Changing the Scenery in ER+, HER2- MBC With New Oral SERDs and Combinations: Foundations, Evidence, and Practicalities

Chair and Presenter, Komal Jhaveri, MD, FACP, Prof. Giuseppe Curigliano, MD, PhD, Professor Stephen Johnston, MA, FRCP, PhD, and Joyce O'Shaughnessy, MD, prepared useful Practice Aids pertaining to breast cancer for this CME/MOC/NCPD/CPE/AAPA/IPCE activity titled “Changing the Scenery in ER+, HER2- MBC With New Oral SERDs and Combinations: Foundations, Evidence, and Practicalities.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/CPE/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3F97VZE. CME/MOC/NCPD/CPE/AAPA/IPCE credit will be available until September 24, 2026.

1. Exploring Options Based on Recent Advances:
Potential Treatment Algorithm for ER+, HER2- MBC
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/XYR40
Adjuvant ET Genomics 1L Treatment Genomics 2L Treatment 3L+ Treatment
None, Tam,
Remote AI
AI
WT
WT
WT
WT
Other ET
Revisit priors
Chemo/ADC
Other ET
Revisit priors
Chemo/ADC
Imlun + abema
Fulv + PI3Ki/AKTi
ESR1m
ESR1m
ESR1m
ESR1m
AI + CDK4/6i
Fulv + CDK4/6i
Imlun + abema
Fulv + CDK4/6i
Fulv + inavo + palbo
PIK3CA/AKT
PIK3CA/AKT
PIK3CA/AKT
PIK3CA/AKT
Imlun + abema
Fulv ± abema
Fulv ± everol
Imlun + abema
Elacestrant
Imlunestrant
Vepdegestrant
Imlun + abema
Elacestrant
Imlunestrant
Vepdegestrant
Fulv + capi
Fulv + alpel
Imlun + abema
Imlun + abema
Fulv ± abema
Fulv ± everol
Fulv + capi
Fulv + alpel
Imlun + abema
Caveats: This proposed algorithm includes investigational therapies not currently approved by regulatory agencies and is intended only as a
forward-looking visualization of where novel oral SERD-based treatment options may fit within the context of standard therapies based on phase 3 data.
1. Adapted from: Burstein H. SABCS 2024. Abstract GS1-02.
Fulv + CDK4/6i
Imlun + abema
Imlunestrant
ctDNA-guided
switch to
camizestrant
+ CDK4/6i?
AI + CDK4/6i

2. Overview of the Standard and Emerging ER-Targeted
Therapies for ER+, HER2- MBC
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/XYR40
Limitations of Standard ETs and Implications for Tumor Evolution
1
AI, tamoxifen, fulvestrant
•Toxicity challenges
•Nonadherence is an issue due to toxicity
Tamoxifen
•Weaker ER suppression
Fulvestrant
•Poor PK
•Poor oral bioavailability necessitates IM
administration  limits dose and 
dose-dependent efcacy
•IM injections can be painful, burdensome, 
and require in-ofce administration; 
patients often prefer oral options
•Modest efcacy post-CDK4/6i
•Activity limited in presence of ESR1 mutations
ER+ MBC
Treatment
Evolution over time on treatment
AI-resistant, 
ERα-dependent tumors
Treat with
next-generation 
anti-ERα therapies
(eg, oral SERDs)
FOXA1-MYC- 
CTCF–altered 
tumors
ERα dependencies
remain unclear;
further research
needed
HER2-EGFR- 
NF1–altered 
tumors
Treat with
anti-HER2 
or MAPK 
therapies
Lineage 
plastic 
tumors
Functional
dependencies
remain unclear;
further research needed
Therapies apply
selective pressure
on tumors and
promote evolution
Loss of ERα
dependence
Gain of RTK
or MAPK 
activity
Loss of ERα and
luminal lineage
factors
Transcription 
factor alterations
Retain dependency
on ERα activity

3. Overview of the Standard and Emerging ER-Targeted
Therapies for ER+, HER2- MBC
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/XYR401. Will M et al. Nat Rev Cancer. 2023;23:673-685. 2. McDonnell DP et al. J Clin Oncol. 2021;39:1383-1388. 3. Ferraro E et al. Cancer Treat Rev. 2022;109:102432.
SERCA (covalent link
inducing inactive
conformation)
ERα dimers
ERα dimers
ER3 
ligase
ESR1
ESR1
Increased
degradation
Dimerization
translocation
C530 link
Decreased
dimerization
translocation
Decreased
dimerization
translocation
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Nucleus
Increased
degradation
Increased
degradation
COA  COA
ERE
ERE
ERE
ERE
CytosolPlasma
ERE
ERE
Tamoxifen
Bazedoxifene
Lasofoxifene
Estrogen
Oral SERD
(conformation change
of ERα)
CERAN
(ligand-binding
domain link)
Fulvestrant
PROTAC
High afnity
Low afnity
Inhibition
Ubiquitin
SERMS
u
u
u
u
u
u
SERM Activity
SERD Activity
Fulvestrant
Elacestrant
Imlunestrant
Giredestrant
Amcenestrant
Camizestrant
Rintodestrant
D-0502
Zb-716
ZN-c5
SHR9549
LSZ102
GDC0810
GDC0927
AZD9496
Vepdegestrant (PROTAC)
OP-1250 (CERAN)
Bazedoxifene Raloxifene
Lasofoxifene
Tamoxifen
Toremifene
H3B-6545 (SERCA)
Green: approved for distinct indications
Blue: currently in clinical development
Orange: clinical development discontinued
Oral SERDs
Ultimate goal:
Downregulate 
ERα with an 
agent that has
an optimal 
therapeutic 
index and 
improved 
efcacy
Numerous
Novel
Endocrine
Agents Under
Investigation
2,3

4. Select Ongoing Clinical Trials of Oral SERDs in
HR+, HER2- Breast Cancer
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/XYR40 Ongoing Trials
Trial Name
ADELA
pionERA
evERA
persevERA
SERENA-4
Treatment Arm
Elacestrant +
everolimus
Giredestrant +
CDK4/6i
Giredestrant +
everolimus
Giredestrant +
palbociclib +
letrozole-matched
PLA
Camizestrant +
palbociclib +
anastrozole-matched
PLA
Elacestrant + placebo
Fulvestrant + CDK4/6i
PCET + everolimus
Letrozole + palbociclib
+ giredestrant-matched
PLA
Anastrozole + palbociclib
+ camizestrant-matched
PLA
BICR-PFS
PFS by the investigator in
ESR1m population and
the full analysis set
PFS by the investigator
in ITT and ESR1m
PFS
PFS
NCT06382948
NCT06065748
NCT05306340
NCT04546009
NCT04711252
Control Arm Primary Endpoint NCT #
1L ORAL SERDs
IN MBC
COMBINATION
THERAPY IN
MBC

5. Select Ongoing Clinical Trials of Oral SERDs in
HR+, HER2- Breast Cancer
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/XYR40 1. https://clinicaltrials.gov/.
Ongoing Trials, Cont’d
Trial Name
TREAT ctDNA
CAMBRIA 1
Treatment Arm
Elacestrant
Camizestrant (5 y)
Tamoxifen, anastrozole
exemestane, letrozole
Tamoxifen, anastrozole
exemestane, letrozole
DMFS
IBCFS
NCT05512364
NCT05774951
CAMBRIA 2
Camizestrant (7 y) ±
abemaciclib (2 y)
PCET (7 y): tamoxifen,
anastrozole, exemestane
or letrozole ± abemaciclib
IBCFS NCT05952557
lidERA
Giredestrant (5 y)
Substudy:
Giredestrant (5 y) +
abemaciclib (2 y)
At least 5 y:
tamoxifen, anastrozole,
exemestane, letrozole
IDFS NCT04961996
EMBER-4 Imlunestrant
Tamoxifen, anastrozole
exemestane, letrozole
IDFS NCT05514054
Control Arm Primary Endpoint NCT #
ORAL SERDs IN
EARLY BC

6. METAvivor: A Resource for Patients,
Care Partners, and Care Providers
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/XYR40
METAvivor exists to sustain hope for those living 
with stage 4 metastatic breast cancer (MBC) and is 
a volunteer-driven, nonproft organization that funds
vital research to help improve the longevity and
quality of life for patients with MBC. 
Scan for more information or visit
www.METAvivor.org
Support Advocacy
Makes every dollar count
as they work with 
researchers to extend and
improve quality of life for
patients with MBC
Helps patients fnd
strength through support
and purpose
Rallies public attention to
the urgent needs of the
MBC community
Research
Resources and Guidance
Collaborate on clinical 
trials and research-funded  
projects through METAvivor 
grants—particularly those 
targeting quality-of-life 
improvements and
survival outcomes
Refer patients and
care partners to 
METAvivor’s peer-to-peer 
support and MBC PREP 
educational portal for 
personalized support
Encourage advocacy 
involvement, especially in 
legislative campaigns like 
the Metastatic Breast 
Cancer Access to Care Act 
and Cancer Drug Parity Act 
to enhance care equity
Physician Engagement Opportunities