status determined in ct-DNA samples at baseline using 
OncoBEAM™ (Sysmex Inostics) assay. 
Study RAD1901-005 ESR1 mutation status determined in ct-DNA samples at baseline using 
Guardant360® assay unless subject had baseline Sysmex result but no baseline Guardant result, 
in which case Sysmex result was used in the analysis. 
All prior therapies includes ITT subjects who received any prior anti-cancer therapies. 
RAD1901-005 database lock date: December 20, 2019; RAD1901-106 database lock date: 
November 27, 2018. 
N=16 subjects receiving 400 mg (with or without 14-day lead in at 200 mg) elacestrant QD 
for RAD1901-106 and N=50 subjects receiving 400 mg elacestrant QD for RAD1901-005. 
aNA = Not available: no subject received prior CDK4/6 inhibitors in this study. 
2.2.2.5.4. Combined Safety from Studies RAD1901-005 and RAD1901-106 
Safety data were combined for subjects enrolled in the 2 Phase 1 studies of elacestrant in post-
menopausal women with mBC and are presented in Table 5 and Table 6 for subjects treated at 
the RP2D of 400 mg QD. Data are presented separately for subjects treated with the capsule 
formulation and the tablet formulation. Two subjects in study RAD1901-106, and 3 subjects in 
study RAD1901-005, initially received capsules and were then switched to tablets; these 5 
subjects are included in the capsule group in the capsule group in the tables below. 
Most subjects receiving either formulation experienced TEAEs and treatment-related TEAEs 
(Table 5). The incidence of subjects experiencing TEAEs leading to dose interruption and Grade 
3 or 4 TEAEs were similar between the 2 formulations, while the incidence of SAEs was higher 
in subjects with tablets as compared to those with capsules. There were no treatment-related 
deaths. 


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Table 5: 
Overall Summary of Adverse Events in Subjects with Breast Cancer using 
Combined Data from RAD1901-106 and RAD1901-005 (ITT Population) 
Adverse Event Category 
Elacestrant 
400 mg 
capsules 
(N=42)a 
n (%) 
Elacestrant 
400 mg 
tablets 
(N=24) 
n (%) 
Overall 
(N=66)a 
n (%) 
TEAEs 
 42 ( 100) 
 22 (91.7) 
 64 (97.0) 
Treatment-Related TEAEs 
 40 (95.2) 
 19 (79.2) 
 59 (89.4) 
Serious TEAEs 
  8 (19.0) 
  8 (33.3) 
 16 (24.2) 
Treatment-Related Serious TEAEs 
  2 ( 4.8) 
  1 ( 4.2) 
  3 ( 4.5) 
TEAEs Leading to Dose Interruption 
 13 (31.0) 
  8 (33.3) 
 21 (31.8) 
Treatment-Related TEAEs Leading to Dose 
Interruption 
  9 (21.4) 
  1 ( 4.2) 
 10 (15.2) 
TEAEs at Grade 3 or 4b 
 16 (38.1) 
 10 (41.7) 
 26 (39.4) 
Treatment-Related TEAEs at Grade 3 or 4 
  9 (21.4) 
  1 ( 4.2) 
 10 (15.2) 
TEAEs Leading to Death 
  1 ( 2.4) 
  1 ( 4.2) 
  2 ( 3.0) 
Treatment-Related TEAEs Leading to Death 
  0 
  0 
  0 
TEAEs Leading to Study Medication 
Discontinuation 
  8 (19.0) 
  1 ( 4.2) 
  9 (13.6) 
Treatment-Related TEAEs Leading to Study 
Medication Discontinuation 
  7 (16.7) 
  0 
  7 (10.6) 
Treatment-Emergent Adverse Events (TEAEs) are those events which started on or after the first dose of study 
medication. 
a Eight patients initiated treatment at 200 mg for 14 days. 
b Severity grad based upon CTCAE version 5.0 
Study RAD1901-106 database lock date: November 27, 2018. 
Study RAD1901-005 database lock date: December 20, 2019. 
Source:  SRT Table 2.1 
For both formulations, TEAEs occurred most frequently in the gastrointestinal disorders system 
organ class. The overall incidence of the most common (≥ 20%) TEAEs in subjects receiving 
capsules (N=42) were, in descending order, nausea, dyspepsia, fatigue, vomiting, and diarrhea. 
For subjects receiving tablets (N=24), TEAEs generally occurred with lower frequency (ie, 
nausea occurred in 66.7% of subjects receiving capsules vs 33.3% of subjects receiving tablets). 
For subjects receiving tablets, the most common (≥ 20%) TEAEs in descending order include 
nausea (33.3%), blood triglycerides increased (25.0%), blood phosphorus decreased (25.0%), as 
well as blood potassium decreased, urinary tract infection, constipation, dyspepsia, fatigue, and 
headache (all 20.8%; Table 6). 


Clinical Study Protocol 
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Table 6: 
Most Common (>10%) Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term Synonyma in Subjects with Breast Cancer 
using Combined Data from RAD1901-005 and RAD1901-106 (ITT 
Population) 
Adverse Event 
Elacestrant 
400 mg 
capsules 
(N=42)b 
n (%) 
Elacestrant 
400 mg 
tablets 
(N=24) 
n (%) 
Overall 
(N=66)* 
n (%) 
Any TEAEs 
 42 ( 100) 
 22 (91.7) 
 64 (97.0) 
Gastrointestinal disorders 
 38 (90.5) 
 19 (79.2) 
 57 (86.4) 
Nausea 
 28 (66.7) 
  8 (33.3) 
 36 (54.5) 
Dyspepsia 
 18 (42.9) 
  5 (20.8) 
 23 (34.8) 
Vomiting 
 17 (40.5) 
  4 (16.7) 
 21 (31.8) 
Diarrhoea 
 11 (26.2) 
  3 (12.5) 
 14 (21.2) 
Constipation 
  6 (14.3) 
  5 (20.8) 
 11 (16.7) 
Gastrooesophageal reflux disease 
  8 (19.0) 
  2 ( 8.3) 
 10 (15.2) 
Dysphagia 
  7 (16.7) 
  1 ( 4.2) 
  8 (12.1) 
Abdominal pain upper 
  5 (11.9) 
  2 ( 8.3) 
  7 (10.6) 
Flatulence 
  6 (14.3) 
  1 ( 4.2) 
  7 (10.6) 
Investigations 
 19 (45.2) 
 15 (62.5) 
 34 (51.5) 
Aspartate aminotransferase increased 
  9 (21.4) 
  3 (12.5) 
 12 (18.2) 
Blood triglycerides increased 
  6 (14.3) 
  6 (25.0) 
 12 (18.2) 
Blood glucose increased 
  7 (16.7) 
  4 (16.7) 
 11 (16.7) 
Blood phosphorus decreased 
  4 ( 9.5) 
  6 (25.0) 
 10 (15.2) 
Alanine aminotransferase increased 
  6 (14.3) 
  3 (12.5) 
  9 (13.6) 
Blood Pressure Increased 
  6 (14.3) 
  2 ( 8.3) 
  8 (12.1) 
Blood cholesterol increased 
  4 ( 9.5) 
  4 (16.7) 
  8 (12.1) 
Blood potassium decreased 
  2 ( 4.8) 
  5 (20.8) 
  7 (10.6) 
General disorders and administration site conditions 
 23 (54.8) 
 10 (41.7) 
 33 (50.0) 
Fatigue 
 17 (40.5) 
  5 (20.8) 
 22 (33.3) 
Oedema peripheral 
  6 (14.3) 
  1 ( 4.2) 
  7 (10.6) 
Musculoskeletal and connective tissue disorders 
 19 (45.2) 
 12 (50.0) 
 31 (47.0) 
Arthralgia 
  7 (16.7) 
  4 (16.7) 
 11 (16.7) 
Back pain 
  7 (16.7) 
  4 (16.7) 
 11 (16.7) 
Nervous system disorders 
 13 (31.0) 
 13 (54.2) 
 26 (39.4) 
Headache 
  4 ( 9.5) 
  5 (20.8) 
  9 (13.6) 
Dizziness 
  6 (14.3) 
  2 ( 8.3) 
  8 (12.1) 
Respiratory, thoracic and mediastinal disorders 
 15 (35.7) 
  8 (33.3) 
 23 (34.8) 
Cough 
  6 (14.3) 
  4 (16.7) 
 10 (15.2) 
Dyspnoea 
  5 (11.9) 
  2 ( 8.3) 
  7 (10.6) 
Infections and infestations 
 13 (31.0) 
  9 (37.5) 
 22 (33.3) 
Urinary tract infection 
  2 ( 4.8) 
  5 (20.8) 
  7 (10.6) 
Metabolism and nutrition disorders 
 10 (23.8) 
  8 (33.3) 
 18 (27.3) 
Decreased appetite 
  6 (14.3) 
  3 (12.5) 
  9 (13.6) 
Vascular disorders 
  9 (21.4) 
  5 (20.8) 
 14 (21.2) 
Hot flush 
  7 (16.7) 
  4 (16.7) 
 11 (16.7) 
Blood and lymphatic system disorders 
  8 (19.0) 
  3 (12.5) 
 11 (16.7) 
Anaemia 
  7 (16.7) 
  3 (12.5) 
 10 (15.2) 


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Adverse Event 
Elacestrant 
400 mg 
capsules 
(N=42)b 
n (%) 
Elacestrant 
400 mg 
tablets 
(N=24) 
n (%) 
Overall 
(N=66)* 
n (%) 
a Synonym terms across different SOCs are grouped together and defined in Appendix D of the Elacestrant 
Investigator’s Brochure (Edition 9.0). 
b Eight subjects initiated treatment at 200 mg for 14 days. 
Coded using MedDRA v17.1. 
Treatment-Emergent Adverse Events (TEAE) are those events which started on or after the 
first dose of study medication. 
Each subject was counted once for the same system organ class and the same preferred term. 
Study RAD1901-106 database lock date: November 27, 2018. 
Study RAD1901-005 database lock date: December 20, 2019. 
Source:  SRT Table 2.16 
2.3. 
Study Rationale 
Although there are an increasing number of therapeutic options available for ER+/HER2- mBC, 
there are, as yet, no curative treatments for these patients. While ER+ breast cancer patients 
typically respond well to initial endocrine therapy, endocrine resistance (both de novo and 
acquired) continues to present a clinical challenge. The SERD fulvestrant and AIs used alone and 
in combination therapy (eg, with CDK4/6i) are important components in the treatment of ER+ 
mBC. Unfortunately, tumors eventually develop resistance to fulvestrant, AIs, and CDK4/6is. 
Thus, there is still a significant unmet medical need for a potent oral agent to treat these 
challenging cases, which could provide patients with a prolongation of life as well as a better 
quality of life. 
Elacestrant is a novel selective SERD with several characteristics that portend its being best-in-
class and an improvement over fulvestrant and other currently available therapies in this 
population. In addition to an oral route of administration, nonclinical data have demonstrated it 
to be efficacious in models of ER+ breast cancer with both mutant and wild-type (WT) ESR1, 
and further, suggest that elacestrant may provide superior antitumor activity in ESR1 mutant 
models compared with fulvestrant. Additionally, in RADIUS’ Phase 1 studies RAD1901-005 
and RAD1901-106, elacestrant demonstrated single-agent efficacy regardless of ESR1 
mutational status, as well as in subjects who progressed on a CDK4/6i and fulvestrant. Five of 
the 6 subjects in Study RAD1901-005 who achieved a PR were found to have tumors harboring 
ESR1 mutations. Thus, there is the potential that elacestrant might provide a preferential benefit 
to patients with tumors harboring ESR1 mutations. To test for this possibility, subjects will be 
tested for ESR1 mutations during the screening process and stratified by mutational status (ESR1 
mutation [ESR1-mut] vs no ESR1 mutation detected [ESR1-mut-nd]). Subjects with ER+/HER2- 
mBC who have received prior endocrine therapy and prior therapy with a CDK4/6i will be 
randomized to treatment with elacestrant monotherapy or treatment with standard of care (SOC) 
endocrine therapy (fulvestrant or an AI). The statistical analyses of the PFS primary endpoint 
will be performed in subjects with ESR1 mutations detected by ctDNA testing (ESR1-mut 
subjects) and in all subjects (ESR1-mut and ESR1-mut-nd) using the Hochberg procedure 
(Hochberg, 1988) to adjust for the multiplicity of the primary endpoints.  


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The study described herein will be conducted to determine if elacestrant provides an 
improvement over the SOC of fulvestrant or AIs and will determine if ESR1 mutational status 
impacts the response to either elacestrant or the SOC. 
2.4. 
Rationale for Study Dose 
The dose of elacestrant to be used in Study RAD1901-308, 400 mg QD, was selected based on 
nonclinical data and safety, efficacy, and PK data from 6 Phase 1 and Phase 2 clinical studies of 
elacestrant. 
The initial dose of 200 mg QD used in the Phase 1 study RAD1901-005 in post-menopausal 
women with metastatic breast cancer was based on the nonclinical safety and efficacy profile, 
and the clinical safety of elacestrant in 106 healthy post-menopausal women who received doses 
up to 200 mg QD in study RAD1901-001 and up to 1000 mg QD in study RAD1901-004. In 
both studies, all doses, administered orally for 7 consecutive days, were well tolerated. At the 
200 mg QD dose in both studies, there were no deaths, SAEs or discontinuations due to AEs, and 
all AEs were mild (RAD1901-001) or mild or moderate (RAD1901-004) in severity. 
In addition, elacestrant at 200 mg QD was determined to be potentially efficacious in patients 
with ER-dependent breast cancers, based on extrapolation of nonclinical xenograft studies in 
mouse models. At doses of 30 mg/kg/d and 60 mg/kg/d in a mouse MCF-7 xenograft model 
elacestrant inhibited tumor growth comparable to tamoxifen and fulvestrant. The human 
equivalent doses are 159 mg QD and 312 mg QD, respectively, when based on a 65 kg body 
weight. 
Based on these observations, the initial dose level of 200 mg QD for subjects enrolled in the dose 
escalation part of Study RAD1901-005 was selected. 
Dose escalation in Study RAD1901-005 Part A proceeded to 600 mg QD. Although no dose 
limiting toxicities were reported per protocol, the 600 mg dose was deemed to be not tolerable 
due primarily to gastrointestinal events; the incidence of nausea, vomiting, and constipation were 
higher in patients who received 600 mg elacestrant (67% to 100%) compared with the 400 mg 
dose (17% to 67%) at the time of the analysis. Therefore, the 400 mg dose, which was associated 
with fewer of these gastrointestinal events, was selected as the RP2D for further testing. 
Expansion cohorts in Parts B, C and D of Study RAD1901-005 confirmed the acceptability of 
the safety profile, and anti-tumor activity was observed at this dose level (ORR 19.4%). This 
dose was also tested in Study RAD1901-106 in post-menopausal women with mBC with an 
acceptable safety profile. Based upon the safety and efficacy observed with elacestrant 400 mg 
QD in both of these studies, 400 mg once daily was selected as the dose for Study 
RAD1901-308. 


Clinical Study Protocol 
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3. 
TRIAL OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary and Key Secondary Objectives 
 Primary:  To demonstrate that elacestrant compared with the SOC options of either 
fulvestrant or an AI is superior in prolonging PFS based on a blinded Imaging Review 
Committee (IRC) assessment in post-menopausal women and men with ER+/HER2- 
mBC, either in subjects with ESR1 mutations (ESR1-mut subjects) or in all subjects 
which includes subjects without detectable ESR1 mutations (ESR1-mut-nd) 
 Key Secondary: 
 To compare overall survival (OS) between treatment groups in ESR1-mut 
subjects 
 To compare OS between treatment groups in all subjects (ESR1-mut and 
ESR1-mut-nd) 
3.1.2. 
Other Secondary Objectives 
The following secondary objectives will be assessed for ESR1-mut-nd subjects: 
 To compare PFS based on blinded IRC assessment between treatment groups 
 To compare OS between treatment groups  
The following secondary objectives will be assessed for ESR1-mut subjects, ESR1-mut-nd 
subjects, and all subjects (ESR-mut and ESR1-mut-nd) 
 To compare PFS based on local Investigator assessment between treatment groups 
 To compare ORRs based on blinded IRC assessment between treatment groups 
 To compare DoR based on blinded IRC assessment between treatment groups 
 To compare CBR based on blinded IRC assessment between treatment groups 
 To compare ORR based on local Investigator assessment between treatment groups 
 To compare DoR based on local Investigator assessment between treatment groups 
 To compare CBR based on local Investigator assessment between treatment groups 
The following other secondary objectives will be assessed for ESR1-mut and all subjects 
(ESR1-mut and ESR1-mut-nd): 
 To compare the safety and tolerability between treatment groups 
 To assess the PK of elacestrant 
 To describe the changes in Patient Reported Outcomes (PROs) and Health-Related 
Quality of Life (HRQOL) and the changes in PROs/HRQOL between treatment 
groups 


Clinical Study Protocol 
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3.1.3. 
Exploratory Objectives 
The following exploratory objectives will be assessed in ESR1-mut subjects, ESR1-mut-nd 
subjects, and all subjects (ESR1-mut and ESR1-mut-nd): 
 To determine the difference in time to chemotherapy (TTC) between treatment 
groups 
 To evaluate alterations in ctDNA relevant to ER+ breast cancer and the CDK4/6 
pathway and to explore the relationship between these findings and clinical response  
 To characterize alterations in tumor-specific genes, proteins, and RNAs related to 
oncogenic pathways and proliferation and cell cycle markers in tumor tissues and to 
explore the relationship between these findings and clinical response 
3.2. 
Endpoints 
3.2.1. 
Primary and Key Secondary Endpoints 
3.2.1.1. 
Primary Endpoints 
The primary endpoints of this study are as follows: 
 IRC-assessed PFS in ESR1-mut subjects 
 IRC-assessed PFS in all subjects (ESR1-mut and ESR1-mut-nd) 
IRC-assessed PFS is defined as the length of time from randomization until the date of objective 
disease progression per RECIST v1.1 (Appendix 1) as assessed by the blinded IRC or death from 
any cause. 
3.2.1.2. 
Key Secondary Endpoints 
The key secondary endpoints are as follows: 
 OS in ESR1-mut subjects 
 OS in all subjects (ESR1-mut and ESR1-mut-nd) 
OS is defined as the length of time from randomization until the date of death from any cause. 
3.2.2. 
Other Secondary Endpoints 
The following endpoints will be analyzed for ESR1-mut-nd subjects: 
 IRC-assessed PFS 
 OS 
The following endpoints will be analyzed for ESR1-mut, ESR1-mut-nd, and all subjects 
(ESR1-mut and ESR1-mut-nd): 
 Local Investigator-assessed PFS, defined as the length of time from randomization 
until the date of objective disease progression per RECIST v1.1 as assessed by local 
Investigators or death from any cause 


Clinical Study Protocol 
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 IRC-assessed ORR, defined as the percentage of subjects with measurable disease 
who have achieved either a confirmed complete response (CR) or PR per RECIST 
v1.1 based on blinded IRC assessment 
 IRC-assessed DoR, defined as the duration of time from the date when criteria are 
met for either a CR or PR, per RECIST v1.1, until the first date that recurrent or 
progressive disease (PD) is objectively documented based on blinded IRC assessment 
 IRC-assessed CBR, defined as the percentage of subjects who have achieved either a 
confirmed CR or PR or stable disease (SD) at ≥ 24 weeks from randomization per 
RECIST v1.1 based on blinded IRC assessment 
 Local Investigator-assessed ORR 
 Local Investigator-assessed DoR 
 Local Investigator-assessed CBR 
The following endpoints will be assessed for ESR1-mut subjects and all subjects (ESR1-mut and 
ESR1-mut-nd): 
 Safety and tolerability, assessed by AEs, SAEs, dose modifications, clinical 
laboratory parameters (ie, hematology, chemistry, and coagulation), ECGs, 
performance status, and vital signs 
 PK, assessed by evaluation of elacestrant concentrations at pre-dose (pre-treatment) 
and 4 hours post-dose on Cycle 1 Day 1 (C1D1), pre-dose (trough concentration 
[Ctrough]) and 4 hours post-dose on C1D15, and pre-dose (Ctrough) on C2D1 
 PRO endpoints, assessed using the HRQOL scales EuroQOL 5 Dimension 5 Level 
(EQ-5D-5L), European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), and PRO Version of 
the Common Terminology Criteria for Adverse Events (PRO-CTCAE) 
3.2.3. 
Exploratory Endpoints 
The following exploratory endpoints will be assessed in ESR1-mut subjects, ESR1 mut-nd 
subjects, and all subjects (ESR1-mut and ESR1-mut-nd): 
 TTC, defined as the number of days from randomization to initiation of 
chemotherapy 
 Alterations in ctDNA relevant to ER+ breast cancer and the CDK4/6 pathway and the 
relationship between these findings and clinical response 
 Alterations in tumor-specific genes, proteins, and RNAs related to oncogenic 
pathways and proliferation and cell cycle markers in tumor tissue and the relationship 
between these findings and clinical response 


Clinical Study Protocol 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an international, multicenter, randomized, open-label, active-controlled, event-driven, 
Phase 3 clinical study comparing the efficacy and safety of elacestrant to the SOC options of 
either fulvestrant or an AI in post-menopausal women and men with ER+/HER2- mBC whose 
disease has relapsed or progressed on at least 1 and no more than 2 prior lines of endocrine 
therapy for mBC, which must have included CDK4/6i therapy in combination with fulvestrant or 
an AI. Subjects must have received no more than 1 line of cytotoxic chemotherapy in mBC. 
Endocrine monotherapy with 1 of the SOC drugs (fulvestrant, anastrozole, letrozole, 
exemestane) must be an appropriate treatment option for subjects enrolled in this study. The 
primary endpoints of IRC-assessed PFS will be analyzed in ESR1-mut subjects and in all 
subjects (ESR1-mut and ESR1-mut-nd) using the Hochberg procedure to adjust for the 
multiplicity of the primary endpoints. A schematic of the study design is provided in Figure 4. 
Subjects who meet all eligibility criteria will be enrolled into the active treatment phase of the 
study. During this phase of the study, subjects will receive study drug as defined in the protocol 
and will undergo the protocol-defined safety, efficacy, and exploratory assessments. Subjects 
will continue to receive treatment until the following: disease progression, a clinically significant 
AE, significant study noncompliance, the subject is unable to receive study treatment for > 14 
consecutive days, treatment discontinuation in the best interest of the subject, or subject refuses 
treatment as defined in Section 5.3.1 requires subject withdrawal. 
Subjects who discontinue the active treatment phase due to disease progression will enter a 
follow-up phase during which survival data and the start date and regimen name of the first new 
anti-cancer therapy will be collected. For subjects who discontinue treatment for reasons other 
than disease progression, death, consent withdrawal, toxicity, or loss to follow-up and who do 
not begin new anti-cancer therapy, tumor assessments will continue until disease progression or 
the first new anti-cancer therapy is initiated. At that time, subjects will discontinue tumor 
assessments and continue to be monitored for survival data and the initiation of the first new 
anti-cancer therapy. 
This is an open-label study and study subjects and Investigators will not be blinded to treatment 
assignment. However, to minimize bias in study conduct, RADIUS personnel performing 
statistical analyses, including biostatisticians, and programmers, will be blinded to treatment 
assignment until after database lock. Clinical Research Organization (CRO) study team members 
and select RADIUS team members will not be blinded to an individual subject’s treatment 
assignment during the conduct of the study but will be blinded to aggregated data by treatment 
assignment until after database lock. 
An independent IRC, blinded to subjects’ treatment assignments, will review radiographic 
images and clinical information collected on study to determine the protocol-defined endpoints 
of disease response and progression. 
Safety and efficacy data (PFS by IRC and local Investigator and OS) will be reviewed at 
prespecified intervals by an Independent Data Monitoring Committee (IDMC). An unblinded 
statistician at the CRO will perform all analyses in preparation for the IDMC evaluations. 


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A survival analysis will be performed at the same time as the final PFS analysis when 
approximately 160 PFS events (objective disease progression assessed by the blinded IRC or 
death) among the ESR1-mut subjects and 340 PFS events among all subjects (ESR1-mut and 
ESR1-mut-nd) have occurred and again when approximately 50% of subjects have died at which 
time the study will be complete. 
Figure 4: 
Study Design 
 
AI = aromatase inhibitor; EOT = end of treatment; ER+ = estrogen-receptor positive; ESR1 = estrogen receptor 
gene 1; HER2- = human epidermal growth factor receptor 2 negative; PD = progressive disease; SOC = standard of 
care 


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4.2. 
Number of Subjects 
This study is event-driven and is planned for a total of approximately 160 PFS events (objective 
disease progression assessed by the blinded IRC or death) among the ESR1-mut subjects and 
340 PFS events among all subjects (ESR1-mut and ESR1-mut-nd). It is estimated that 
approximately 466 subjects (220 ESR1-mut; 246 ESR1-mut-nd) will need to be enrolled in the 
study in a 1:1 randomization at approximately 230 clinical study sites experienced in conducting 
oncology clinical trials in Europe, North America, Middle East, Asia-Pacific and South America. 
Additional or fewer subjects and regions may be required to achieve the planned total number of 
events. 
4.3. 
Treatment Assignment 
Subjects will be randomized in a 1:1 to ratio to one of the following treatment groups: 
 Elacestrant 400 mg QD orally on a continuous dosing schedule 
 SOC with one of the following options:  
 Fulvestrant 500 mg administered IM into the buttocks as two 5 mL injections on 
C1D1, C1D15 and C2D1 and Day 1 of every subsequent 28-day cycle  
 Anastrozole 1 mg QD orally on a continuous dosing schedule 
 Letrozole 2.5 mg QD orally on a continuous dosing schedule 
 Exemestane 25 mg QD orally on a continuous dosing schedule 
Crossover from 1 treatment group or therapy to another will not be allowed while participating in 
the trial. 
Subjects will be stratified by the following criteria: 
 ESR1 mutational status detected by ctDNA (ESR1-mut vs ESR1-mut-nd) 
 Prior treatment with fulvestrant (yes vs no) 
 Presence of visceral metastases (yes vs no); visceral includes lung, liver, brain, 
pleural, and peritoneal involvement 
The following contraindications must be adhered to: 
 Known hypersensitivity to any of the SOC options or their excipients would preclude 
treatment with that particular therapy  
 Therapeutic anticoagulation therapy or bleeding disorder that would, in the 
Investigator’s opinion, preclude treatment with fulvestrant 
4.4. 
Disease Progression and Tumor Assessments 
Tumor assessments will be performed every 8 weeks (± 7 days) from the date of randomization 
during the active treatment phase of the study. Subjects with bone lesions identified by 
radionuclide bone scan or whole body magnetic resonance imaging (MRI) at baseline (during 
Screening) will have repeat bone scans or whole body MRI (using the same modality as used 


Clinical Study Protocol 
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during Screening) performed every 24 weeks (± 7 days) from the date of randomization and at 
time of confirmation of a CR. All assessments will be performed as scheduled at the required 
intervals according to the Schedule of Events (Appendix 2), regardless of any dosing delay to 
prevent the introduction of bias into the assessment of efficacy. 
Tumor assessments will be performed until radiographically- and/or clinically-documented (ie, 
for photographed or palpable lesions) disease progression as per RECIST v1.1, initiation of new 
anti-cancer therapy, or discontinuation from overall study participation (Section 7.4), whichever 
occurs first. 
Subjects who discontinue study treatment for reasons other than radiographically- and/or 
clinically- (ie, for photographed or palpable lesions) documented disease progression, per 
RECIST v1.1, will continue to have tumor assessments performed every 8 weeks (± 7 days) in 
the follow-up period, and bone scans or whole body MRI (as applicable) as clinically indicated 
and/or every 24 weeks (± 7 days) until RECIST-defined disease progression, initiation of the 
first new anti-cancer therapy, or discontinuation from overall study participation (eg, death, 
withdrawal of consent, lost to follow-up), whichever occurs first. 
Subjects no longer undergoing tumor evaluations will continue to be monitored every 8 weeks 
for survival data and the initiation of the first new anti-cancer therapy. 
The follow-up period will conclude at the time of the final OS analysis when approximately 
50% of subjects in the study have died. 
Efficacy analyses will be performed using tumor assessments made by the blinded IRC as the 
primary data source. Analyses of endpoints based on local Investigator assessment will also be 
performed as supportive analyses. 
4.5. 
Dose Adjustment, Interruption, or Discontinuation Criteria 
4.5.1. 
Criteria for Elacestrant 
Each subject will be assessed periodically for the development of any toxicity. Toxicity will be 
assessed according to the National Cancer Institute Common Terminology Criteria for AEs (NCI 
CTCAE) v5.0. Subjects should be monitored closely and receive supportive care and agents to 
treat AEs and manage cancer symptoms (pain medications, antiemetics, antidiarrheals, etc.) as 
per local institutional guidance. 
General guidelines regarding management and dose reduction for AEs considered by the 
Investigator to be related to elacestrant treatment are provided in Table 7. Dose reduction 
decisions should be based on the judgment of the Investigator. Once a dose has been reduced, it 
may not be re-escalated to the original dose. 


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Table 7: 
Dose Modification Guidelines for AEs Related to Elacestrant 
 
Action and Dose Modification 
Grade 1 
Continue elacestrant treatment at current dose level 
Grade 2 
 Consider interruption of elacestrant treatment if clinically indicated 
 When toxicity resolves to Grade 1 or baseline, restart elacestrant treatment at current dose 
level 
Grade 3 
 Interrupt elacestrant treatment if clinically indicated 
 When toxicity resolves to Grade 1 or baseline, restart elacestrant treatment reduced by 1 dose 
level 
 If the Grade 3 toxicity recurs, interrupt elacestrant treatment 
 When toxicity resolves to Grade 1 or baseline, restart elacestrant treatment reduced by another 
dose level 
Grade 4 
 Interrupt elacestrant treatment 
 When toxicity resolves to Grade 1 or baseline, restart elacestrant treatment reduced by 
1 dose level 
 If the Grade 4 toxicity recurs either: 
 Permanently discontinue elacestrant treatment or 
 If the subject is clinically benefitting, elacestrant treatment may be reinitiated only if 
reduced by another dose level and with agreement of the medical monitor and RADIUS 
Dose reductions of elacestrant due to AEs are allowed in this study; dose levels are provided in 
Table 8. A dose reduction below 200 mg elacestrant QD is not allowed and, if required in the 
opinion of the Investigator, the subject should be discontinued from treatment. 
Dose interruptions of elacestrant of ≤14 consecutive days are permitted at any point during 
treatment. A dose interruption of >14 consecutive days requires discussion with RADIUS prior 
to continuation on study. 
No dose escalations above the starting dose of 400 mg QD are permitted. 
Table 8: 
Elacestrant Dose Reduction Guidelines 
Dose Level 
Elacestrant Dose 
Starting dose 
400 mg QD 
-1 (1st dose reduction) 
300 mg QD (25% dose reduction)a 
-2 (2nd dose reduction) 
200 mg QD (50% dose reduction)b 
QD = once daily 
a Three 100 mg tablets 
b Two 100 mg tablets 
4.5.2. 
Criteria for Standard of Care  
Dose reductions for subjects receiving the SOC AI treatments are not allowed. 
Dose reductions for subjects receiving the SOC fulvestrant are permitted for subjects who 
develop moderate hepatic impairment (Child-Pugh class B; see Appendix 7) if deemed unrelated 
to study drug or disease progression, for whom the dose of fulvestrant should be reduced to 
250 mg. 


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Treatment interruptions and/or withdrawals due to AEs should be based on the Investigator’s 
clinical judgment. 
SOC dose interruptions of ≤ 14 consecutive days are permitted at any point during treatment. 
Dose interruptions of > 14 consecutive days requires discussion with RADIUS prior to 
continuation on study. 
Note: During SOC treatment the Investigator will follow any warnings or precautions for use as 
detailed in each PI or SmPC. 
4.5.3. 
Criteria for QTcF Prolongation 
Instructions on management of prolongations in the QTcF interval, regardless of study drug 
assignment, are provided in Table 9. 
Table 9: 
Mandatory Dose Interruptions and Dose Reductions for Prolonged QTcF 
QTcF or QT Prolongationa 
Action and Dose Modification 
 
QTcF is prolonged ≥ 500 msec 
or 
 
Uncorrected QT is > 600 msec 
or 
 
QTcF is > 530 msec for subjects with 
left bundle branch block 
 
Study treatment should be interrupted 
 
Appropriate clinical assessment and treatment should be 
conducted (eg, assess serum electrolytes and correct with 
supplements if below lower limit of normal, review concomitant 
medication) 
 
Cardiology consultation/management should be considered 
 
If QTcF resolves to Grade 1 or baseline and the Investigator 
believes that the subject would benefit from continued 
treatment, study drug may be restarted with agreement of the 
medical monitor and RADIUS either at a reduced dose level 
(elacestrant only) or the current dose level (SOC) 
 
If event does not resolve or recurs after restarting study drug, 
subject should permanently discontinue treatment and follow up 
with cardiology care as appropriate. 
QTcF = QT corrected by Fridericia's formula; SOC =standard of care 
a Based on average value of triplicate ECGs 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Subject Inclusion Criteria 
Subjects must meet all the following inclusion criteria: 
1. Must have a histologically- or cytologically-proven diagnosis of adenocarcinoma of the 
breast with evidence of either locally advanced disease not amenable to resection or 
radiation therapy with curative intent or metastatic disease not amenable to curative 
therapy  
2. Must be appropriate candidates for endocrine monotherapy 
3. Must have 1 of the following as defined by RECIST v1.1: 
a. Measurable disease  
b. Bone only disease with evaluable lesions. Subjects must have at least 1 lytic or 
mixed lytic/blastic bone lesion; blastic lesions only are not evaluable and allowed. 


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Subjects who have had prior radiation to bone must have at least 1 evaluable 
lesion in a nonirradiated area 
4. Female or male ≥ 18 years of age 
5. Female subjects must be post-menopausal women, defined by 1 of the following criteria: 
a. Documented bilateral surgical oophorectomy 
b. Age ≥ 60 years with amenorrhea ≥ 1 year since last menses 
c. Age < 60 years with amenorrhea ≥ 1 year since last menses with no alternative 
pathological or physiological cause (including ongoing or recent chemotherapy, 
treatment with tamoxifen or toremifene, or a GnRH agonist), and serum estradiol 
and follicle stimulating hormone (FSH) levels within the laboratory reference 
range for post-menopausal women  
d. Age < 60 years with tamoxifen or toremifene therapy within the last 12 months, 
with documentation of 12 months of amenorrhea prior to tamoxifen or toremifene 
therapy and serum estradiol and FSH levels within the laboratory reference range 
for post-menopausal women 
e. Females with hormonally-induced menopause (ie, requiring ongoing hormone 
suppression) are not eligible 
6. Male subjects must, even if surgically sterilized (ie, status post-vasectomy):  
a. Agree to practice highly effective barrier contraception (use condoms) during the 
entire study treatment period and through 120 days after the last dose of study drug. 
For subjects (who have not undergone vasectomy) with female partners of 
childbearing potential, the subject and his partner must, in addition to condoms, use 
highly effective contraceptive measures when engaging in sexual intercourse 
throughout the treatment period and for at least 120 days after the last dose of study 
drug (ie, oral contraceptive and condoms; intrauterine device and condoms; 
diaphragm with spermicide and condoms; other forms of contraception must be 
approved by the medical monitor)  
OR 
Agree to practice true abstinence during the entire study treatment period and through 
120 days after the last dose of study drug 
Note: Abstinence should only be used as a contraceptive method if it is in line with 
the subject’s usual and preferred lifestyle. Periodic abstinence (calendar 
symptothermal, post-ovulation methods) is not an acceptable method of 
contraception. 
b. Agree not to donate sperm during the course of treatment period of this study or 
within 120 days after receiving the last dose of the study drug 
7. Must have ER+ and HER2- tumor status confirmed per local laboratory testing. Status 
may be confirmed on original diagnosis tissue samples or post-treatment samples (most 
recent biopsy preferred, if testing available). ER and HER2 testing must be performed in 
the following manner: 


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a. Documentation of ER+ tumor with ≥ 1% staining by immunohistochemistry 
(IHC) as defined in the 2010 American Society for Clinical Oncology 
(ASCO) recommendations for ER testing (Hammond et al, 2010), with or 
without PGR positivity 
AND 
b. Documentation of HER2- tumor with an IHC result of 0 or 1+ for cellular 
membrane protein expression or an in situ hybridization negative result as 
defined in the 2013 or 2018 ASCO recommendations for HER2 testing 
(Wolff, 2013; Wolff, 2018) 
8. Must have previously received at least 1 and no more than 2 lines of endocrine therapy, 
either as monotherapy or as a combination therapy with another agent (eg, 
phosphoinositide 3-kinase [PI3K] inhibitor), for mBC 
a. Must have progressed during or within 28 days of completion of each line of 
endocrine therapy; ie, if a subject was discontinued due to toxicity without 
progression, this would not count as a line of prior therapy 
b. For subjects who progress during or within 12 months of adjuvant endocrine 
therapy, this will count as 1 line of endocrine therapy for mBC. In the absence of 
such progression, adjuvant therapy does not count as 1 of the required lines of 
endocrine therapy  
9. Must have progressed during or within 28 days of completion of prior treatment with a 
CDK4/6 inhibitor in combination with either fulvestrant or an AI (this counts as a line of 
prior endocrine therapy) for mBC 
a. Prior treatment with a CDK4/6 inhibitor not in combination with fulvestrant or an 
AI will not fulfill this criterion 
b. Discontinuation of prior CDK4/6 inhibitor due to toxicity, in the absence of 
progression, will not fulfill this criterion 
10. Must have received no more than 1 line of cytotoxic chemotherapy in the 
advanced/metastatic setting  
a. Cytotoxic chemotherapy does not include: CDK4/6 inhibitors, mTOR inhibitors, 
PI3K inhibitors, or immunotherapy. There are no restrictions on prior use of these 
agents 
b. There is no requirement for documentation of progressive disease to prior 
chemotherapy 
c. Chemotherapy given in combination with endocrine therapy counts as both a line 
of endocrine therapy and a line of chemotherapy 
d. Chemotherapy administered for less than 1 cycle will not be counted as a prior 
line of chemotherapy 
e. For subjects who progress within 12 months of neoadjuvant or adjuvant 
chemotherapy, this will count as 1 prior line of therapy for advanced/metastatic 
disease 
11. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 


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12. Resolution of all toxic effects of prior therapies or surgical procedures to Grade ≤ 1 
(except alopecia and peripheral neuropathy)  
13. Adequate organ function as defined below: 
a. Hematologic function (in the absence of transfusion of red blood cells or platelets 
or the use of growth factors within the preceding 4 weeks) 
 Absolute neutrophil count ≥ 1.0 x 109/L 
 Platelet count ≥ 75 x 109/L 
 Hemoglobin ≥ 9.0 g/dL  
b. Renal function 
 Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 or creatinine 
clearance calculated by Cockcroft-Gault equation ≥ 30 mL/min (Appendix 4) 
c. Hepatic function 
 Alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN) 
 Aspartate aminotransferase (AST) ≤ 3x ULN 
 Total bilirubin ≤ ULN or total bilirubin ≤ 1.5x ULN with direct bilirubin 
≤ ULN of the laboratory in subjects with documented Gilbert’s Syndrome 
d. Chemistry 
 Potassium, sodium, calcium (corrected for albumin), magnesium, and 
phosphorus NCI CTCAE v5.0 Grade ≤ 1. If Screening assessments are 
abnormal, chemistry assessments may be repeated up to 2 times; subjects may 
receive appropriate supplementation or treatment (eg, for hypercalcemia) prior 
to re-assessment 
e. Coagulation 
 International normalized ratio (INR) ≤ 1.5  
Note: Subjects who are receiving anticoagulation treatment which is monitored by 
INR (eg, warfarin) may be allowed to participate if they have a stable INR (ie, 
within therapeutic range) for at least 28 days prior to the first dose of study drug, 
in the absence of any exclusionary medical conditions, and provided that an AI 
would be appropriate therapy for the subject 
14. Ability to understand the protocol and provide informed consent 
5.2. 
Subject Exclusion Criteria 
Subjects must meet none of the following exclusion criteria: 
1. Prior treatment with elacestrant or investigational SERD or ER antagonist (eg, D-0502, 
GDC-0810, GDC-0927, GDC-9545, G1T-48, LSZ102, AZD9496, SAR439859, ZN-c5, 
H3B-6545, bazedoxifene, lasofoxifene) 


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2. Prior anti-cancer or investigational drug treatment within the following windows: 
a. Fulvestrant treatment (last injection) < 42 days before first dose of study drug 
b. Any other endocrine therapy < 14 days before first dose of study drug  
c. Chemotherapy or other anti-cancer therapy < 21 days before first dose of study drug 
d. Any investigational anti-cancer drug therapy < 28 days or 5 half-lives (whichever is 
shorter) before the first dose of study drug. Enrollment of subjects whose most recent 
therapy was an investigational agent should be discussed with RADIUS 
e. Bisphosphonates or RANKL inhibitors initiated or dose changed < 3 months prior to 
first dose of study drug 
3. Radiation therapy within 14 days (28 days for brain lesions per Exclusion Criterion 4) 
before the first dose of study drug 
4. Presence of symptomatic metastatic visceral disease, including but not limited to, 
extensive hepatic involvement, untreated or progressive central nervous system (CNS) 
metastases, or symptomatic pulmonary lymphangitic spread. Subjects with discrete 
pulmonary parenchymal metastases are eligible provided their respiratory function is not 
significantly compromised as a result of disease in the opinion of the Investigator. 
Subjects with previously treated CNS metastases are eligible provided that all known 
lesions were previously treated, they have completed radiotherapy at least 28 days prior 
to first dose of study drug and are clinically stable. If anticonvulsant medication is 
required, subjects must be stable on a non-enzyme inducing anticonvulsant regimen 
(Appendix 8) 
5. Intact uterus with a history of endometrial intraepithelial neoplasia (atypical endometrial 
hyperplasia or higher-grade lesion) 
6. Diagnosis of any other malignancy within 5 years before enrollment, except for 
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the 
cervix, or second primary breast cancer 
7. Any of the following within 6 months before enrollment: myocardial infarction, 
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v5.0 Grade ≥2, 
prolonged QTcF ≥ Grade 2 (ie, > 480 msec), uncontrolled atrial fibrillation of any grade, 
coronary/peripheral artery bypass graft, heart failure ≥ Class II as defined by the New 
York Heart Association guidelines (Appendix 6), or cerebrovascular accident including 
transient ischemic attack 
8. Child-Pugh Score greater than Class A (ie, score > 6; Appendix 7) 
9. Coagulopathy or any history of coagulopathy within the past 6 months, including history 
of deep vein thrombosis or pulmonary embolism. However, subjects with the following 
conditions will be allowed to participate: 
a. Adequately treated catheter-related venous thrombosis occurring > 28 days prior to 
the first dose of study drug 
b. Treatment with an anticoagulant, eg, warfarin or heparin, for a thrombotic event 
occurring > 6 months before enrollment, or for an otherwise stable and allowed 
medical condition (eg, well controlled atrial fibrillation), provided dose and 
coagulation parameters (as defined by local standard of care) are stable for at least 28 


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days prior to the first dose of study drug and provided that an AI would be an 
appropriate therapy for the subject 
10. Known bleeding disorder which, in the opinion of the Investigator, would prohibit 
administration of fulvestrant if that would be SOC choice for the subject 
11. Known difficulty in tolerating oral medications or conditions which would impair 
absorption of oral medications such as: uncontrolled nausea or vomiting (ie, CTCAE 
≥ Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility 
disorder, malabsorption syndrome, or prior gastric bypass 
12. Unable or unwilling to avoid prescription medications, over-the-counter medications, 
dietary/herbal supplements (eg, St. John’s wort), and/or foods (eg, grapefruit, pomelos, 
star fruit, Seville oranges and their juices) that are moderate/strong inhibitors or inducers 
of CYP3A4 activity (Appendix 8). Participation will be allowed if the medication, 
supplements, and/or foods are discontinued for at least 5 half-lives or 14 days (whichever 
is longer) prior to study entry and for the duration of the study 
13. Major surgery < 28 days before the first dose of study drug 
14. Any concurrent severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with compliance with study 
procedures or the interpretation of study results and, in the judgment of the Investigator, 
would make the subject inappropriate for entry into this study 
15. Known hypersensitivity reaction to drugs chemically related to elacestrant or their 
excipients 
16. Known hypersensitivity to fulvestrant, anastrozole, letrozole, or exemestane (or to any of 
their excipients), unless treatment with 1 of the other 3 of these 4 treatment options would 
be appropriate therapy 
17. Subjects who meet any contraindication, according to the respective PI or SmPC, for any 
SOC drug that the Investigator would choose for that subject should the subject be 
randomized to the SOC group 
5.3. 
Subject Withdrawal Criteria 
5.3.1. 
Subject Withdrawal from Active Treatment Phase 
Discontinuation of treatment or subject withdrawal is not the same as interruption of treatment. 
An interruption in treatment occurs when a subject stops taking the study drug for a period of 
time, with the intention of subsequently resuming study medication. All treatment interruptions 
should be noted and the dates and reasons for treatment interruptions should be documented. 
Note: a maximum interruption of 14 consecutive days is permitted. Dose interruptions of 
> 14 consecutive days require discussion with RADIUS prior to continuation on study. 
Treatment discontinuation refers to the permanent discontinuation of study treatment. When 
treatment is discontinued, the subject is no longer in the active treatment phase of the study; 
however, the subject continues on study with appropriate follow-up as outlined in the Schedule 
of Events (Appendix 2). 


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Reasons for treatment discontinuation include: 
 Disease progression (per RECIST v1.1 or symptomatic deterioration that in the 
opinion of the Investigator represents disease progression) 
 A clinically significant AE, laboratory abnormality, or other medical condition or 
situation that in the opinion of the Investigator precludes further study treatment 
 Significant study noncompliance (with discussion with the medical monitor and 
RADIUS) 
 Subject unable to receive study treatment for > 14 consecutive days (at the discretion 
of RADIUS) 
 Investigator believes that treatment discontinuation is in the best interest of the 
subject 
 Subject refusal of further investigational treatment 
Based on median duration of treatment of 3.8 months in Study RAD1901-005 for all subjects 
treated with 400 mg elacestrant, subjects randomized to treatment with elacestrant are expected 
to remain on treatment for approximately 4 months. Subjects exhibiting a response would be 
expected to have longer treatment duration. 
5.3.2. 
Subject Withdrawal from the Study 
Subjects are free to withdraw from participation in the study for any reason at any time. The 
reason for terminating study participation will be recorded in each subject’s medical records 
(source documents) and entered into the End of Study electronic Case Report Form (eCRF).  
If a subject withdraws from the study, every effort should be made to complete the end of 
treatment (EOT) assessments; however, if a subject withdraws consent, no further assessments 
should be performed and no additional data should be collected. RADIUS may retain and 
continue to use any data collected before consent was withdrawn. 
Reasons for a subject to be withdrawn from the study include: 
 Subject or proxy withdraws consent 
 In the opinion of the Investigator it is not in the best interests of the subject to 
continue on study 
 Inability of the subject to comply with the protocol 
 Lost to follow-up 
 RADIUS decision to terminate study 
 Death 


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6. 
STUDY TERMINATION 
The study may be terminated by the sponsor for any of the following reasons: 
 Serious safety concern 
 Reduced efficacy for elacestrant compared to SOC drugs 
 Recommendation of the IDMC 
 Administrative decision (eg, termination of product development) 
7. 
STUDY PROCEDURES 
The Schedule of Events is provided in Appendix 2. 
7.1. 
Demographic, Medical History, Prior and Concomitant Medication 
Each subject’s demographic and medical history and all prior anti-cancer treatments, including 
all surgical procedures related to the cancer diagnosis will be collected. 
All prior and concomitant medications (including over-the-counter medicines, herbal treatments, 
supplements, vitamins, and substance use) and treatments taken from 35 days prior to signing 
consent until 30 days after the last dose of study drug will be recorded. 
7.2. 
Physical Examination and Vital Signs 
A full physical examination, including a total body examination of all major body systems (eg, 
general appearance, skin, neck [including thyroid], ears, eyes, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, and extremities and a clinical neurological examination), height, 
weight, respiratory rate, sitting blood pressure, and sitting pulse rate must be performed by a 
physician, registered nurse, or other qualified health care provider at Screening. Post-Screening 
physical examinations should be performed per the Schedule of Events and may be targeted 
based on findings present at Screening or subject complaints (see Appendix 2). Vital sign 
measurements should also be performed according to the Schedule of Events. 
Clinically-significant findings at Screening should be recorded either as medical history or as an 
AE as appropriate. Clinically-significant new findings at post-Screening visits should be 
recorded as AEs. 
7.3. 
Electrocardiograms and Prolonged QTcF Guidelines 
ECG machines to be utilized in this study will be supplied by a third-party vendor. All ECG 
tracings will be sent electronically to a central ECG laboratory; this laboratory will provide all 
ECG results to the study site. 
Twelve-lead ECGs will be performed according to the schedule in the Pharmacokinetic and ECG 
Schedule of Events (Table 19 of Appendix 2). Each ECG, both at Screening and during the 
study, is to be performed in triplicate approximately 2 minutes apart after the subject has been 
supine for at least 5 minutes. Mean QTcF interval will be calculated by the central ECG 
laboratory using the average of the triplicate ECG measurements. The pre-treatment on Day 1 


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average value will serve as each subject’s baseline QTcF value to which all subsequent ECGs 
will be compared. Information and instructions for performing the ECGs are provided in the 
Investigator Site Manual. 
Instructions on management of prolongations in the QTcF interval are outlined in Section 4.5.3. 
7.4. 
Tumor Assessments 
7.4.1. 
Overview 
 Tumor assessments will be performed following the RECIST v1.1 criteria 
(Appendix 1) 
 Tumor assessments will be performed at Screening and every 8 weeks, (± 7 days) 
from the date of randomization during the active treatment phase of the study (and in 
the follow-up period for subjects who have discontinued study drug for reasons other 
than PD [clinical PD or PD confirmed by RECIST] and have not yet started new anti-
cancer therapy) 
 For Screening assessments, radiographic assessments obtained per the subject’s 
SOC prior to signing consent for the study do not need to be repeated and are 
acceptable to use as Screening evaluations, if (1) they were obtained within 
28 days before randomization (with the exception of radionuclide bone scans/ 
whole body MRI scans which must be within 12 weeks of randomization and 
brain computed tomography (CT) or MRI scans which must be within 6 weeks of 
randomization); (2) they were performed using the method requirements outlined 
in RECIST v1.1 and they meet all imaging requirements as outlined herein and 
the Bioclinica Site Manual; (3) the same technique/modality can be used to follow 
identified lesions throughout the trial for a given subject; and (4) appropriate 
documentation indicating that these radiographic tumor assessments were 
performed as SOC is available in the subject’s source notes  
 All assessments performed during the active treatment phase of the study will be 
performed as scheduled at the required intervals according to the Schedule of 
Events, regardless of any dosing delay, to prevent the introduction of bias into the 
assessment of efficacy (Table 18 in Appendix 2) 
 All tumor assessments, including those performed during Screening to assess 
eligibility and baseline tumor measurements, will be collected and sent to a core 
imaging vendor for blinded IRC analysis. Instructions on collection and 
transmission/shipping will be provided in the Bioclinica Site Manual 
7.4.2. 
CT or MRI Tumor Assessment 
 CT of the chest and CT or MRI of the abdomen and pelvis, and other sites as 
clinically indicated will be performed at Screening and every 8 weeks (± 7 days) from 
the date of randomization during the active treatment phase of the study 
 Diagnostic CT for tumor assessment may be used even if acquired during PET/CT 
hybrid imaging providing the CT images are of sufficient quality 


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 A contrast agent should be used, except when contraindicated for medical reasons. 
(See RECIST v1.1 and the Bioclinica Site Manual for recommended/required 
imaging modalities for each required scan) 
 For subjects who achieve a CR or PR, a confirmation scan must be repeated at least 
4 weeks after the first documented response 
 All lesions followed for tumor response should continue to be assessed using the 
same modality (CT scan, PET CT, bone window settings on CT scan, or MRI) 
 Enrolled subjects with history of stable brain metastases should have brain CT or 
MRI imaging in parallel with systemic imaging for evaluation of non-target lesions in 
the brain; brain CT or MRI scans are not otherwise required as part of standard 
imaging unless new metastases are suspected 
7.4.3. 
Radionuclide Bone Scan or Whole Body MRI Tumor Assessment of Bone 
Lesions and Follow-up Assessments of Bone Lesions 
 A radionuclide bone scan or whole body MRI should be performed at Screening in all 
subjects. Positive areas on bone scans must be assessed by CT scan with bone 
windows (PET hybrid with bone window settings on CT scan is acceptable providing 
the CT images are of sufficient quality) or MRI prior to the first dose of study 
medication and continue to be assessed throughout the study using the same modality. 
Screening CT of chest and CT or MRI of abdomen and pelvis acquired for tumor 
assessment are sufficient for evaluation of bone lesions involving the axial skeleton. 
Additional imaging of appendicular skeletal lesions (eg, skull, cervical spine, 
extremities) by bone window settings on CT scan or MRI is required if these sites are 
the only bone lesions to be followed. 
 If subjects present with both irradiated and nonirradiated bone lesions, all lesions 
should be followed for tumor assessments, but only non-irradiated lesions should be 
followed as target lesions per RECIST v1.1 (f they meet criteria for a bone target 
lesion); previously irradiated lesions should be followed as non-target lesions. 
Subjects with bone only disease must have at least 1 non-irradiated lesion to be 
eligible. 
 If bone lesions were identified by radionuclide bone scan or whole body MRI at 
baseline, bone scans or whole body MRI (using the same modality as used during 
Screening) will be repeated during the active treatment phase as clinically indicated 
and every 24 weeks (±7 days) from the date of randomization and at the time of 
confirmation of a CR. If no bone lesions were identified at baseline, bone scans  or 
whole body MRI will only be repeated during the active treatment phase when 
clinically indicated (ie, subject describes new or worsening bone pain, has an 
increasing alkaline phosphatase level, or other signs and symptoms of 
new/progressing bone metastases), but are required at the time of confirmation of a 
CR. Bone lesions confirmed by CT or MRI (or PET CT when CT images are of 
sufficient quality) at baseline, and documented as target (when a measurable soft 
tissue component is present) and/or non-target lesions will be assessed every 8 weeks 
(± 7 days) using the required CT of chest and CT or MRI of abdomen and pelvis (or 


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PET CT when PET CT was used at baseline) and additional imaging by bone window 
settings on CT scan or MRI of any appendicular bone lesions that are being followed 
as a target and/or non-target lesions. New abnormalities found on subsequent bone 
scans or whole body MRI must also be confirmed by bone window settings on CT 
scan or MRI (Table 20 in Appendix 2) 
7.4.4. 
Clinical Lesions 
 Any skin lesions that are to be followed as either target or nontarget lesions must 
have color photographs taken at Screening and every 8 weeks (± 7 days) from the 
date of randomization during the active treatment phase of the study. Photographs 
should include measurement markers, such as a ruler 
 Palpable lesions that are to be followed as either target or nontarget lesions must be 
assessed and measured at Screening and every 8 weeks (± 7 days) from the date of 
randomization during the active treatment phase of the study 
7.5. 
Laboratory Assessments 
During the treatment period, laboratory tests in addition to those mandated per protocol (shown 
in the Schedule of Events in Appendix 2) may be obtained at the Investigator’s discretion if 
clinically indicated.  
7.5.1. 
Estradiol and Follicle Stimulating Hormone 
Estradiol and FSH levels will be tested at Screening in female subjects only. These tests do not 
need to be performed in subjects who have undergone bilateral surgical oophorectomy. 
7.5.2. 
Urinalysis 
Urinalysis will be performed at Screening. Urinalysis includes protein, glucose, blood, ketones, 
nitrites, and leukocyte esterase. Microscopic examination is required only when urinalysis is 
positive for nitrites, leukocyte esterase, protein, or blood. Urinalysis after Screening may be 
performed if indicated, based on the clinical judgment of the Investigator. 
7.5.3. 
Chemistry 
Chemistry assessments will be performed as shown in the Schedule of Events (Appendix 2). 
Chemistry includes blood urea nitrogen (BUN) or urea, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, phosphorous, magnesium, albumin, total protein, total bilirubin (direct and 
indirect if total is > ULN), alkaline phosphatase, ALT, AST, and a glucose and lipid panel (total 
cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides). If possible, the 
glucose and lipid profile should be performed with the subject in a fasting state. 
7.5.4. 
Special Chemistry 
Hemoglobin A1c is to be measured at Screening and EOT. 


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7.5.5. 
Coagulation 
Coagulation profile, including prothrombin time (PT), or INR (per the site’s standards for 
follow-up assessments; INR is required at Screening), activated partial thromboplastin time 
(aPTT; PTT is allowed if aPTT is not available), and fibrinogen will be performed as outlined in 
the Schedule of Events (Appendix 2). 
7.5.6. 
Hematology 
Hematology assessments will be performed as shown in the Schedule of Events (Appendix 2). 
Hematology includes hemoglobin, hematocrit, white blood cell with differential (including 
absolute neutrophil count and lymphocyte, monocyte, eosinophil, and basophil counts), and 
platelet count. 
7.6. 
Tumor Biomarkers 
7.6.1. 
Tumor Biopsy 
Analysis of pharmacodynamic biomarkers predictive of elacestrant response is an important 
exploratory objective of this study. 
All subjects with accessible lesions are requested to provide tumor biopsies; however, these 
biopsies are optional and are not required for eligibility. For subjects agreeing to provide 
biopsies, biopsies will be taken at 3 time points during the study: pre-treatment, on-treatment, 
and post-treatment. On-treatment and post-treatment biopsies are only required if the pre-
treatment biopsy was successful (ie, tissue obtained; confirmed to contain adequate tumor cells 
by central laboratory). 
Pre-treatment biopsies should be obtained after progression on the most recent systemic 
anticancer therapy and should be performed on a metastatic lesion or site of recurrent disease, if 
accessible. Biopsies obtained for other reasons within 3 months of first dose of study treatment 
that meet these criteria may be submitted in lieu of a fresh biopsy. On-treatment biopsy should 
be performed between C1D28 and C3D28, as close as feasible to C2D28. Post-treatment biopsy 
should be performed at the time of study drug discontinuation and prior to initiation of new 
anti-cancer therapy. Biopsies should be taken from the same lesion at each time point, when 
feasible. 
All biopsies will be used for retrospective pharmacodynamic analysis of ER and other oncogenic 
pathway markers (eg, PGR, PIK3CA) and proliferation markers (eg, Ki67, pRb). Results from 
biopsy samples will be analyzed and correlated with clinical response to support the 
identification of biomarkers that may be predictive of a subject’s response to treatment. 
Details of sample collection, processing, shipping, and storage are described in the Medpace 
Laboratory Manual. 
7.6.2. 
Circulating Tumor DNA 
Blood samples for ctDNA analysis will be collected and submitted to Guardant Health at 
Screening (see Guardant Laboratory Manual). These samples will be analyzed using the 
Guardant360 (Guardant Health, Redwood City, CA) assay to determine ESR1 mutational status. 


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The Guardant360 assay uses digital sequencing technology to detect all missense nucleotide 
variants within the ligand binding domain (LBD) of the ESR1 gene. Detection of any ESR1 
mutation(s), as defined by Guardant Health for the assay, will be reported as ESR1 mutation 
present (ie, ESR1-mut). No mutation may be detected if there is no mutation present in the ESR1 
gene (ie, wild-type) or if there is no detectable ctDNA present in the blood sample; these will be 
reported and analyzed together as ESR1 mutation not detected (ESR1-mut-nd). 
ESR1 test results will be used for stratification at randomization; however, the site will not be 
provided with a subject’s mutational status during the subject’s active treatment phase, unless 
otherwise required by regulation. Results will be provided back to sites semi-blinded to ESR1 
mutational status (ie, coded as Group A or Group B) for randomization. ESR1 mutational status 
may be requested by the study site to help guide treatment decisions at the time of 
discontinuation of study treatment; study sites may also request results for subjects who fail 
screening. 
Additional ctDNA samples will be collected and submitted to the central laboratory as indicated 
in the Schedule of Assessments (Appendix 2) (see Medpace Laboratory Manual). 
Other tumor alterations relevant to ER+ breast cancer, such as PIK3CA, CDK4/6, and RB1, may 
also be assessed using this same assay run on the same blood sample. 
Details on sample collection, processing, and shipping are provided in the Medpace Laboratory 
Manual. 
7.6.3. 
Residual Samples for Exploratory Biomarker Analysis 
Any residual biological samples collected during the conduct of the study will be stored in a 
central location for potential exploratory biomarker research to be conducted either during or 
after the study. Samples may be stored at a central laboratory facility for up to 15 years after 
completion of the final study report or for a length of time dictated by local laws and regulatory 
requirements, whichever is shorter. 
Note:  The exploratory biomarker research component of the study may include analysis of 
pre-treatment and post-treatment samples for additional exploratory biomarkers to assess 
potential correlations between known signal transduction pathway markers, or other associated 
biological activities and antitumor response. The results of this exploratory biomarker research 
will be reported separately and will not form part of the Clinical Study Report. 
Further, the results of this exploratory biomarker research may be pooled with biomarker data 
from other studies with elacestrant to generate hypotheses to be tested in future studies. 
7.6.4. 
Disposal of Samples 
Biological samples will be destroyed no later than after the maximum storage duration of 
15 years or according to local legal and regulatory requirements, whichever is shorter. 
Subjects who withdraw consent following collection of biological study samples may request the 
destruction of their biological study samples and any materials derived from the collected 
samples which have not yet been processed. 


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7.7. 
Patient Performance Status and Patient Reported Outcomes 
7.7.1. 
ECOG Performance Status 
ECOG performance status (Appendix 3) will be assessed per the Schedule of Events 
(Appendix 2). 
7.7.2. 
Patient Reported Outcomes 
Three PROs, EQ-5D-5L, EORTC QLQ-C30 and PRO-CTCAE, with relevance to the mBC 
population, will be used during this study to assess the subject’s self-report of his/her well-being 
and quality of life.  
 The EQ-5D-5L is a simple descriptive profile developed by the EuroQol Group (an 
international network of multidisciplinary researchers) with broad applicability for 
use in clinical trials. The EQ-5D-5L measures a subject’s self-assessment of mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression  
 The EORTC QLQ-C30 was developed by the European Organization for Research 
and Treatment of Cancer (EORTC). This is a questionnaire developed to measure the 
self-reported quality of life of cancer subjects. The instrument was designed to 
measure several dimensions of HRQOL, including disease and treatment-related 
symptoms, physical, psychological and social functioning 
 The PRO-CTCAE was developed by the National Cancer Institute/National Institute 
of Health to measure subject reporting of symptomatic toxicity while participating in 
cancer clinical trials. It characterizes the frequency, severity and interference of 
symptomatic treatment toxicities, such as pain, fatigue, nausea, and cutaneous side 
effects, reported from the subject’s perspective. It was designed as a correlate to the 
NCI CTCAE standard for reporting of AEs 
The PRO questionnaires EQ-5D-5L, EORTC QLQ-C30 and PRO-CTCAE are to be completed 
by the subject using the provided electronic tablets containing the PRO questionnaires at the 
study site as per the Schedule of Events (Appendix 2). These assessments are to be performed at 
the start of the visit, prior to other assessments, and prior to any significant interactions between 
the subject and study staff. 
Note: If a certified translation for any PRO questionnaire is not available for a subject, that 
specific PRO assessment can be omitted, but the reason must be documented. 
7.8. 
Pharmacokinetic Samples 
Pharmacokinetic samples are to be collected as per the Schedule of Events (Table 18 in 
Appendix 2). Additionally, Investigators may obtain blood samples for elacestrant plasma 
concentrations at the time(s) significant AEs and SAEs occur that are considered potentially 
related to the study drug. Refer to the Medpace Laboratory Manual for detailed instructions on 
the collection, handling, and shipment of PK samples. 
PK sampling and measurement will not be performed for the SOC treatment group. 


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7.9. 
Adverse and Serious Adverse Events 
7.9.1. 
Definition of Adverse Events 
7.9.1.1. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject during the study; the event 
does not necessarily have a causal relationship with study drug treatment. This includes any 
newly occurring event or previous condition that has increased in severity or frequency after the 
informed consent form (ICF) is signed. 
Study assessments including laboratory tests, ECGs, physical examinations, and vital signs 
should be performed and those deemed a clinically significant worsening from baseline will be 
documented as an AE. When possible, a clinical diagnosis for the study assessment should be 
provided rather than the abnormal test result alone (eg, urinary tract infection, anemia). In the 
absence of a diagnosis, the abnormal study assessment itself should be listed as the AE (eg, lung 
nodule on CT scan). 
Investigators will be requested to evaluate abnormal study assessments for clinical significance. 
A clinically-significant finding could include: 
 Worsening from baseline (eg, by at least 1 grade) 
 Concomitant signs or symptoms related to the abnormal study assessment 
 Further diagnostic testing or medical/surgical intervention is required 
 A change in the dose of study drug, if study drug is withheld, or discontinuation from 
study drug 
Determination of clinical significance must be made by the Investigator. 
Events that do not meet the definition of an AE or SAE (see Section 7.9.1.2) include: 
 Planned hospital admissions or surgical procedures for a condition that existed before 
the subject signed the informed consent are not to be considered AEs unless the 
condition deteriorates in an unexpected manner during the study (eg, surgery had to 
be performed earlier than planned) 
 Anticipated day-to-day fluctuations of pre-existing disease(s), condition(s), and signs 
or symptoms present or detected prior to the start of the study that are not more severe 
than expected for the subject’s condition 
 Disease progression, hospitalization, or death due to disease progression 
7.9.1.2. 
Serious Adverse Event 
An AE is considered serious if, in the view of either the Investigator or RADIUS, it meets any of 
the following criteria: 
 Death 
 Death due to disease progression is not considered an SAE and should not be 
reported as such. 


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 Life-threatening 
 An AE is considered life-threatening if, in the view of either the Investigator or 
RADIUS, its occurrence places the subject at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused 
death 
 Inpatient hospitalization or prolongation of existing hospitalization  
Note: Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
 Congenital anomaly/birth defect 
 Important medical events that may not result in death, are not life-threatening, and do 
not require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
7.9.2. 
Relationship to Study Drug 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is 
considered to be related to study drug, indicating on the eCRF that an AE is either related or 
unrelated. The following guidance should be taken into consideration when determining the 
relationship of an AE to study drug (either elacestrant or SOC): 
 Temporal relationship of event onset to initiation of study drug 
 Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
 Known association of the event with study drug or with similar treatments 
 Known association of the event with the disease under study 
 Presence of risk factors in the subject or environment, or use of concomitant 
medications known to be associated with the event 
 Presence of treatment-unrelated factors that are known to be associated with the 
occurrence of the event 
 Whether there is a reasonable alternative explanation for the event 


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7.9.3. 
Study Drug Action Taken 
The Investigator will determine the study drug action (either elacestrant or SOC) taken with 
regard to the AE. The action taken should be classified according to the categories shown in 
Table 10. 
Table 10: 
Classification for Study Drug Action Taken with Regard to an Adverse 
Event 
Classification 
Definition 
Dose Not Changed 
Study drug dose or frequency not changed in response to an AE 
Dose Reduced1 
Study drug dose reduced in response to an AE  
Drug Interrupted 
Study drug administration interrupted in response to an AE 
Drug Withdrawn 
Study drug administration permanently discontinued in response to an AE 
Not Applicable 
Action taken regarding study drug administration does not apply. 
“Not applicable” should be used in circumstances such as when the 
investigational treatment had ended before the AE began and no 
opportunity to decide whether to continue, interrupt, or withdraw 
treatment is possible. 
AE = adverse event 
1Dose reduction is not allowed for aromatase inhibitors.  
7.10. 
Adverse Event Outcome 
An AE should be followed until the Investigator has determined and provided the final outcome. 
The outcome should be classified according to the categories shown in Table 11. 
Table 11: 
Classifications for Outcome of an Adverse Event 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved with 
Sequelae 
Resolution of an AE with residual signs or symptoms 
Recovering/Resolving 
(Ongoing) 
Improvement of an AE but not yet resolved 
Not Recovered/Not 
Resolved (Ongoing) 
No improvement of an AE, such that it remains ongoing 
Fatal 
Outcome of an AE is death. “Fatal” should be used when death is at least 
possibly related to the AE 
Unknown 
Outcome of an AE is not known (eg, a subject lost to follow-up) 
AE = adverse event  
7.10.1. 
Treatment Given 
The Investigator will ensure adequate medical care is provided to subjects for AEs. In addition, 
the Investigator will describe whether any treatment was given for the AE. “Yes” is used if any 
treatment was given in response to an AE and may include treatments such as other medications, 
hospitalization, radiation therapy, surgery, or physical therapy. “No” indicates the absence of any 
kind of treatment for an AE. 


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7.10.2. 
Follow-up of Adverse Events 
All subjects will be followed for AEs until 30 days post-treatment or until resolution or 
stabilization of all treatment-related AEs to either ≤ Grade 2 or baseline, whichever is longer, or 
until the subject is lost to follow-up. 
At any time after 30 days from the last dose of study treatment, the Investigator may report any 
SAE that he/she believes is related to study treatment. 
7.10.3. 
Overdose and Medication Error 
Occurrences of events of overdose and medication error must be reported to RADIUS.  
Any AEs/SAEs associated with either an overdose or medication error should be reported as AEs 
or SAEs as appropriate (Section 7.12). 
An overdose is defined as administration of a quantity of a medicinal product greater than the 
dose or more frequently than defined in the protocol for the investigational product. 
A medication error is defined as an error made in prescribing, dispensing, administration, and/or 
use of study drug. The administration and/or use of expired study drug should be considered as a 
reportable medication error to RADIUS. Cases of subjects missing doses of the study drug are 
not considered reportable as medication errors to RADIUS. 
7.10.3.1. Elacestrant 
In the event of an elacestrant overdose, the Investigator should contact the Medical Monitor 
immediately and closely monitor the subject for AEs/SAEs and laboratory abnormalities. No 
specific treatment is recommended; the Investigator will use clinical judgment to treat any 
overdose. Decisions regarding dose modifications or interruptions should be made by the 
Investigator in consultation with the Medical Monitor based on the clinical evaluation of the 
subject. A plasma sample for PK analysis may be requested by the Medical Monitor on a case-
by-case basis. This plasma sample should be collected as soon as possible. Information regarding 
the quantity of the excess dose as well as the duration of the overdosing should be documented in 
the eCRF. 
7.10.3.2. Standard of Care 
In the event of a fulvestrant or AI overdose, the Investigator should contact the Medical Monitor 
immediately and closely monitor the subject for AEs/SAEs and laboratory abnormalities. The PI 
or SmPC should be consulted; during SOC treatment the Investigator will follow any warnings 
or precautions for use as detailed in the PI or SmPC. Information regarding the quantity of the 
excess dose as well as the duration of the overdosing should be documented in the eCRF. 
7.11. 
Recording Adverse Events 
All AEs will be collected from the time the ICF is signed until the following time points: 
 For subjects who are not enrolled: until time of screen failure 
 For enrolled subjects: through 30 days after the last dose of study treatment 


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 For subjects who remain on study after the EOT safety follow-up visit, no AE 
reporting is required post safety follow-up; however, the Investigator may report any 
SAE that he/she believes is related to study treatment 
 At any time after 30 days from the last dose of study treatment, the Investigator may 
report any SAE that he/she believes is related to study treatment (AEs other than 
treatment-related SAEs should not be reported during this time) 
All AEs will be entered into the eCRF whether or not the event is believed to be associated with 
use of the study drug. Signs or symptoms reported as AEs will be graded and recorded by the 
Investigator according to the NCI CTCAE v5.0. 
When specific AEs are not listed in the NCI CTCAE v5.0, they will be graded by the 
Investigator according to grades and definitions listed in Table 12. 
Table 12: 
Grading of Adverse Events 
Grade 
Description 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (eg, packing, cautery) indicated; 
limiting age-appropriate instrumental activities of daily living 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
AE = adverse event 
All subjects will be queried using nonleading questions about the occurrence of AEs at each 
study visit. When possible, a constellation of signs and/or symptoms should be identified as one 
overall event or diagnosis. All AEs for enrolled subjects will be recorded in the eCRF and the 
subject’s source documents. AEs for subjects who are screened, but not subsequently enrolled in 
the study will be recorded only in the subject’s source documents unless an AE is related to a 
study-mandated procedure (eg, hemorrhage post tumor biopsy; anaphylaxis to CT contrast dye), 
in which case the AE should be reported as a pre-treatment AE. The following data should be 
documented for each AE: 
 Description of the event term as diagnosis, if possible 
 Classification of “serious” or “not serious” 
 Start date and date of resolution (if applicable) 
 Severity (using NCI CTCAE v5.0 criteria when applicable) 
 Causal relationship to study drug (see Section 7.9.2) 
 Action taken with study drug (Table 10) 
 Outcome (Table 11) 
 Concomitant medication or other treatment given 


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7.12. 
Reporting Adverse Events 
SAEs (initial reports and follow-up information) must be reported by the Investigator using the 
SAE reporting form; the form must be completed and emailed to PV@radiuspharm.com within 
24 hours after learning of the event. Prompt notification of SAEs by the Investigator is essential 
so that legal obligations and ethical responsibilities towards the safety of subjects are met. 
RADIUS will comply with country-specific regulatory requirements related to safety reporting to 
regulatory authorities, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) and Investigators. 
Safety reports will be prepared for Suspected Unexpected Serious Adverse Reactions according 
to local regulatory requirements and RADIUS policy and will be forwarded to Investigators as 
necessary. 
An Investigator who receives a safety report describing an SAE or other specific safety 
information from RADIUS will file it in the Trial Master File and will notify the IRB/IEC, if 
appropriate, according to local requirements. 
7.13. 
Partner Pregnancy 
Any pregnancy for the female partner of a male study participant must be reported within 
24 hours to the RADIUS Pharmacovigilance Department using the Pregnancy Report Form. 
Every effort should be made to gather information regarding the pregnancy course and outcome. 
It is the responsibility of the Investigator to obtain this information within 30 calendar days after 
the initial notification and approximately 30 calendar days post-partum. 
8. 
SCHEDULE OF PROCEDURES AND OBSERVATIONS 
Study-specific assessments are outlined in the Schedule of Events (Appendix 2). All on-study 
visits procedures are allowed a window of ± 2 days unless otherwise noted. 
8.1. 
Screening and Randomization 
Written informed consent for participation in the study must be obtained before performing any 
study-specific Screening tests or evaluations. ICFs for enrolled subjects and for subjects who are 
not subsequently enrolled will be maintained at the study site.  
Screening tests and evaluations will be performed within 35 days prior to C1D1. All imaging 
must be completed within 28 days prior to C1D1. All Screening evaluations must be completed 
and reviewed by the Medical Monitor to confirm that patients meet all eligibility criteria before 
randomization. If hematology, chemistry, coagulation assessments are performed > 7 days prior 
to C1D1, they must be repeated and eligibility criteria must still be met. Randomization may 
occur on Day -1 or on Day 1. Note: there is no Day 0 in this study. The planned first dose of 
C1D1 is to start within 1 day after randomization. 
See Appendix 2 for the schedule of Screening assessments. 


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8.2. 
Assessments during Treatment 
All assessments must be performed on the day of the specified visit (± 2 days). Assessments 
scheduled on the day of study drug administration should be performed prior to administration of 
study drug, unless otherwise noted in the schedule of assessments (see Appendix 2). PRO 
assessments should be performed prior to the completion of other study assessments. 
8.3. 
Assessments at End of Treatment 
Subjects who complete the study or discontinue from the study early will return to the site 
14 days after the last dose of study drug. If the EOT visit falls on Day 1 of a cycle and the 
subject is withdrawing, the EOT assessments are to be completed instead of Day 1 assessments. 
Unless otherwise specified, assessments that have been completed within the previous 14 days of 
the EOT visit do not need to be repeated at the EOT visit. 
See Appendix 2 for the schedule of EOT assessments. 
8.4. 
Post-Treatment Safety Follow-Up 
The Safety Follow-Up assessments are to be completed at 30 days (± 3 days) after the last dose 
of study drug (see Appendix 2). An onsite visit is preferred; however, if this is not feasible, 
telephone contact is acceptable. PRO assessments should be performed prior to the completion of 
other safety follow-up assessments. If follow-up assessments are conducted by telephone, the 
PRO assessments are to be omitted. 
8.5. 
Post-Treatment Follow-Up 
Post-treatment Follow-Up is to occur every 8 weeks (± 7 days) (see Appendix 2). 
For subjects who discontinue study treatment because of objective disease progression or clinical 
progression in the absence of progression by RECIST, survival data will be collected every 8 
weeks (± 7 days), calculated from the last dose of study treatment, for the duration of the study. 
The start date and regimen name of the first new anti-cancer therapy will also be collected. 
Telephone contact is acceptable. 
Note: Subjects who discontinue treatment for reasons other than disease progression and who do 
not begin a new anti-cancer therapy will continue to have tumor assessments every 8 weeks 
(± 7 days) from the date of randomization, and bone scans or whole body MRI every 24 weeks 
(± 7 days) as indicated, until disease progression is documented, or new anti-cancer therapy is 
initiated, at which time they will continue to be monitored every 8 weeks (± 7 days) for first new 
anti-cancer therapy and survival for the duration of the study. 
At any time after 30 days from the last dose of study treatment, the Investigator may report any 
SAE that he/she believes is related to study treatment. 
8.6. 
Study Completion 
The study will be complete when approximately 50% of subjects have died. However, subjects 
will be provided with study treatment, if still on active treatment, until all subjects discontinue 


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study participation or elacestrant is approved for marketing in a subject’s country, at which time 
the study may be closed for subject participation. 
9. 
TREATMENT OF SUBJECTS 
9.1.1. 
Description of Study Drugs 
9.1.1.1. 
Elacestrant (Investigational Product) 
Information about the investigational product in this study, elacestrant, is provided in Table 13. 
Table 13: 
Investigational Product 
 
Investigational Product 
Product Name 
Elacestrant 
Dosage Form 
Tablet 
Unit Dose 
100 mg or 400 mg of elacestrant·2HCl per tablet 
Route of Administration 
Oral 
Physical Description 
White, immediate release Opadry II film-coated tablet, containing 
100 mg or 400 mg of elacestrant·2HCl drug substance per tablet 
and microcrystalline cellulose, croscarmellose sodium, 
crospovidone, sodium starch glycolate, colloidal silicon dioxide, 
magnesium stearate (nonbovine), mannitol, and partially 
pre-gelatinized maize starch 
How Supplied 
Tablets (30 counts) are filled into 30 cc (100 mg tablet) or 100 cc 
(400 mg tablet) high density polyethylene (HDPE) bottles equipped 
with a child resistant cap and a desiccant. The cap contains an inner 
foil liner which is induction sealed during the packaging process 
Manufacturer 
Patheon Inc., Ontario Canada 
9.1.1.2. 
Standard of Care Options 
SOC option includes 1 of the following single agents: 
 Fulvestrant (Faslodex®): 500 mg administered IM into the buttocks as two 5 mL 
injections on C1D1, C1D15 and C2D1 and Day 1 of every subsequent 28-day cycle 
 Anastrozole (Arimidex®): 1 mg QD orally on a continuous dosing schedule 
 Letrozole (Femara®): 2.5 mg QD orally on a continuous dosing schedule 
 Exemestane (Aromasin®): 25 mg QD orally on a continuous dosing schedule 
For subjects randomized to SOC, the Investigator should select 1 of the above options according 
to what is appropriate based on an individual subject’s prior treatment history and the 
Investigator’s judgment. The following is provided as general guidance: 
 Subjects who have not previously received fulvestrant should be treated with 
fulvestrant (unless there is a known contraindication, see contraindications below) 
 Subjects who have progressed on prior fulvestrant should be treated with an AI 


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 The selection of an AI should be based on prior AI therapy and any known 
contraindications 
 If the subject has previously progressed on a non-steroidal AI (anastrozole or 
letrozole) but not received exemestane, the preferred option would be exemestane 
 If the subject has previously progressed on exemestane but not received a 
non-steroidal AI, the preferred option would be a non-steroidal AI 
They may not be given in combination with any other anti-cancer agent. 
9.1.2. 
Prior and Concomitant Medications 
All prior and concomitant medications (including oral, topical, intravaginal, rectal and inhaled 
over-the-counter medicines, herbal treatments, supplements, vitamins, and substance use) taken 
from 35 days prior to signing consent until 30 days after the last dose of study drug will be 
recorded. Subjects may receive supportive care agents to treat AEs and manage cancer symptoms 
(such as pain medications, heartburn medications, anti-emetics, anti-diarrheals) as per local 
institutional guidance. 
Prothrombin time (or INR) should be monitored in subjects receiving elacestrant concurrently 
with warfarin or other coumadin derivatives. 
9.1.3. 
Prohibited Medications 
All subjects are prohibited from taking any of the following medications: 
 Hormonal medications or medications known to affect serum luteinizing hormone 
(LH), FSH (except spironolactone which is allowed if medically indicated), or 
estrogen estradiol levels within 14 days (42 days for fulvestrant) of the first dose of 
study drug or anytime during the study. This includes, but is not limited to 
medications, herbal remedies, and/or supplements for the treatment of vasomotor hot 
flush symptoms administered via any route, including topical or intravaginal 
administration. 
 Any systemic anti-cancer therapy or any other chemotherapeutic agents. 
 Bisphosphonates and RANKL inhibitors to manage bone metastases are permitted 
only if the subject was receiving these agents and was on a stable dose for at least 3 
months prior to first dose of study treatment; such agents should not be initiated 
during study treatment. 
 In general, surgical tumor resection, tumor embolization, and radiation therapy are 
not permitted. Localized palliative radiation therapy may be permitted if no other 
option is available for pain management, only with approval of the Medical Monitor. 
For Elacestrant Treatment Group: 
 Medications, herbal preparations, supplements, and herbs or foods known to be 
moderate/strong inhibitors or inducers of CYP3A should not be used or consumed for 
the duration of the study because elacestrant undergoes biotransformation primarily 
by CYP3A. A more detailed listing of these products is provided in Appendix 8 


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For SOC Treatment Group: 
 Refer to the PI or SmPC for complete information about potential drug interactions 
 For subjects taking exemestane: CYP3A4 inducers may significantly decrease 
exposure. Therefore, medications and supplements that are known to be strong 
inducers of CYP3A4 should not be used/consumed for the duration of the study for 
subjects taking exemestane (Appendix 8) 
9.1.4. 
Compliance 
For subjects taking elacestrant or an AI, the elacestrant bottles or AI bottle(s)/blisters including 
any unused tablets will be returned to the clinic for drug accountability. Drug accountability will 
be performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle. 
For subjects taking fulvestrant, the dose, date and time of fulvestrant administration must be 
documented in both the medical record (source) and the eCRF. 
9.1.5. 
Randomization and Blinding 
Subjects will be randomized into the study provided they have satisfied all subject eligibility 
criteria and eligibility has been confirmed by the Medical Monitor prior to randomization. 
Randomization is to occur after eligibility is determined. The planned first dose of study drug for 
C1D1 is to start within 1 day after randomization; randomization may occur on Day -1 or on Day 
1. Note: there is no Day 0 in this study. 
The Investigators will randomize eligible subjects by Interactive Randomization Technology 
(IRT) as described in the IRT User Guide. Eligible subjects will be randomized in a 1:1 ratio to 
either elacestrant or SOC with randomization stratified by the following: 
 ESR1 mutational status as detected by ctDNA at central laboratory (ESR1-mut or 
ESR1-mut-nd) 
 Prior treatment with fulvestrant (yes vs no) 
 Presence of visceral metastases (yes vs no); visceral includes lung, liver, brain, 
pleural, and peritoneal involvement 
At the time of randomization, information about subject demographics and stratification factors 
will be entered into the IRT system. The IRT will provide the randomization number and 
treatment assignment. 
This is an open-label study; thus, study subjects and Investigators will not be blinded to 
treatment assignment. However, to minimize bias in study conduct, RADIUS personnel 
performing statistical analyses, including biostatisticians and programmers, will be blinded to 
treatment assignments and aggregated data by treatment assignment until after database lock. 
CRO study team members and select RADIUS team members will not be blinded to an 
individual subject’s treatment assignment during the conduct of the study but will be blinded to 
aggregated data by treatment assignment until after database lock. 


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An independent central IRC, blinded to subjects’ treatment assignments, will review 
radiographic images and clinical information collected on-study to determine the endpoints of 
disease response and progression. 
Safety data and efficacy data based on local Investigator and IRC assessment and OS will be 
reviewed at pre-specified intervals by the IDMC. An unblinded statistician at the CRO will 
perform all analyses in preparation for the IDMC evaluations. 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
Elacestrant 
Elacestrant is a white, IR film-coated tablet, containing 100 mg or 400 mg of elacestrant·2HCl 
per tablet.  
10.1.2. 
Standard of Care 
Investigators should refer to the PI or SmPC for a description of each agent (fulvestrant, 
anastrozole, letrozole, exemestane). 
10.1.2.1. Fulvestrant 
Commercially-available fulvestrant, 50 mg/mL solution. 
10.1.2.2. Anastrozole 
Commercially-available anastrozole, 1 mg tablets. 
10.1.2.3. Letrozole 
Commercially-available letrozole, 2.5 mg tablets. 
10.1.2.4. Exemestane 
Commercially-available exemestane, 25 mg tablets. 
10.1.3. 
Elacestrant Packaging and Labeling 
Tablets (30 counts) are filled into 30 cc (100 mg tablet) or 100 cc (400 mg tablet) HDPE bottles 
equipped with a child resistant cap and a desiccant. The cap contains an inner foil liner which is 
induction sealed during the packaging process. 
10.1.4. 
Storage, Handling, and Accountability 
A drug inventory/dispensing record must be kept up to date and maintained by the site at all 
times to document the receipt, distribution, return and/or destruction of all study drug received. 
All study drug will be dispensed by the pharmacist, the Investigator, or by a qualified individual 
under the Investigator’s supervision. Training on study drug dispensing and return will be 


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provided to the site by the Clinical Research Associate (CRA) at the Site Initiation Visit, then as 
needed during the study. 
Storage conditions and instructions on dispensation and management of temperature excursions 
and Product Quality Complaints are provided in the Pharmacy Manual. 
Investigators and site staff are reminded to monitor temperatures on an ongoing basis (see 
Pharmacy Manual) and ensure that thermometers are working correctly as required for proper 
storage of study drugs. These include thermometers for both room storage and refrigerator 
storage. Any temperature excursion and Product Quality Complaint must be reported to 
RADIUS. The study drugs must be stored as outlined in the Pharmacy Manual. Deviations from 
the storage requirements and product quality, including any actions taken, must be documented 
and reported to RADIUS. Once a deviation is identified, the study drug must be quarantined and 
not used, unless and until RADIUS provides documentation of permission to use it. 
10.1.4.1. Elacestrant Storage 
Elacestrant should be stored in a limited access secure location according to the storage 
conditions provided on the label and instructions provided in the Pharmacy Manual. 
Instructions regarding the storage and handling of elacestrant for off-site treatment will be 
provided in the Pharmacy Manual. 
10.1.4.2. Standard of Care Storage 
SOC study drugs should be stored in a limited access secure location according to the storage 
conditions and instructions provided in the Pharmacy Manual. 
Instructions for storage and handling of SOC therapies for off-site treatment (if applicable) are 
provided in the Pharmacy Manual. 
10.1.5. 
Administration 
On days of study visits, subjects should be told to not take their medication prior to coming to 
the study site. If possible, they should come to the clinic in a fasting state. If the subject is 
fasting, a light meal (eg, juice, toast and jam, yogurt) will be eaten after laboratory samples have 
been drawn and approximately 30 minutes prior to study drug administration. 
10.1.5.1. Elacestrant 
Elacestrant will be administered at the study visit as follows: 
 If fasting, subjects will be given a light meal (eg, juice, toast and jam or yogurt) 
approximately 30 minutes prior to taking their study medication 
 Subjects should take their study medication with a glass of water (at least 250 mL or 
8 oz.) and should remain in an upright position for at least 2 hours after taking their 
study medication. With the exception of water, subjects should fast for 1 hour after 
taking their study medication 
 Subjects should be instructed to swallow the tablet(s) whole (unchewed), 1 tablet at a 
time 


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Elacestrant will be administered on an outpatient basis as follows: 
 Subjects should be instructed to take their study medication at approximately the 
same time each day, preferably in the morning 
 Subjects are recommended to have a light meal (eg, juice, toast and jam or yogurt) at 
approximately 30 minutes prior to taking their study medication 
 Subjects should take their study medication with a glass of water (at least 250 mL or 
8 oz.) and should remain in an upright position for at least 2 hours after taking their 
dose(s). With the exception of water, subjects should fast for 1 hour after taking their 
dose(s) 
 Subjects should be instructed to swallow the tablet(s) whole (unchewed), and 1 tablet 
at a time 
 Subjects will receive a daily dosing diary and will be instructed to record at a 
minimum: 
 The date and time they took their dose 
 If a dose was missed or delayed, the subject must record the event and the 
duration of delay 
Note: In the event that dose reductions are warranted, the appropriate number of 100 mg tablets 
should be provided to the subject. No subject will take more than one 400 mg dose per day and 
no subject will take less than one 200 mg dose per day. 
If vomiting occurs within 1 to 2 hours following a dose, the subject does not need to take a 
replacement dose but should attempt to take their next scheduled dose. 
If the subject forgets to take a dose at the scheduled time, the subject should take the scheduled 
dose if less than 6 hours have passed. If more than 6 hours have passed after the scheduled time, 
then that missed dose should be omitted, and the subject should continue treatment with the next 
scheduled dose. 
Dose interruptions of elacestrant of ≤ 14 consecutive days are permitted at any point during 
treatment. Dose interruptions of > 14 consecutive days requires discussion with RADIUS prior 
to continuation on study. 
10.1.5.2. Standard of Care 
10.1.5.2.1. Fulvestrant 
Fulvestrant will be administered by qualified study personnel at the site. Fulvestrant 
administration will be documented on the corresponding study drug administration e-CRF. 
Fulvestrant will be administered at the study visits as follows: 
 Fulvestrant drug preparation and administration will be performed at the site by a 
physician, registered nurse, or other qualified health care provider 
 The 500 mg dose should be administered IM into the buttocks slowly (1-2 minutes 
per injection) as two 5 mL injections, one in each buttock on C1D1, C1D15, and 


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Day 1 of every cycle thereafter. Refer to the PI or SmPC for instructions and steps 
necessary for drug preparation and administration of fulvestrant 
A single fulvestrant injection can be skipped in case of a fulvestrant-related toxicity or dosing 
can be delayed. Treatment delay for fulvestrant-related toxicities will be performed as per the 
Investigator’s best medical judgment, but by no more than 28 days (± 2 days). If delay of longer 
than 28 days (± 2 days) is required, then the dose should be skipped. Fulvestrant should not be 
administered if the platelet count is < 50 x 109/L. 
10.1.5.2.2. Aromatase Inhibitors 
AIs will be administered at the study visits as follows: 
 Subjects will be given a light meal prior to taking their study medication 
 Subjects should take their study medication with a glass of water (at least 250 mL or 
8 oz.) 
 Subjects should be instructed to swallow the tablet(s) whole (unchewed) 
AIs will be administered on an outpatient basis as follows: 
 Anastrozole will be administered on an outpatient basis as one 1 mg tablet taken 
orally once daily 
 Letrozole will be administered on an outpatient basis as one 2.5 mg tablet taken orally 
once daily 
 Exemestane will be administered on an outpatient basis as one 25 mg tablet taken 
orally QD after a meal 
Subjects taking an AI will receive a daily dosing diary and be instructed to record at a minimum 
the date and time they took their dose 
Subjects should be instructed that if they miss a dose, they should take it as soon as they 
remember, however, if it is almost time for their next dose they should skip the missed dose and 
go back to their regular dosing schedule. They should not “double up” to make up for a missed 
dose. 
If a dose was missed or delayed, the subject must record the event and the duration of delay. 
Dose interruptions of any study drug of up to ≤ 14 consecutive days are permitted at any point 
during treatment. Dose interruption of > 14 consecutive days requires discussion with RADIUS 
prior to continuation on study. 
10.1.5.3. Unused Study Drug 
Patients will be required to return all bottles/blister packs of study drug as well as the completed 
patient diary at the beginning of each cycle for drug accountability. Drug accountability will be 
performed on Day 1 of every cycle prior to dispensing drug supply for the next cycle (drug 
accountability will also be performed on C1D15; drug may be dispensed at this visit if needed). 
The number of remaining tablets will be documented and recorded. 


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11. 
DATA ANALYSIS AND STATISTICAL METHODS 
A Statistical Analysis Plan (SAP) will be developed and finalized before database lock. This plan 
will specify all statistical methods to be used in analysis of the data. 
11.1. 
Statistical Hypotheses and Type I Error Control 
11.1.1. 
Statistical Hypotheses 
The null hypothesis for the primary endpoint in ESR1-mut subjects is that elacestrant does not 
differ from the SOC treatment group in IRC-assessed PFS for ESR1-mut subjects; the alternative 
hypothesis is that elacestrant differs from the SOC treatment group in IRC-assessed PFS for 
ESR1-mut subjects. 
The null hypothesis for the primary endpoint in all subjects (ESR1-mut and ESR1-mut-nd) is that 
elacestrant does not differ from the SOC treatment group in IRC-assessed PFS for all subjects 
(ESR1-mut and ESR1-mut-nd); the alternative hypothesis is that elacestrant differs from the 
SOC treatment group in IRC-assessed PFS for all subjects (ESR1-mut and ESR1-mut-nd). 
11.1.2. 
Type I Error Control 
The 2 primary endpoints will be evaluated using the Hochberg procedure to maintain the overall 
alpha level at 2-sided 5.0%: 
 The p-value for each of the 2 primary endpoints will be derived without any 
adjustment. These 2 p-values will be sorted in a numerical order so that 1 p-value is 
larger than or equal to the other 
 If the larger p-value is < 0.05, statistical significance will be claimed for both 
endpoints 
 If the larger p-value is ≥ 0.05 and the smaller p-value is < 0.025, statistical 
significance will be claimed only for the endpoint associated with smaller p-value 
 If the larger p-value is ≥ 0.05 and the smaller p-value is ≥ 0.025, no statistical 
significance will be claimed 
Unless otherwise specified, analyses of all other efficacy endpoints will be performed at the 
2-sided alpha level of 5% without adjustment for p-values. 
11.2. 
Analysis Populations 
The following populations will be defined and used for analysis: 
 The Intention-to-Treat (ITT) population consists of all randomized subjects. This is 
the primary population for PFS and OS analyses. Subjects will be analyzed according 
to randomized treatment assignments. 
 The Safety population consists of all subjects who received at least 1 dose of study 
medication. All safety analyses will be performed using the Safety population. 
Subjects will be analyzed according to the treatments they actually received in 
Cycle 1. 


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 The Response Evaluable (RE) population includes all ITT subjects who had 
measurable disease (ie, at least 1 target lesion) at baseline and at least 1 post-baseline 
RECIST assessment on any (target or non-target) lesions and/or had a new lesion. 
The RE population is used for the analyses of best overall response and ORR.  
 The Clinical Benefit Evaluable (CBE) population includes all ITT subjects who had 
measurable and/or evaluable disease (ie, target and/or non-target lesions) at baseline 
and at least 1 post-baseline RECIST assessment on any (target or non-target) lesions 
and/or had a new lesion. The CBE population is used for the analyses of CBR. 
 The PK population consists of all subjects who received at least 1 dose of elacestrant 
and have PK concentration data for at least 1 scheduled time point. PK analyses will 
be performed using the PK population. 
 The Biomarker population consists of all subjects in the Safety population for whom 
adequate quality and volume of biomarker samples are available for analysis. The 
exploratory biomarker analysis will be performed using the Biomarker population. 
11.3. 
Description of Statistical Methods 
11.3.1. 
General Approach 
For continuous variables, descriptive statistics will include the number of subjects, mean, 
standard deviation, median, first quartile (Q1), third quartile (Q3), minimum and maximum. For 
categorical variables, descriptive statistics will include the frequency counts and percentages. 
Unless otherwise stated, baseline is defined as the last value obtained before the start of study 
drug. 
11.3.2. 
Procedures for Handling Missing, Unused, and Spurious Data 
All available data will be included in the analysis. For time-to-event analysis such as that of PFS, 
subjects who did not experience the event will be censored in the analysis. For other analyses 
where appropriate, imputations of values for missing data will be performed as specified in the 
SAP. 
All data recorded on the CRF will be included in the data listings that accompany the clinical 
study report. 
11.3.3. 
Demographics and Baseline Subject Characteristics 
Subject characteristics will be summarized by treatment group using the ITT population for 
2 sets of study subjects: ESR1-mut subjects and all subjects (ESR1-mut and ESR1-mut-nd). 
Standard descriptive statistics for continuous and categorical variables will be provided for 
subject demographics, baseline disease characteristics, prior anti-cancer therapies, and other 
baseline characteristics. No hypothesis testing will be conducted. 


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11.3.4. 
Treatment Exposure 
Treatment exposure will be summarized by treatment group as duration on treatment and extent 
of exposure to study drug. Duration on treatment will be calculated as the days from first dose 
until last dose and summarized quantitatively. 
Measures of extent of exposure include the total number of doses per subject and compliance. 
Compliance will be calculated as the percentage of total number of doses relative to the expected 
number of doses and summarized quantitatively. The reasons for dose(s) withheld or delayed 
will also be summarized. 
11.3.5. 
Analysis of the Primary Endpoints 
The primary endpoints are 
 PFS based on blinded IRC assessment in the ESR1-mut subjects 
 PFS based on the blinded IRC assessment in all subjects (ESR1-mut and ESR1-mut-nd) 
Final analyses of the primary endpoints will be performed when approximately 160 events for 
IRC-assessed PFS have occurred among the ESR1-mut subjects and approximately 340 events 
for IRC-assessed PFS have occurred among all subjects (ESR1-mut and ESR1-mut-nd). Based 
on an enrollment period of 15 months, this is estimated to occur at approximately 27 months 
after randomization of the first subject. 
For subjects without objective disease progression or death, PFS will be censored on the date of 
the last tumor assessment, or, if no tumor assessment was performed after the baseline visit, at the 
date of randomization. Detailed censoring rules are described in Table 14. 
Table 14: 
Rules for Deriving Date of Progression or Censor for IRC-Assessed PFS 
Situation 
Date of Progression or Censor 
Outcome 
No baseline tumor assessments 
Date of Randomization 
Censored 
No post-baseline assessments and no death 
Date of Randomization 
Censored 
No documented progression and no death (with 
a post-baseline tumor assessment) 
Date of last adequate tumor assessment Censored 
Subject lost to follow-up (or withdrew consent) 
before documented progression or death 
Date of last adequate tumor assessment Censored 
Documented progression 
Date of documented progression 
Progressed 
Death without documented progression 
Date of death 
Progressed 
Documented progression or death after missing 
one post-baseline tumor assessment 
Date of documented progression or 
death  
Progressed 
Documented progression or death after missing 
≥2 consecutive post-baseline tumor 
assessments 
Date of last adequate tumor assessment 
before missed assessments or date of 
randomization, whichever is later  
Censored 
Note: If more than one situation applies, date of PFS and associated outcome will be determined by the earliest date 
and associated outcome above.  
The analyses will be performed based on the ITT population for ESR1-mut subjects and all 
subjects (ESR1-mut and ESR1-mut-nd) in the entire ITT population using Kaplan-Meier (KM) 
methods and displayed graphically with median event times and 95% confidence intervals (CIs). 
The differences in the primary endpoints between treatment groups will be analyzed using the 
stratified log-rank test, with the stratification factors of prior treatment with fulvestrant (yes vs 


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no) and presence of visceral metastases (yes vs no), as the primary analyses. The unstratified log-
rank test will be performed as a sensitivity analysis. The Cox regression model, including 
treatment and the stratification factors as above, will be used to estimate the hazard ratio and 
95% CI. 
11.3.6. 
Analyses of Secondary Endpoints 
Key Secondary Endpoints 
Key secondary efficacy endpoints include the following: 
 OS in ESR1-mut subjects 
 OS in all subjects (ESR1-mut and ESR1-mut-nd) 
Analyses of OS in ESR1-mut subjects and in all subjects (ESR1-nut and ESR1-mut-nd) will be 
performed using the ITT population for the ESR1-mut subjects and the entire ITT population, 
respectively. 
For each of the 2 sets of study subjects, OS will be analyzed at the following 2 time points: 
 At the time of the final PFS analysis (when approximately 160 and 340 PFS events are 
observed among the ESR1-mut and all subjects [ESR1-mut and ESR1-mut-nd], 
respectively) 
 At the time of the final OS analysis (when 50% of the subjects have died) 
At each time point, OS for the treatment groups will be analyzed using KM methods and 
displayed graphically, with median event times and 95% CIs displayed. The Cox regression 
model that includes treatment and the stratification factors of prior treatment with fulvestrant 
(yes vs no) and presence of visceral metastases (yes vs no) will be used to estimate the hazard 
ratio and 95% CI. In addition, the difference between treatment groups will be analyzed using 
the stratified log-rank test. A 2-sided alpha level of 0.01% will be allocated at the final PFS 
analysis time point and a 2-sided alpha level of 4.99% will be allocated at the final OS analysis 
time point. 
Other Secondary Endpoints  
The following secondary efficacy endpoints will be analyzed for ESR1-mut-nd subjects: 
 IRC-assessed PFS 
 OS 
The following endpoints will be analyzed for ESR1-mut, ESR1-mut-nd, and all subjects 
(ESR1-mut and ESR1-mut-nd): 
 Local Investigator-assessed PFS 
 IRC-assessed ORR and DoR 
 IRC-assessed CBR 
 Local Investigator-assessed ORR and DoR 
 Local Investigator-assessed CBR 


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Analyses of IRC-assessed PFS in ESR1-mut-nd subjects will be performed using the ITT 
population for the ESR1-mut-nd subjects in the same manner as the analyses of the primary 
endpoints. 
Analyses of OS in ESR1-mut-nd subjects will be performed using the ITT population for the 
ESR1-mut-nd subjects in the same manner as the analyses of OS in ESR1-mut subjects and in all 
subjects (ESR1-mut and ESR1-mut-nd). 
Local Investigator-assessed PFS will be analyzed in the same manner as IRC-assessed PFS. 
ORR will be summarized for the RE population. 
ORR and CBR will be summarized as a binomial response rate and compared between treatment 
groups using stratified Fisher’s exact test. 
DoR will be summarized for subjects in the RE population who achieved either a confirmed CR 
or PR post-baseline using the KM method. Estimated median values of DoR along with 95% CI 
will be provided. 
Results of the efficacy analyses for the 3 sets of study subjects, ESR1-mut subjects, 
ESR1-mut-nd subjects, and all subjects (ESR1-mut and ESR1-mut-nd), will be presented using 
Forest plots. 
Subgroup analysis of PFS, OS, ORR, and CBR based on prior treatment with fulvestrant and 
presence of visceral metastases will be performed in the same manner as the analyses in the 
overall populations. 
11.3.7. 
Patient Reported Outcomes 
Analyses of the PROs will be performed using the ITT population for ESR1-mut subjects and all 
subjects (ESR1-mut and ESR1-mut-nd). 
For each set of study subjects, the PRO endpoint values and changes from baseline by visit will 
be summarized by treatment group. A 95% CI for changes from baseline by visit will also be 
provided. 
11.3.8. 
Pharmacokinetic Analysis 
Elacestrant plasma concentrations will be summarized descriptively (with n, mean, standard 
deviation, coefficient of variation [CV], median, minimum, maximum, geometric mean and its 
associated CV) by visit and nominal time point (pre-dose or 4 hours post-dose; see Table 18 and 
Table 19 in Appendix 2) for ESR1-mut subjects and all subjects (ESR1-mut and ESR1-mut-nd). 
Plot of geometric mean of elacestrant plasma concentrations by nominal time point will also be 
presented. 
11.3.9. 
Safety Analyses 
Safety analyses will be performed using the Safety population for ESR1-mut subjects and all 
subjects (ESR1-mut and ESR1-mut-nd). 
For each set of study subjects, safety analysis will be performed by treatment group and include 
summaries of the following: 


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 AEs, including NCI CTCAE v5.0 severity grade and relationship to study drug 
 Deaths, SAEs, and AEs leading to study drug withdrawal 
 Dose interruptions and reductions due to AEs 
 Laboratory values over time and shifts in laboratory measurements by NCI CTCAE 
v5.0 grade 
 ECG values over time and change from baseline 
 ECOG performance status over time and shifts in ECOG performance status 
 Vital sign values over time and incidence of potentially clinically significant values 
11.3.10. 
Exploratory Analyses 
The following exploratory analyses will be assessed in ESR1-mut subjects, ESR1-mut-nd 
subjects, and all subjects (ESR1-mut and ESR1-mut-nd): 
 TTC, defined as the number of days from randomization to initiation of 
chemotherapy will be summarized by treatment group descriptively for the subjects 
who require initiation of chemotherapy due to disease progression 
 Alterations in ctDNA relevant to ER+ breast cancer and the CDK4/6 pathway and the 
relationship between these findings and clinical response  
 Alterations in tumor-specific genes, proteins, and RNAs related to oncogenic 
pathways and proliferation and cell cycle markers in tumor tissue and the relationship 
between these findings and clinical response 
11.4. 
Interim Analysis 
At about 70% enrollment, an interim futility analysis will be provided to the IDMC. At this 
interim data look, the IDMC will evaluate the primary endpoint in conjunction with other 
efficacy endpoints, including OS, ORR, DoR and CBR. These additional efficacy data will assist 
the IDMC in checking consistency of the totality of the data. The IDMC will make 1 of the 
following recommendations according to the conditional power of the primary efficacy endpoint 
for all subjects (ESR1-mut and ESR1-mut-nd), which will be derived based on the observed data 
at the interim futility analysis: 
 Continue trial unmodified if the conditional power is ≥ 20% at the alpha level of 2.5% 
 Terminate enrollment of ESR1-mut-nd subjects due to futility if the conditional power is 
< 20% at the alpha level of 2.5% 
If the conditional power is < 20% for all subjects at the alpha level of 2.5%, further enrollment of 
ESR1-mut subjects will be evaluated by the IDMC. Study drug administration for ongoing 
subjects will remain unchanged unless otherwise determined by the Investigator. 
Further details of the statistical methods will be specified in the interim SAP as part of the IDMC 
Charter. 


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11.5. 
Sample Size Assumptions 
Among the ESR1-mut subjects, the study requires approximately 160 PFS events to have a 
power of 80% power to detect a hazard ratio of 0.610 at the 2-sided alpha level of 2.5%. 
Assuming a median PFS of 5.3 months for the SOC treatment group, this treatment effect 
represents a median PFS of 8.7 months for the elacestrant treatment group, an increase of 
approximately 3.4 months among the ESR1-mut subjects. 
Among all subjects (ESR1-mut and ESR1-mut-nd), a total of approximately 340 PFS events will 
have 92% power to detect a hazard ratio of 0.667 at the 2-sided alpha level of 2.5%. 
The 2-sided alpha level of 2.5% for sample size calculation was selected to ensure that at least 
1 of the 2 primary efficacy endpoints will pass the Hochberg procedure to control the overall 
alpha level at 5.0% (see Section 11.1.2). 
The study will need to randomize approximately 220 ESR1-mut subjects (110/treatment group) 
and a total of approximately 466 subjects of both types (ESR1-mut and ESR1-mut-nd; 
233/treatment group) in a 1:1 ratio to the 2 treatment groups. To prevent exceeding the target 
recruitment by more than 10% (ie, 512 subjects total), if a total of 292 ESR1-mut-nd subjects is 
reached before 220 ESR1-mut subjects are enrolled, further enrollment will be restricted to 
ESR1-mut subjects only until the target of 220 is achieved. 
Final analysis of the primary endpoints will be performed at approximately 160 PFS events 
among the ESR1-mut subjects and 340 PFS events among all subjects (ESR1-mut and 
ESR1-mut-nd), estimated to occur at 30-33 months after the first subject is randomized. 
11.6. 
Study Committees 
11.6.1. 
Independent Data Monitoring Committee 
An IDMC external to both RADIUS and the CRO will be responsible for ongoing monitoring of 
the safety and efficacy according to the IDMC Charter. The IDMC will meet on a regular basis 
and will make recommendations as to whether the trial should continue, be amended, or be 
discontinued based on ongoing reviews of safety and efficacy data. Details of the IDMC 
responsibilities are described in the IDMC Charter. 
11.6.2. 
Study Steering Committee 
A Study Steering Committee (SSC) composed of international physicians with expertise in 
management of ER+ mBC has been convened by RADIUS. The remit of the SSC is to provide 
guidance to RADIUS on protocol development and implementation, Investigator selection, and 
recruitment strategies. The SSC will also inform RADIUS on advances in the field that could 
impact the trial. The SSC will not be provided with any efficacy or safety data during the trial. 
11.6.3. 
Imaging Review Committee 
A blinded, independent IRC will perform a review of radiographic images and clinical 
information collected on study to determine the protocol-defined endpoints of disease response 
and progression. Further information on the independent review process will be provided in the 
Bioclinica Imaging Charter. 


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12. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
12.1. 
Study Monitoring 
RADIUS is responsible for ensuring the proper conduct of the study with regard to protocol 
adherence and validity of data recorded in the clinical database. RADIUS or its designee will 
assign CRAs to the study. The CRA is responsible for reviewing the study at regular intervals, 
verifying adherence to the protocol, completeness, consistency and accuracy of the data, study 
source documents, and drug accountability records. Data will be verified against the original 
medical records and laboratory results as part of source document verification to ensure its 
validity. The Investigator is responsible for ensuring that any issues detected in the course of a 
monitoring visit are resolved. 
12.2. 
Audits and Inspections 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, quality assurance audits may be conducted. Regulatory agencies may also conduct 
regulatory inspections of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the Investigator and institution agree to 
allow the auditors/inspectors direct access to all relevant documents and to allocate his/her time 
and the time of his/her staff to the auditors/inspectors to respond to requests and questions, and 
discuss findings and any relevant issues. In the case of an audit or inspection, the Investigator or 
a delegate will alert RADIUS as soon as he/she becomes aware of an audit or inspection. 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate 
filing system of all study-related documentation that will be suitable for inspection at any time 
by RADIUS, its designees, and/or regulatory agencies. In signing this protocol, the Investigator 
understands and agrees to give access to study-related documentation and files to the Study 
Monitor, RADIUS, other authorized representatives of RADIUS, representatives of the IRB/IEC, 
and regulatory agencies. 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, RADIUS may 
conduct a quality assurance audit. Please see Section 12.2 for more details regarding the audit 
process. 
14. 
ETHICS 
14.1. 
Ethics Review 
It is the responsibility of the Investigator to submit this protocol, the final approved ICF that has 
been previously approved by RADIUS or its designee, relevant supporting information, and all 
types of subject recruitment or advertisement information (approved by RADIUS or its designee) 
to the IRB/IEC for review and all material must be approved before the study is initiated. Prior to 


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implementing changes in the study, RADIUS will provide a protocol amendment and the 
IRB/IEC must also approve any protocol amendments. 
On the IRB/IEC approval letter, the study (title, protocol number and version), the documents 
reviewed (protocol, informed consent material, amendments), and the date of review should be 
clearly stated. Drug supplies will not be released, and subject recruitment will not begin until this 
written approval has been received by RADIUS or its designee. 
The Investigator is responsible for keeping the IRB/IEC apprised of the progress of the study and 
of any changes made to the protocol as deemed appropriate, but in any case, at least once a year. 
The Investigator must also keep the IRB/IEC informed of any serious and significant AEs. 
All materials approved by the IRB/IEC for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection. 
14.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference of Harmonization/GCP, 
applicable regulatory requirements and RADIUS’ policy on Bioethics. 
14.3. 
Written Informed Consent 
The Investigator will submit the site-specific ICF to RADIUS for approval prior to submitting to 
the IRB/IEC. The Investigator is responsible for obtaining written, informed consent from each 
subject interested in participating in this study prior to conducting any study-related procedures. 
Written informed consent should be obtained after an adequate, thorough, and clear explanation 
of the study objectives, procedures, and the potential hazards of the study. The Investigator must 
use the most current IRB/IEC approved ICF for documenting written informed consent. Each 
ICF will be appropriately signed and dated by the subject and the person obtaining consent. The 
site must retain the original signed ICF and provide a copy to the subject. 
14.4. 
Subject Confidentiality and Privacy 
Subjects will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the Health Insurance Portability and Accountability Act form or local equivalent and 
informed consent documents. The original signed document will become part of the subject’s 
medical records and each subject will receive a copy of the signed document. The use and 
disclosure of protected health information will be limited to the individuals described in the 
informed consent document. 
Participant confidentiality and privacy is strictly held in trust by the participating Investigators, 
their staff, and RADIUS. This confidentiality is extended to cover testing of biological samples 
in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study, or the data will be released to any unauthorized third party 
without prior written approval of RADIUS. 
All research activities will be conducted in as private a setting as possible. 


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The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB/IEC, Institutional policies, 
or RADIUS. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at RADIUS. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by RADIUS research staff will be secure and password 
protected. At the end of the study, all study databases will be de-identified and archived at 
RADIUS. 
15. 
DATA HANDLING AND RECORD KEEPING 
15.1. 
Inspection of Records 
RADIUS, and authorized representatives of RADIUS, will be allowed to conduct site visits to 
the investigation facilities for the purpose of monitoring any aspect of the study. The Investigator 
agrees to allow the monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, subject charts, study source documents, and other records related to study 
conduct. 
15.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or, if not approved, 2 years following the 
discontinuance of the test article for investigation. If it becomes necessary for RADIUS or a 
regulatory authority to review any documentation related to the study, the Investigator must 
permit access to such records. Records will be retained by the Sponsor per the local regulations. 
16. 
PUBLICATION POLICY 
The Investigator must submit to RADIUS any proposed publication or presentation along with 
information about the scientific journal or presentation forum at least 30 days prior to submission 
of the publication or presentation (2 weeks for abstracts). The Investigator will comply with 
requests from RADIUS to delete references to its confidential information in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days to 
obtain patent protection if deemed necessary. 


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17. 
LIST OF REFERENCES 
AstraZeneca: FASLODEX (fulvestrant) Full Prescribing Information (package insert). 
https://www.azpicentral.com/faslodex/faslodex.pdf#page=1, 2017. Accessed on: June 18, 2018 
Bentzon N, During M, Rasmussen BB, Mouridsen H, Kroman N: Prognostic effect of estrogen 
receptor status across age in primary breast cancer. Int J Cancer 2008;122:1089-1094. 
Bihani T, Patel HK, Arlt H, Tao N, Jiang H, Brown JL, et al.: Elacestrant (RAD1901), a 
Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER(+) 
Breast Cancer Patient-derived Xenograft Models. Clin Cancer Res 2017;23:4793-4804.  
Breastcancer.org: U.S. Breast Cancer Statistics 
http://www.breastcancer.org/symptoms/understand_bc/statistics, 2018. Accessed on: April 16, 
2018. 
Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, et al.: Prevalence of ESR1 
Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis 
of the BOLERO-2 Clinical Trial. JAMA Oncol 2016;2:1310-1315. 
Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41. 
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al.: Fulvestrant plus 
palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-
negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): 
final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 
2016;17:425-439. 
DeSantis CE, Bray F, Ferlay J, Lortet-Tieulent J, Anderson BO, Jemal A: International variation 
in female breast cancer incidence and mortality rates. Cancer Epidemiol Biomarkers Prev 
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Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al.: Results of 
the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in 
post-menopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol 
2010;28:4594-4600. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.: New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-247. 
Fanning SW, Mayne CG, Dharmarajan V, Carlson KE, Martin TA, Novick SJ, et al.: Estrogen 
receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance 
by stabilizing the activating function-2 binding conformation. Elife 2016;5. 
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al.: Cancer incidence and 
mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 
2015;136:E359-386. 
Finn RS, Crown JP, Ettl J, Schmidt M, Bondarenko IM, Lang I, et al.: Efficacy and safety of 
palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, 


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advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial 
PALOMA-1/TRIO-18. Breast Cancer Res 2016;18:67. 
Fribbens C, O'Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M, et al.: Plasma ESR1 
Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. J Clin 
Oncol 2016;34:2961-2968. 
Garner F, Shomali M, Paquin D, Lyttle CR, Hattersley G: RAD1901: a novel, orally bioavailable 
selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer 
xenograft models. Anticancer Drugs 2015;26:948-956. 
Glück S: Extending the clinical benefit of endocrine therapy for women with hormone receptor-
positive metastatic breast cancer: differentiating mechanisms of action. Clin Breast Cancer 
2014;14:75-84. 
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al.: American 
Society of Clinical Oncology/College Of American Pathologists guideline recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin 
Oncol 2010;28:2784-2795. 
Hawkins RA, White G, Bundred NJ, Dixon JM, Miller WR, Stewart HJ, et al.: Prognostic 
significance of oestrogen and progestogen receptor activities in breast cancer. Br J Surg 
1987;74:1009-1013. 
Hochberg Y: A Sharper Bonferroni Procedure for Multiple Tests of Significance. Biometrika  
1988;74:800-802. 
Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, 
et al.: Emergence of constitutively active estrogen receptor-alpha mutations in pretreated 
advanced estrogen receptor-positive breast cancer. Clin Cancer Res 2014;20:1757-1767. 
Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, et al.: Endocrine-therapy-resistant ESR1 
variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep 
2013;4:1116-1130. 
McDonnell DP, Wardell SE: The molecular mechanisms underlying the pharmacological actions 
of ER modulators: implications for new drug discovery in breast cancer. Curr Opin Pharmacol 
2010;10:620-628. 
NCCN: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology 
(NCCN Guidelines) Breast Cancer. Version 4. 2018 – February 8, 2019.  
New York Heart Association Criteria Committee DM, Fox AC, Gorlin R, Levin RI: 
Nomenclature and criteria for diagnosis of diseases of the heart and great vessels, ed 9th. Boston, 
MA, Lippincott Williams and Wilkins, 1994. 
Oesterreich S, Davidson NE: The search for ESR1 mutations in breast cancer. Nat Genet 
2013;45:1415-1416. 
Osborne CK, Schiff R: Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 
2011;62:233-247. 


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Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al.: ESR1 ligand-binding domain 
mutations in hormone-resistant breast cancer. Nat Genet 2013;45:1439-1445. 
van Kruchten M, de Vries EG, Glaudemans AW, van Lanschot MC, van Faassen M, Kema IP, et 
al.: Measuring residual estrogen receptor availability during fulvestrant therapy in patients with 
metastatic breast cancer. Cancer Discov 2015;5:72-81. 
Wardell SE, Ellis MJ, Alley HM, Eisele K, VanArsdale T, Dann SG, et al.: Efficacy of 
SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-
Resistant Breast Cancer. Clin Cancer Res 2015;21:5121-5130. 
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. American 
Society of Clinical Oncology; College of American Pathologists. Recommendations for human 
epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical 
Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 
2013 Nov 1;31(31):3997-4013. doi: 10.1200/JCO.2013.50.9984. Epub 2013 Oct 7. 
Wolff AC, Hammond MEH, Allison KH, Harvey BE, McShane LM, Dowsett M: HER2 Testing 
in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists 
Clinical Practice Guideline Focused Update Summary. J Oncol Pract 2018;14:437-441. 


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18. 
APPENDICES 
 
 


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APPENDIX 1. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) V1.1 
Response and progression will be evaluated in this trial using the new international criteria 
proposed by the RECIST committee (Eisenhauer, 2009). Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria for 
determination of tumor response. Additionally, per the RECIST working group, CT scan (with 
contrast) is currently the best available and reproducible method to measure lesions selected for 
response assessment. 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter in the plane of measurement is to be recorded) with a 
minimum size of: 
10 mm by CT scan (CT scan slice thickness  5 mm) 
10 mm caliper measurement by clinical exam (lesions that cannot be accurately measured 
with calipers should be recorded as non-measurable). 
20 mm by chest x-ray. 
- 
Malignant lymph node: To be considered pathologically enlarged and measurable, 
a lymph node must be  15 mm in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed. Lymph nodes  10 
mm are non-pathological. Lymph nodes measuring 10 mm to  15 mm are 
considered non-target.  
Non-measurable disease: Non-measurable disease is defined as all other lesions (or sites of 
disease), including small lesions (longest diameter  10 mm or pathological lymph nodes with  
10 mm to  15 mm in short axis) as well as truly nonmeasurable lesions. Lesions considered to 
be truly non-measurable include: leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitic involvement of the skin or lung, inflammatory breast disease, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Special considerations 
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT scan or 
MRI can be considered as measurable lesions if the soft tissue component meets the definition of 
measurable disease. Blastic bone lesions are considered nonmeasurable disease. Note: Bone 
scan, PET scan or plain films are not considered adequate imaging techniques to measure bone 
lesions. However, these can be used to confirm the presence or disappearance of bone lesions. 
Cystic lesions: Lesions that meet the criteria to be radiographically defined as simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) because 
they are, by definition, simple cysts. Cystic lesions thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of measurable disease. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 


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Lesions with prior local treatment: Tumor lesions situated in a previously irradiated area, or in 
an area subjected to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion. 
Measurement of Lesions: All measurements should be recorded in metric notation, using 
calipers if clinically assessed. All baseline evaluations should be performed as close as possible 
to the treatment start and never more than 4 weeks before the beginning of the treatment. 
Target lesions: When more than one measurable lesion is present at baseline, all measurable 
lesions, up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ), 
representative of all involved organs should be identified as target lesions and be recorded and 
measured at baseline. This means that, in instances where subjects have only one or 2 organ sites 
involved, a maximum of 2 or 4 lesions, respectively, will be recorded. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, and should be those that lend themselves to reproducible repeated 
measurements. In situations in which the largest lesion does not lend itself to reproducible 
measurement, the next largest lesion that can be measured reproducibly should be selected. 
Lymph nodes as target lesions: Pathological nodes, which are defined as measurable and may be 
identified as target lesions, must meet the criterion of a short axis of 15 mm by CT scan. Only 
the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size 
is normally reported as 2 dimensions in the plane in which the image is obtained (for CT scan, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, sagittal or 
coronal). The smaller of these measures is the short axis. All other pathological nodes (those 
with short axis  10 mm but  15 mm) should be considered non-target lesions. Nodes that have 
a short axis  10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum of diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum of diameters will be used as reference to further characterize the objective tumor response in 
the measurable dimension of the disease. 
Non-target lesions: All other lesions (or sites of disease), including pathological lymph nodes, 
should be identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required but these lesions should be noted at baseline and should be followed as 
“present”, “absent”, or in rare cases, “unequivocal progression”. In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case record 
form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 


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Best response 
All subjects will have their best response on trial classified as outlined below and summarized 
in Table 15, Table 16, and Table 17. 
Evaluation of response in target lesions 
Complete response (CR): disappearance of all target lesions (both target and non-target). 
Any pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to  10 mm. 
Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions 
taking as the reference the baseline sum of diameters. 
Stable disease (SD): steady state of disease. Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking as a reference, the smallest sum of 
diameters while in the trial. 
Progressive disease (PD): at least a 20% increase in the sum of diameters of the target lesions, 
taking as a reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on trial). In addition to a relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. Appearance of new lesions will also 
constitute PD. 
Special notes on assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero, even if complete response criteria are met, 
because a normal lymph node is defined as having a short axis of  1 0mm. For PR, SD and PD, 
the actual short axis measurement of the nodes is to be included in the sum of target lesions 
Target lesions that become too small to measure 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes that are recorded as target lesions at baseline become 
so faint on CT scan that the radiologist may not feel comfortable assigning an exact measure and 
may report them as being ‘too small to measure’. When this occurs, it is important that a value be 
recorded on the eCRF. If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned. 
Evaluation of response in non-target lesions 
Complete response: Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size ( 10 mm short axis). 
Non-CR / Non-PR: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive disease: Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression.) 


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Disease progression in subjects with only non-measurable disease 
For subjects with only non-measurable disease, disease progression is defined as development of 
new lesions or “unequivocal progression” of existing lesions. Because worsening in non-target 
disease cannot be easily quantified (by definition: if all lesions are truly non-measurable), a useful 
test that can be applied when assessing subjects for unequivocal progression is to consider if the 
increase in overall disease burden, based on the change in non-measurable disease, is comparable 
in magnitude to the increase that would be required to declare PD for measurable disease, i.e., an 
increase in tumor burden representing an additional 73% increase in ‘volume’ (which is equivalent 
to a 20% increase diameter in a measurable lesion). If ‘unequivocal progression’ is seen, the 
subject should be considered to have had overall PD at that point. 
New lesions 
The appearance of new malignant lesions denotes disease progression; however, the finding of a 
new lesion should be unequivocal, i.e., not attributable to differences in scanning technique, 
change in imaging modality or findings thought to represent something other than tumor (eg, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal (eg, because of small size), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan. 
Table 15: 
Target and Non-Target Lesion Response 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for this Category 
also requires 
CR 
CR 
No 
CR 
4-6 weeks Confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
4-6 weeks Confirmation 
CR 
Not evaluated 
No 
PR 
4-6 weeks Confirmation 
PR 
Non-PD or not all 
evaluated 
No 
PR 
4-6 weeks Confirmation 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Documented at least once >6 weeks 
from baseline 
PD 
Any 
Yes or No 
PD 
— 
Any 
PD 
Yes or No 
PD 
— 
Any 
Any 
Yes 
PD 
— 
Not all evaluated 
Non-PD 
No 
Unevaluable 
— 
CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease 
Subjects with global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”. Every effort 
should be made to document the objective progression even after discontinuation of treatment. 
 


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Table 16: 
Time Point Response: Subjects with Non-Target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
Best Response Also Requires 
CR 
No 
CR 
4-6 weeks Confirmation 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
— 
Unequivocal PD 
Yes and No 
PD 
— 
Any 
Yes 
PD 
— 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
a: ‘Non-CR/non-PD’ is preferred over ‘SD’ for non-target disease because SD is increasingly used as an 
endpoint for assessment of efficacy in some trials, therefore, to assign this category when no lesions can 
be measured is not advised. 
 
Table 17: 
Best Overall Response when Confirmation of CR or PR is Required 
Overall Response First Time 
Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
CR = complete response; NE = non-evaluable; PD = progressive disease; PR = partial response; SD =stable 
disease. 
a: If a CR is truly met at the first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (because the disease must have 
re-appeared after CR). Best response would depend on whether minimum duration for SD was met. 
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely 
present and, in fact, the subject had PR, or CR at the first time point. Under this circumstances, the original 
CR should be changed to PR and the best response is PR. 
 


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Response duration 
Response duration will be measured from the time that measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent disease or PD is 
objectively documented. 
Stable disease duration 
Stable disease duration will be measured from the time of start of therapy until the criteria for 
progression are met, taking as a reference the smallest measurements recorded since the start of 
treatment. 
Methods of measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions - Clinical lesions will only be considered measurable when they are superficial 
(eg, skin nodules, palpable lymph nodes). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. When lesions 
can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
because it is more objective and may also be reviewed at the end of the study. 
Chest x-ray - Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, because CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined 
and surrounded by aerated lung. 
CT/MRI - CT scan is the best currently available and reproducible method to measure target 
lesions selected for response assessment. MRI is acceptable in certain situations (eg, for body 
scans). CT scans should be performed with cuts of 5 mm or less in slice thickness, contiguously. 
This applies to the chest, abdomen and pelvis. Head and neck and extremities usually require 
specific protocols. 
Ultrasound - Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy/laparoscopy - The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor markers - Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject to 
be considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated. 


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100 
 
 
  
 
 
Cytology/histology - These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
Bone lesions - Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these can be used to confirm the presence or disappearance of 
bone lesions. 


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APPENDIX 2. SCHEDULE OF EVENTS 
Table 18: 
Schedule of Events 
Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Demography/Informed consentg 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
Medical/Surgical history/Current 
medical conditions 
X 
 
 
 
 
 
 
Breast cancer diagnosis, ER, 
HER2 statush 
X 
 
 
 
 
 
 
Prior anti-cancer therapyi 
X 
 
 
 
 
 
 
Randomizationj 
 
X 
 
 
 
 
 
Patient Reported Outcomesk 
EQ-5D-5L 
EORTC QLQ-C30 
PRO-CTCAE 
 
X 
X 
X 
X 
Xe 
 
Height 
X 
 
 
 
 
 
 


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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Weight 
X 
X 
 
X 
X 
 
 
Physical examinationl 
X 
X 
 
X 
X 
 
 
Vital signsm 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
 
X 
X 
 
 
12-lead ECGn 
X 
Xn 
Xn 
Xn 
Xn 
 
 
Estradiol and FSH testing (women 
only)o 
X 
 
 
 
 
 
 
Urinalysisp 
X 
 
 
 
 
 
 
Hematologyq 
Xr 
X 
X 
X 
X 
 
 
Chemistrys 
Xr 
X 
X 
X 
X 
 
 
Special Chemistryt 
X 
 
 
 
X 
 
 
Coagulationu 
Xr 
X 
X 
X 
X 
 
 
CT of chest, CT/MRI of abdomen, 
pelvis, and clinically indicated 
sites of disease; color photographs 
with measurement markers of 
superficial diseasev 
Xw 
◄--------------------► 
Performed every 8 weeks (± 7 days) from 
the date of randomization) 
X 
 
Xf 


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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Radionuclide bone scan or whole 
body MRIx 
Xw 
◄--------------------► 
Performed every 24 weeks (± 7 days) from 
the date of randomization 
Xv 
 
Xf 
Evaluation of abnormal bone scan 
or whole body MRIy 
Xw 
X 
Xv 
 
Xf 
Blood sample for PKz 
 
X 
X 
Cycle 2 only 
 
 
 
Blood sample for ctDNA 
(Biomarker testing)aa 
X 
 
 
Cycle 2 and 
Cycle 3 only 
X 
 
 
Tumor biopsybb 
X 
 
 
Xcc 
Xcc 
 
 
Elacestrant groupdd 
 
◄---------►Once Daily 
 
 
 
SOC treatment group -aromatase 
inhibitoree 
 
◄---------►Once Daily 
 
 
 
SOC treatment group – 
fulvestrantff 
 
C1D1, C1D15, and Day 1 of every 
subsequent cycle 
 
 
 
Drug compliancegg 
 
◄--------------------------------------► 
 
 
Adverse eventshh 
◄--------------------------------------► 
 


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Procedures/Assessments 
Screeninga 
Active Treatment Period 
End of 
Treatment 
(EOT)b 
Post-Treatment (PTx) 
Cycle 1c 
Subsequent 
Cyclesc 
 
 
Study Day 
(visit window in days) 
Day -35 
to -1 
Day 1d 
 
Day 15d 
(± 2 d) 
Day 1d 
(±2 d) 
(+14 d; 
within 14 d 
of last dose 
of study 
drug) 
PTx Safety 
Follow-up 
30 days after 
last dose of 
study druge 
(± 3 d) 
PTx 
Follow-up 
every 8 
weekf 
(± 7 d) 
Prior/Concomitant 
medications/treatmentsii 
◄--------------------------------------► 
 
Survival follow-up for subjects 
who discontinue treatmentf 
 
 
 
 
 
X 
a. 
All Screening assessments must be completed within 35 days prior to randomization (all imaging must be completed within 28 days prior to randomization 
unless otherwise specified). All surgical procedures related to breast cancer diagnosis must be recorded. 
b. 
If EOT falls on Day 1 of a cycle and the subject is withdrawing, the EOT assessments are to be completed instead of the Cycle Day 1 assessments. 
Assessments completed within the previous 14 days do not have to be repeated at the EOT visit. 
c. 
A Cycle is 28 days. 
d. 
All assessments are to be performed pre-dose on scheduled visit days unless otherwise indicated. Procedures may be performed ±2 days relative to the visit. 
e. 
Onsite visit preferred; if this is not feasible, telephone contact is acceptable. If follow-up assessments are conducted by telephone, the PROs are to be 
omitted.  
f. 
For subjects who discontinue study treatment due to objective disease progression, survival data and start date and regimen name of the first new anti-cancer 
therapy should be collected every 8 weeks (± 7 days) calculated from the last dose of study drug for the duration of the study. For subjects who discontinue 
treatment for reasons other than disease progression, and who do not begin new anti-cancer therapy, tumor assessments will continue every 8 weeks 
(± 7 days, from the date of randomization), and for subjects with bone lesions at baseline radionuclide bone scan or whole body MRI will be performed 
every 24 weeks (± 7 days), as indicated, until disease progression is documented, or new anti-cancer therapy is initiated; at that time, they will continue to be 
monitored every 8 weeks for survival and first new anti-cancer therapy information for the duration of the study. 
g. 
Informed consent must be obtained prior to any protocol-required assessments (except for certain imaging assessments if they meet the criteria defined in 
Table 20). 
h. 
ER and HER2 status must be confirmed per local laboratory testing. 
i. 
Prior anti-cancer therapy, including drug names, treatment start/end date, dose, setting (neoadjuvant, adjuvant, or recurrent/metastatic line of therapy), best 
response, date of disease progression, and reason for treatment discontinuation, are to be recorded. 


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j. 
Randomization is to occur after eligibility is determined by the study site and and confirmed by the Medical Monitor. The planned first dose of C1D1 is to 
start within 1 day after randomization; randomization may occur on D-1 or on D1. Note: there is no Day 0 in this study. C1D1 is the date of first dose of 
study drug. 
k. 
PRO questionnaires are to be completed by the subject using the electronic tablet provided while in clinic (cannot be taken home) at the beginning of the 
study visit and prior to any other assessments or significant interactions with site staff. PRO questionnaires will be performed on C1D1, C1D15, C2D1, and 
D1 of each subsequent cycle through  C4, then D1 of every other cycle thereafter starting with C6 (ie, C2, C3, C4, C6, C8, C10, etc), at EOT, and at the 
Safety Follow-Up visit (unless this visit is performed via phone contact). Note: If a certified translation for any PRO questionnaire is not available for a 
subject, that specific PRO assessment can be omitted, but the reason must be documented. 
l. 
Physical examination at Screening to include total body examination of general appearance, skin, neck (including thyroid), ears, eyes, nose, throat, lungs, 
heart, abdomen, back, lymph nodes and extremities and a clinical neurological examination. Post-Screening physical examinations may be targeted based on 
findings present at Screening or subject complaints. Significant findings at Screening should be recorded as medical history or AEs as appropriate and 
clinically significant findings at subsequent visits should be recorded as AEs.  
m. 
Vital signs (temperature, respiratory rate, sitting blood pressure, and sitting pulse rate) are to be performed prior to phlebotomy at Screening and at every 
visit. On C1D1 and C1D15, all vital signs are to be assessed pre-dose and blood pressure is to be performed 4 hours (± 30 minutes) post-dose (all subjects) 
and prior to phlebotomy for PK assessment (subjects taking elacestrant). On Day 1 of every subsequent cycle, all vital signs are to be assessed pre-dose. 
n. 
12-lead ECG is to be performed in triplicate, 2 minutes apart, at all time points after the subject has been supine for at least 5 minutes using the Sponsor-
provided ECG equipment. ECGs will be performed pre-dose and 4 hours (± 30 minutes) post-dose on C1D1 and pre-dose and 4 hours (± 30 minutes) post-
dose on C1D15. ECG will be performed pre-dose on C2D1, and each subsequent cycle through cycle 4, then D1 of every other cycle thereafter starting with 
C6 (ie, C6, C8, C10, etc) and at EOT. See Table 19. 
o. 
Not required in women who have undergone bilateral surgical oophorectomy. 
p. 
Urinalysis includes protein, glucose, blood, ketones, nitrites, and leukocyte esterase. Microscopic examination is required only when urinalysis is positive for 
nitrites, leukocyte esterase, protein, or blood. 
q. 
Hematology includes hemoglobin, hematocrit, white blood cell count with differential (including absolute neutrophil count, lymphocyte, monocyte, 
eosinophil, and basophil counts), and platelet count. 
r. 
If performed > 7 days prior to C1D1, must be repeated and eligibility criteria must still be met. 
s. 
Chemistry includes BUN or urea, creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, magnesium, albumin, total protein, total 
bilirubin (direct and indirect if total is > ULN), alkaline phosphatase, ALT, AST, glucose and lipid panel (total cholesterol, LDL, HDL, and triglycerides). If 
possible, the glucose and lipid panel should be performed with the subject in a fasting state. If performed > 7 days prior to C1D1, must be repeated and 
eligibility criteria must still be met. 
t. 
Hemoglobin A1c is to be measured at Screening and EOT. 
u. 
Coagulation tests include PT or INR (per the sites’s standards), aPTT (PTT is allowed if aPTT is not available), and fibrinogen. INR is required at Screening. 
If performed > 7 days prior to C1D1, must be repeated and eligibility criteria must still be met. 
v. 
Diagnostic CT for tumor assessment may be used even if acquired during PET/CT hybrid imaging providing the CT images are of sufficient quality. 
Screening tumor assessments must be performed during the Screening period (Day -28 through Day -1) as noted in Table 20. For subjects who achieve a CR 
or PR, a confirmation scan must be repeated at least 4 weeks after the first documented response. Subjects with history of stable brain metastases should 
have brain CT or MRI imaging in parallel with systemic imaging for evaluation of non-target lesions in the brain; brain CT or MRI scans are not otherwise 
required as part of standard imaging. Color photographs must be taken of any skin lesions that will be followed as either target or non-target lesions. Tumor 
evaluation will be performed at EOT unless an evaluation has been performed within the preceding 28 days or disease progression has already been 
documented per RECIST v1.1. See Table 20. For subjects who discontinue treatment for reasons other than disease progression (clinical PD or PD by 


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RECIST criteria), and who do not begin new anti-cancer therapy, tumor assessments will continue every 8 weeks from the date of randomization until 
documentation of progression or start of new anti-cancer treatment; for these subjects, additional assessments do not need to be performed at the EOT visit. 
w. 
To be completed within 28 days prior to randomization. 
x. 
If bone lesions are identified at baseline (ie, during Screening), bone scans or whole body MRI are to be repeated during the active treatment phase (using 
the same modality used during Screening), every 24 weeks (±7 days), and as clinically indicated, from the date of randomization, and at time of confirmation 
of CR. If no bone lesions are identified at baseline, bone scans or whole body MRI are to be repeated during active treatment phase only when clinically 
indicated and are required at time of confirmation of CR. At EOT, bone scans or whole body MRI are required for subjects with bone lesions identified at 
Screening, unless disease progression has been confirmed elsewhere or a scan has been performed within the last 12 weeks. See Table 20. 
y. 
Suspicious abnormalities (ie, hotspots) identified on bone scan or whole body MRI at baseline and on subsequent bone scans or whole body MRI MUST be 
confirmed. Diagnostic CT of chest and CT (with bone window settings) or MRI of abdomen and pelvis (or PET CT if CT images are of sufficient quality) 
are sufficient for evaluation of bone lesions involving the axial skeleton. Additional imaging of appendicular skeletal lesions (eg, skull, cervical spine, 
extremities) by bone window settings on CT scan or MRI are required if these sites are the only bone lesions to be followed. If a lesion is not confirmed to 
be metastatic by CT with bone windows or MRI, it should not be followed as a target or non-target lesion and it does not require re-assessment. The same 
modality must be used throughout the study for confirmation for a given lesion/subject. Areas that have received palliative radiotherapy should be followed 
as non-target lesions. 
z. 
Blood samples for PK are to be collected at the following time points for subjects randomized to the elacestrant group only: C1D1 and C1D15: 0 h (pre-
dose) and 4 h (± 30 min) post-dose; C2D1: 0 h (pre-dose). Investigators may obtain additional blood samples for PK analysis at the time(s) that significant 
AE or SAEs occur that are considered potentially related to the study drug. See Table 19. 
aa. Blood sample for ctDNA to be collected at Screening, pre-dose on C2D1, pre-dose on C3D1, and at EOT. Four tubes of blood will be drawn at Screening, 
and 2 tubes will be drawn for all other time points (see Guardant’s Whole Blood Sample Collection, Handling, Shipping and Result Instructions for the 
RAD1901-308 (EMERALD) study for Screening ctDNA samples; see Medpace Laboratory Manual for management of on-treatment ctDNA samples) 
bb. All subjects with accessible lesions are requested to provide tumor biopsies; however, these biopsies are optional and are not required for eligibility. For 
subjects agreeing to provide biopsies, biopsies will be taken at 3 time points during the study: pre-treatment, on-treatment, and post-treatment. Pre-treatment 
biopsies should be obtained after progression on the most recent systemic anticancer therapy and should be performed on a metastatic lesion or site of 
recurrent disease, if accessible. Biopsies obtained for other reasons within 3 months of first dose of study treatment that meet these criteria may be submitted 
in lieu of a fresh biopsy. 
cc. On-treatment and post-treatment biopsies are only required if the pre-treatment biopsy was successful (ie, tissue obtained; confirmed to contain adequate 
tumor cells by central laboratory). On-treatment biopsy should be performed between C1D28 and C3D28, as close as feasible to C2D28. Post-treatment 
biopsy should be performed at the time of study drug discontinuation and prior to initiation of new anti-cancer therapy. Biopsies should be taken from the 
same lesion at each time point, when feasible. 
dd. For subjects randomized to elacestrant, elacestrant should be taken at approximately the same time(s) each day on a continuous dosing schedule. However, 
on days of planned clinic visits, subjects should be informed to take their study drug at the study site. Subject is to be instructed to complete a daily dosing 
diary. 
ee. For subjects randomized to SOC, with Investigator selection of AI, AI should be taken at approximately the same time(s) each day on a continuous dosing 
schedule. However, on days of planned clinic visits, subjects should be informed to take their study drug at the study site. Subject is to be instructed to 
complete a daily dosing diary. 
ff. 
For subjects randomized to SOC, with Investigator selection of fulvestrant, fulvestrant dose (500 mg) is to be administered IM slowly (1-2 minutes per 
injection) divided as two 5-mL injections into gluteal area (one in each buttock) on C1D1, C1D15 and Day 1 of each subsequent cycle. 


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gg. Elacestrant or AI bottle(s) or blisters, including any unused capsules/tablets, are to be returned to clinic for drug accountability. Drug accountability is to be 
performed on Day 1 of every cycle. Dose, date and time of fulvestrant administration must be documented in both medical record and electronic Case Report 
Form. 
hh. All AEs are to be recorded from time of signed informed consent until 30 days after last dose of study drug. At any time after 30 days from the last dose of 
study treatment, the Investigator may report any SAE that he/she believes is related to study treatment.  
ii. 
All prior medications and concomitant medications (including oral, topical, intravaginal, rectal, and inhaled over-the-counter medications, herbal treatments, 
supplements, vitamins, or any substance use) and medical treatments taken from 35 days prior to signing informed consent until 30 days after the last dose of 
study drug are to be recorded. 
AI = aromatase inhibitor; C1D1 = Cycle 1 Day 1; CR = complete response; CT = computed tomography; ctDNA = circulating tumor DNA; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire-Core 30; EOT = End of Treatment; EQ-5D-5L = EuroQol 5 dimension 5 level; ER = estrogen receptor; FSH = follicle stimulating 
hormone; HER2 = human epidermal growth factor receptor 2; MRI = magnetic resonance image; PK = pharmacokinetics; PR = partial response; PRO = patient-
reported outcome; PRO-CTCAE = Patient Reported Outcome-Common Terminology Criteria for Adverse Events; PTx = Post-treatment; RECIST = Response 
Evaluation Criteria in Solid Tumors; ULN = upper limit of normal. 
 


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Table 19: 
Pharmacokinetics, Vital Signs, and ECG Schedule of Events Relative to Elacestrant and SOC Dosing 
 
Screening 
 
Active Treatment Phase 
Post-
Treatment 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and 
every other 
cycle 
thereafter 
(ie, 4, 6, 8 
etc.) 
EOT 
Protocol Activity 
Day -35 to Day -1 
Day 1 
Day 15 
Day 1 
Day 1 
Day 1 
 
 
Pre-dose 
0 Hrs 
Post-dose 
4 Hrs 
(± 30 min) 
Pre-dose 
0 Hrs 
Post-dose 
4 Hrs  
(± 30 min) 
Pre-dose 
0 Hrs 
Pre-dose 
0 Hrs 
Pre-dose 
0 Hrs 
 
Pulse Rate, 
Respiratory Rate, 
Temperature 
X 
X 
 
X 
 
X 
X 
X 
X 
Blood Pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 12-lead 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics  
 
X 
X 
X 
X 
X  
 
 
 
Notes: 
The following sequence should be followed: (1) vital sign assessment, (2) ECG recording, and (3) PK blood sampling. 
Vital signs are to be collected at every cycle. 
PK assessments only to be performed for subjects randomized to elacestrant; ECG and vital sign assessments to be performed for all subjects. 
All ECGs will be performed using the Sponsor-provided ECG equipment and sent electronically to a central ECG laboratory. A 12-lead ECG will be performed 
in triplicate, 2 minutes apart, at all protocol defined time points after the subject has been supine for at least 5 minutes as per the ECG Manual. Additional ECGs 
may be performed as clinically indicated. ECGs for eligibility will be performed during the Screening period for all subjects, to determine the mean QTc interval 
for eligibility purposes. ECGs should be performed immediately before PK blood draws.  
Study treatment should be administered immediately after the Day 1 and Day 15 pre-dose sample for PK has been collected (preferably within 30 minutes). 
Additional PK blood samples may be collected in subjects experiencing unexpected or SAEs, or AEs that lead to discontinuation. 


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Table 20: 
Tumor Assessment Requirements Flowchart 
Procedure 
Screeninga 
(Day -28 to Day -1) 
Treatment Periodb 
End of Treatment 
(EOT)c 
Post-Treatment Follow-upc 
(for subjects who have 
discontinued study drug for 
reasons other than PD and 
who have not yet started new 
anti-cancer therapy) 
CT of chest and CT or 
MRI of abdomen and 
pelvisd 
Requirede 
Required 
Required 
Required 
CTd or MRI of any other 
site of disease, as 
clinically indicated 
Requirede,f 
Required for sites in 
which disease identified at 
Screening and if new 
metastases clinically 
suspected 
Required for sites in 
which disease 
identified at 
Screening and if new 
metastases clinically 
suspected 
Required for sites in which 
disease identified at Screening 
and if new metastases clinically 
suspected 
Radionuclide bone scan or 
whole body MRI 
Requiredg 
Required for subjects in 
which disease identified at 
Screening, if clinically 
indicated, and in all 
subjects with CRh 
Required for subjects 
in which disease 
identified at 
Screening or if 
clinically indicatedh 
Required for subjects in which 
disease identified at Screening 
or if clinically indicatedh 
Evaluation of abnormal 
bone scan or whole body 
MRIi 
Required 
Required for sites in 
which disease identified 
by bone scan or whole 
body MRIj 
Required for sites in 
which disease 
identified by bone 
scan or whole body 
MRIj 
Required for sites in which 
disease identified by bone scan 
or whole body MRIj 
Color photographs of all 
superficial lesions as 
applicablek 
Required 
Required for sites in 
which disease identified at 
Screening 
Required for sites in 
which disease 
identified at 
Screening 
Required for sites in which 
disease identified at Screening 
Note: Radiographic tumor assessments may be done at any time if there is clinical suspicion of disease progression at the discretion of the Investigator. If 
progressive disease is confirmed per RECIST v1.1, subjects are expected to discontinue study therapy and begin the follow-up phase of the trial. For subjects 
who achieve a CR or PR, confirmatory scans, including bone scan or whole body MRI, as applicable, must be repeated at least 4 weeks after first documentation 
of CR or PR. 


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a Screening scans must occur within 28 days prior to randomization unless otherwise specified. 
b Tumor assessment by CT and/or MRI (or PET CT if CT images are of sufficient quality), including bone lesions followed as non-target lesions, and assessment 
of superficial lesions by photography, must be done during the treatment period every 8 weeks ( 7 days), and in subjects with baseline bone lesions, bone scans 
or whole body MRI (as applicable) every 24 weeks ( 7 days), from randomization until radiographically and/or clinically (ie, for photographed or palpable 
lesions) documented PD as per RECIST v1.1, initiation of new anti-cancer therapy, or discontinuation of subject from overall study participation (eg, death, 
subject's request, lost to follow up), whichever occurs first. The tumor assessment schedule should be fixed from the date of randomization, according to the 
Schedule of Events, regardless of treatment delays/interruptions. Imaging assessment delay to conform to treatment delay is not permitted. Imaging assessments 
are to be scheduled using the randomization date as the reference date for all time points and are NOT to be scheduled based on the date of the previous imaging 
time point. The same tumor assessment technique MUST be used throughout the study for a given lesion/subject. 
c Subjects who have already demonstrated objective disease progression as per RECIST v1.1 do not need to have scans repeated at the end of treatment visit or 
during the post-treatment follow-up. For subjects who do not have documented objective disease progression at time of study treatment discontinuation, tumor 
assessment will continue to be performed every 8 weeks ( 7 days), and bone scans or whole body MRI (as applicable) every 24 weeks ( 7 days) until 
radiographically and/or clinically confirmed objective disease progression, initiation of first new anti-cancer therapy, or discontinuation of subject from overall 
study participation (eg, death, subject's request, lost to follow-up).  
d CT scans, including brain CT scan if applicable, should be performed with contrast agents unless contraindicated for medical reasons. If IV contrast is 
medically contraindicated, the imaging modality to be used to follow the disease (either CT without contrast or MRI) should be the modality which best evaluates 
the disease, and the choice should be determined by the Investigator in conjunction with the local radiologist per RECIST v1.1. MRI of the abdomen and pelvis 
can be substituted for CT if MRI adequately depicts the disease. However, MRI of the chest should not be substituted for CT of chest even if IV contrast is 
contraindicated. In such cases, CT will be performed without contrast. MRI of the chest should only be performed in extenuating circumstances. If MRI is used 
to follow bone lesion(s), it must be performed a few days before any treatment that may affect bone marrow cellularity (eg, G-CSF). Diagnostic CT for tumor 
assessment may be used even if acquired during PET/CT hybrid imaging providing the CT images are of sufficient quality. 
e Radiographic assessments obtained per the subject’s standard of care prior to randomization into the study do not need to be repeated and are acceptable to use 
as baseline evaluations if: (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 subject, and (4) appropriate documentation indicating 
that these radiographic tumor assessments were performed as standard of care is available in the subject’s source notes. 
f Baseline brain CT or MRI scans are only required if signs and symptoms suggest presence of metastatic brain disease and for subjects with a history of stable 
brain metastases. Brain CT or MRI 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 baseline 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 subject (3) appropriate documentation indicating that these 
radiographic tumor assessments were performed as standard of care is available in the subject’s source notes. Post-baseline brain CT or MRI scans in subjects 
without documented lesions at baseline will only be required if metastases are suspected.  
g Bone scans or whole body MRI will be carried out at baseline (ie, during Screening) for all subjects within 12 weeks prior to randomization in order to detect 
bone metastases. 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 baseline 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 subject (3) appropriate documentation confirming that these 
radiographic tumor assessments were performed as standard of care is available in the subject’s source notes. 
h If bone lesions were identified on baseline bone scan or whole body MRI (regardless of whether these lesions were confirmed by CT scan with bone windows 
or MRI to be metastatic), these scans will be repeated during the active treatment phase (using the same modality as used during Screening) as clinically 
indicated and every 24 weeks ( 7 days) from the date of randomization and at the time of confirmation of CR. If no bone lesions were identified at baseline, 
bone scan or whole body MRI will only be repeated during the active treatment phase when clinically indicated (ie, subject describes new or worsening bone 


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pain, or has increasing alkaline phosphatase level, or other signs and symptoms of new/progressing bone metastases), but is required at the time of confirmation 
of a CR. 
i Suspicious abnormalities (ie, hotspots) identified on bone scan or whole body MRI at baseline and on subsequent bone scans or whole body MRI MUST be 
confirmed. Diagnostic CT of chest and CT (with bone window settings) or MRI of abdomen and pelvis (or PET CT if CT images are of sufficient quality) are 
sufficient for evaluation of bone lesions involving the axial skeleton. Additional imaging of appendicular skeletal lesions (eg, skull, cervical spine, extremities) 
by bone window settings on CT scan or MRI are required if these sites are the only bone lesions to be followed. If a lesion is not confirmed to be metastatic by 
CT with bone windows or MRI, it should not be followed as a target or non-target lesion and it does not require re-assessment. The same modality must be used 
throughout the study for confirmation for a given lesion/subject. Areas that have received palliative radiotherapy should be followed as non-target lesions.  
j Bone lesions confirmed by CT or MRI (or PET CT when CT images are of sufficient quality) at baseline, and documented as target (when a measurable soft 
tissue component is present)  and/or non-target lesions will be assessed every 8 weeks (± 7 days) using the required CT of chest and CT or MRI of abdomen and 
pelvis (or PET CT when PET CT was used at baseline) and additional imaging by bone window settings on CT scan or MRI of any appendicular bone lesions 
that are being followed as a target and/or non-target lesions. New abnormalities found on subsequent bone scan or whole body MRI must be confirmed by bone 
window settings on CT scan or MRI. At EOT, bone scan or whole body MRI is required if abnormalities were identified at Screening, unless disease progression 
has been confirmed elsewhere or a scan has been performed within the last 12 weeks 
k Clinical assessment of superficial disease must be carried out within the same +/- 7-day window applied to imaging studies and any other modalities which are 
part of the tumor evaluation by RECIST v1.1. and will include photographs with measurement markers of all superficial metastatic lesions. 
CR = complete response; CT = computed tomography; EOT = end of treatment; MRI = magnetic resonance image; PD = progressive disease; PR = partial 
response; RECIST = Response Evaluation Criteria in Solid Tumors. 


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APPENDIX 3. ECOG PERFORMANCE STATUS 
Grade Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (eg, light housework, office work) 
2 
In bed <50% of the time 
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 
In bed >50% of the time 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 
NOTE: From https://training.seer.cancer.gov/followup/procedures/dataset/ecog.html 


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APPENDIX 4. COCKCROFT-GAULT FORMULA 
To determine eligibility for the study, Investigators may calculate a subject’s creatinine clearance 
(CrCL) by the Cockcroft-Gault formula as follows [Cockcroft and Gault, 1976]: 
Creatinine when reported in mg/dL: 
 
CrCL for females (mL/min)   =   
0.85 × (140 - age [years]) × (weight [kg]) 
72 × (serum creatinine [mg/dL]) 
 
CrCL for males (mL/min)   =  
(140 - age [years]) × (weight [kg]) 
                                                        72 × (serum creatinine [mg/dL]) 
 
 
 
 
Creatinine when reported in International System of Units (SI): 
 
CrCL for females (mL/min)   =   
(140 - age [years]) × (weight [kg]) × 1.04 
(serum creatinine [umol/L]) 
 
CrCL for males (mL/min)   =  
(140 - age [years]) × (weight [kg]) × 1.23 
(serum creatinine [umol/L]) 
 
 
 


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APPENDIX 5. NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
NCI-CTCAE V 5.0 
NCI-CTC Version 5.0 reference, accessible through the NCI website at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf 
Toxicity grade should reflect the most severe degree occurring during the evaluated period, not 
an average. When 2 criteria are available for similar toxicities, the one resulting in the more 
severe grade should be used. The evaluator must attempt to discriminate between 
disease/treatment and related signs/symptoms. An accurate baseline prior to therapy is essential. 


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APPENDIX 6. NEW YORK HEART ASSOCIATION GUIDELINES 
The New York Heart Association Functional Classification provides a simple way of classifying 
the extent of heart failure [The Criteria Committee of the New York Heart Association, 1994]. It 
places subjects in one of 4 categories based on the level of limitation experienced during 
physical activity: 
Functional Capacity 
Objective Assessment 
Class I: Subjects with cardiac disease, but without resulting 
limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or anginal pain. 
A: No objective evidence of 
cardiovascular disease. 
 
Class II: Subjects with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitation, dyspnea, 
or anginal pain. 
B: Objective evidence of minimal 
cardiovascular disease. 
 
Class III: Subjects with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. Less 
than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
C: Objective evidence of 
moderately severe cardiovascular 
disease. 
 
Class IV: Subjects with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased. 
D: Objective evidence of severe 
cardiovascular disease. 
 
 


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APPENDIX 7. CHILD-PUGH ASSESSMENT OF HEPATIC FUNCTION 
 
Points Scored for Observed Findings 
Parameter 
1 
2 
3 
Hepatic encephalopathy gradea 
0 
1 or 2b 
3 or 4b 
Ascitesc 
Absent 
Slight 
Moderate 
Serum bilirubin (mg/dL) 
<2 
≥2 to ≤3 
>3 
Serum albumin (g/dL) 
>3.5 
≥2.8 to ≤3.5 
<2.8 
International normalized ratio 
<1.7 
≥1.7 to ≤2.3 
>2.3 
a Grade 0: normal consciousness, personality, neurological examination, or electroencephalogram. 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, or 5 cycles per second (cps) 
waves. 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, or slow triphasic waves. 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, or slower waves. 
Grade 4: unarousable coma, no personality/behavior, decerebrate, or slow 2 to 3 cps delta activity. 
b A subject with hepatic encephalopathy of Grade 2 or above would not be admitted into the study. 
c Absent: No ascites is detectable by manual examination or by ultrasound investigation, if ultrasound investigation 
is performed. 
Slight: Ascites palpation doubtful, but ascites measurable by ultrasound investigation, if performed. 
Moderate: Ascites detectable by palpation and by ultrasound investigation, if performed. 
Severe: Necessity of paracentesis; does not respond to medication treatment. Subject would not be admitted into 
the study. 
 
Class A 
Class B 
Class C 
Total points 
5-6 
7-9 
10-15 
Source: https://www.mdcalc.com/child-pugh-score-cirrhosis-mortality 


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APPENDIX 8. MEDICATIONS AND FOODS THAT ARE MODERATE 
OR STRONG INDUCERS OR INHIBITORS OF CYP3A4/5 
CYP3A4/5 Moderate or Strong Inducers 
CYP3A4/5 Moderate or Strong 
inhibitors 
Apalutamide 
Bosentan 
Carbamazepine 
Enzalutamide 
Etravirine 
Mitotane 
Phenobarbital 
Phenytoin 
Primidone 
Rifampin 
St. John’s Wort 
 
Aprepitant 
Boceprevir 
Ciprofloxacin 
Cobicistat 
Conivaptan 
Crizotinib 
Cyclosporine 
Diltiazim 
Dronedarone 
Eruthromycin 
Fluconazole 
Fluvoxamine 
Grapefruita 
Imatinib 
Itraconazole 
Ketoconazole 
Pomeloa 
Posaconazole 
Ritonavir (alone or with danoprevir, 
dasabuvir, elvitegravir, indinavir, 
lopinavir, paritaprevir, ombitsavir, 
saquinavir, tipranavir) 
Seville Orangea 
Star Fruita 
Telaprevir 
Telithromycin 
Tofisopam 
Troleandomycin 
Verapimil 
Voriconazole 
aNote: Subjects should avoid consumption of the following fruits, and juices and products derived from them: 
grapefruit, pomelo, Seville orange and Star Fruit 
Source: Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm 
 


Signature Page for RAD-CLIN-000990 v6.0
Signature Page for RAD-CLIN-000990 v6.0
Approval
Maureen Conlan
Clinical
25-Mar-2020 21:27:29 GMT+0000
Approval
Miriam Annett
Biometrics
26-Mar-2020 14:54:30 GMT+0000
Approval
Maryann Toto
Regulatory
26-Mar-2020 16:15:40 GMT+0000