The document discusses selective estrogen receptor degraders (SERDs) for the treatment of HR+/HER2- breast cancer. It provides background on HR+/HER2- breast cancer and how SERDs work as a novel class of anti-estrogen drugs that degrade the estrogen receptor. Several key SERDs in clinical development are discussed, including elacestrant by Radius Pharmaceuticals and AZD9833 by AstraZeneca. Clinical strategies being evaluated for SERDs include combinations with CDK4/6 inhibitors and mTOR inhibitors. Many ongoing clinical trials are in phases 2 and 3, focusing on SERDs for the first and second line of therapy against breast cancer.
2. Table of Contents
❖ Executive Summary
❖ What is HR+/HER2- Breast Cancer
❖ What is SERD’s
❖ SERD’s Mechanism of action relative to HR+/HER2- Breast Cancer
❖ Why are SERD’s important
❖ SERD’s Role And Where Are They Best Positioned In The Treatment Paradigm
❖ Clinical Landscape
❖ Clinical Strategies Are Being Evaluated For SERDs
❖ Key SERD’s In Clinical Development
❖ Key Insight
3. Executive Summary
Key Players
Key Insight
Clinical Trial Focus
• G1 Therapeutics
• Sanofi
• Zeno Alpha
• Novartis
• AstraZeneca
• Radius Pharmaceuticals
• Hoffmann-La Roche
• Borstkanker Onderzoek Groep
• In coming years Roche,
Radius, and Borstkanker are
going to capture the market of
SERDs (Selective Estrogen
Receptor Degrader) in
HR+/HER2- Breast Cancer.
SERD’s in
HR+/HER2- Breast
Cancer
• All the clinical trial are focused on
1st and 2nd line of therapy. Some of
the players are also exploring the
3rd line of therapy.
• Combination therapies
are focused by
industry players.
4. What is HR+/HER2- Breast Cancer
• Breast cancer is a type of cancer that starts in the breast. Cancer starts when cells begin to grow out of control.
• Breast cancer cells taken out during a biopsy or surgery will be tested to see if they have certain proteins that are
estrogen or progesterone receptors.
• The hormones estrogen and progesterone attach to these receptors, they fuel the cancer growth.
• Cancers are called hormone receptor-positive or hormone receptor-negative based on whether or not they have these
receptors (proteins).
HER2-negative:
• HER2 is short for human epidermal
growth factor receptor 2.
• HER2 is sometimes called ERBB2,
which stands for Erb-B2 receptor
tyrosine kinase 2.
• HER2 is a gene that produces HER2
proteins, or receptors.
HR+:
• HR is short for hormone receptor. Breast
tumors are tested for both estrogen
receptors (ER) and progesterone receptors
(PR).
• These breast cancers can be treated with
hormone therapy drugs that lower estrogen
levels or block estrogen receptors.
Source: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-hormone-receptor-status.html,
https://www.healthline.com/health/breast-cancer/understanding-managing/understanding-hr-breast-cancer-diagnosis#What-HER2-negative-means
5. What is SERD’s
• SERD’s - Selective estrogen receptor degrader OR Selective estrogen receptor
downregulators.
• SERD’s are pure anti-estrogens.
• A novel class of compounds capable of reducing the ERα protein level and blocking ER
activity.
• SERDs are considered as a significant therapeutic approach to treat ER+ breast cancer in
both early stage and more advanced drug-resistant cases.
• SERD for the treatment of breast cancer in patients who have progressed on antihormonal
agents, several molecules with diverse chemical structures have been rapidly developed,
studied and evaluated for selective estrogen receptor downregulation activity.
• Fulvestrant is a first-generation SERD approved by FDA, indicated for
metastatic/advanced HR+ breast cancer.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508469/, https://www.x-mol.com/paper/1236082111706546176
6. SERD’s Mechanism of action relative to HR+/HER2- Breast Cancer
Source: https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2095, https://www.clinical-breast-cancer.com/article/S1526-8209(11)70479-
7/fulltext#:~:text=When%20fulvestrant%20binds%20to%20estrogen,results%20in%20pure%20antiestrogenic%20effects.
SERD’s mechanism of action:
• Binds ER to prevent estrogen binding its receptor thereby inhibiting ER signaling.
• Degrades ER.
SERD’s (fulvestrant):
• Binds to estrogen receptor monomers it inhibits receptor dimerization, activating function 1 (AF1) and AF2
are rendered inactive, translocation of receptor to the nucleus is reduced, and degradation of the estrogen
receptor is accelerated. This results in pure antiestrogenic effects.
Figure: Representation of the action of fulvestrant. AF1, activation function 1; AF2, activation function 2; ER, estrogen receptor;
ERE, estrogen receptor response element; F, fulvestrant; RNA POL II, ribonucleic acid polymerase II.
7. Why are SERD’s important
Source: https://www.nature.com/articles/s41416-018-0354-9#:~:text=Background,bioavailability%20are%20major%20clinical%20limitations.,
Raising the need for a novel oral SERD
with a more favorable bioavailability profile.
SERD’s inhibits receptors
dimerization.
SERD’s is a potent anti-oestrogen that antagonises
and degrades ER with anti-tumour activity in both
endocrine-sensitive and endocrine-resistant models.
8. SERD’s Role And Where Are They Best Positioned In The Treatment Paradigm
Source: https://pubmed.ncbi.nlm.nih.gov/31562570/
SERD approved by the FDA
as a drug for the treatment
of breast cancer, and
several non-steroidal
molecules such as RAD-
1901, AZD-9496 and GDC-
0927 etc.
SERD’s work as first- or second-
line use as a single agent or in
combination with cyclin dependent
kinase or phosphatidylinositol 3-
kinase inhibitors for the treatment
of metastatic breast cancer.
SERDs emerged as one of the
possible approaches to treat drug-
resistant breast cancer.
SERD’s act as a pure antagonist by
interfering with the binding of estradiol to
estrogen receptors (ERs) and inducing
the rapid downregulation of ER.
12. Clinical Landscape
Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul
ator&cntry=&state=&city=&dist=
NCT Number Title Status Conditions Interventions Phases Enrollment
Line of
Therapy
Sponsor/Col
laborators
NCT03455270
G1T48, an Oral SERD,
Alone and in Combination
With Palbociclib in ER-
Positive, HER2-Negative
Advanced Breast Cancer
Recruiting
Carcinoma, Ductal,
Breast|Breast Cancer
Female|Breast
Neoplasm|Breast
Cancer|Metastatic Breast
Cancer|Advanced Breast
Cancer|Stage IV Breast
Cancer
Drug:
G1T48|Drug:
Palbociclib
Phase 1 184
1st line
therapy
G1 Therapeutics,
Inc.
NCT03560531
Drug: ZN-c5|Drug:
Palbociclib
Recruiting Breast Cancer
Drug: ZN-
c5|Drug:
Palbociclib
Phase
1|Phase
2
458
2nd line
therapy
Zeno Alpha Inc.
NCT02734615
Phase I/Ib Trial of
LSZ102 Single Agent or
LSZ102 + LEE011 or
LSZ102 + BYL719 in ER+
Breast Cancers
Active,
not
recruiting
Advanced or Metastatic
ER+ Breast Cancer
Drug:
LSZ102|Drug:
LEE011|Drug:
BYL719
Phase 1 200
2nd line
therapy
Novartis
4/6
14. Clinical Landscape
Source:https://www.clinicaltrials.gov/ct2/results?recrs=&cond=&term=SERD+OR+selective+estrogen+receptor+degrader+OR+selective+estrogen+receptor+downregul
ator&cntry=&state=&city=&dist=
NCT Number Title Status Conditions Interventions Phases Enrollment
Line of
Therapy
Sponsor/Col
laborators
NCT03778931
Phase 3 Trial of Elacestrant
vs. Standard of Care for the
Treatment of Patients With
ER+/HER2- Advanced
Breast Cancer
Active,
not
recruiting
Breast Cancer
Drug:
Elacestrant|Drug:
Standard of Care
Phase 3 466
2nd
line
therapy
Radius
Pharmaceuticals,
Inc.
NCT04546009
A Study Evaluating the
Efficacy and Safety of
GDC-9545 Combined With
Palbociclib Compared With
Letrozole Combined With
Palbociclib in Participants
With Estrogen Receptor-
Positive, HER2-Negative
Locally Advanced or
Metastatic Breast Cancer
Recruitin
g
Estrogen Receptor-
Positive, HER2-
Negative Locally
Advanced or
Metastatic Breast
Cancer
Drug: GDC-
9545|Drug: GDC-
9545-matched
Placebo|Drug:
Letrozole|Drug:
Letrozole-matched
Placebo|Drug:
Palbociclib|Drug:
LHRH Agonist
Phase 3 978
1st line
therapy
Hoffmann-La
Roche
NCT03425838
Endocrine Therapy Plus
CDK4/6 in First or Second
Line for Hormone (SONIA)
Receptor Positive
Advanced Breast Cancer
Recruitin
g
Breast Neoplasm
Female
Drug: CDK 4/6
inhibitor|Drug:
Non-Steroidal
Aromatase
Inhibitor|Drug:
Fulvestrant
Phase 3 1050
1st or
2nd line
therapy
Borstkanker
Onderzoek Groep
6/6
15. Clinical Strategies Are Being Evaluated For SERDs
Source: https://www.precisiononcologynews.com/cancer/eli-lilly-zentalis-pharma-partner-study-selective-estrogen-receptor-degrader-verzenio-combo#.X7aJC2gzZPY,
https://onlinelibrary.wiley.com/doi/full/10.1002/cam4.2095
• The combination with mTOR inhibitor,
everolimus, and CDK 4/6 inhibitors
(abemaciclib, palbociclib, and ribociclib) are
noted as emerging therapy for patients with
HR+/HER2− BC.
• For Instances, In July 2020, Zentalis
Pharmaceuticals collaborated with Eli Lilly to
evaluate Zentalis' ZN-c5, an investigational
oral selective estrogen receptor degrader
(SERD), in combination with Lilly's CDK4/6
inhibitor abemaciclib (Verzenio), in patients
with estrogen receptor-positive, HER2-
negative, advanced breast cancer. Zentalis is
responsible for conducting the study involving
the combination therapy. Lilly will provide all
required doses of abemaciclib, and Zentalis
will maintain full ownership of ZN-c5.
• Monotherapy is successful in treating majority of
patients with HR+/HER2− BC. Treating the patient
suffering from postmenopausal women with ER+,
advanced or metastatic BC, either for disease
relapse, on or after adjuvant antiestrogen therapy
or for disease progression following endocrine
therapy.
• In SERD’s studies by industry players and
other players (academic, individual) are
focusing on monotherapy and in
combination both.
16. Key SERD’s In Clinical Development
Source: https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.1070, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/giredestrant,
https://adisinsight.springer.com/drugs/800050643, https://www.futuremedicine.com/doi/full/10.2217/fon-2019-0370
Sponsor/Co
llaborators
NCT Number Title Conditions Interventions Type Analysis
Radius
Pharmaceuticals,
Inc.
NCT03778931
Elacestrant vs. Standard of Care
for the Treatment of Patients
With ER+/HER2- Advanced
Breast Cancer
Breast Cancer
Drug:
Elacestrant|Drug:
Standard of Care
Postmenopausal
, vs SoC
The elacestrant can be use as
monotherapy and combination
therapies in 2nd or 3rd line
therapy for the patients with
ER+/HER2- advanced or
metastatic breast cancer.
Hoffmann-La
Roche
NCT04546009
A Study Evaluating the Efficacy
and Safety of GDC-9545
Combined With Palbociclib
Compared With Letrozole
Combined With Palbociclib in
Participants With Estrogen
Receptor-Positive, HER2-
Negative Locally Advanced or
Metastatic Breast Cancer
Estrogen
Receptor-
Positive, HER2-
Negative Locally
Advanced or
Metastatic Breast
Cancer
Drug: GDC-
9545|Drug: GDC-
9545-matched
Placebo|Drug:
Letrozole|Drug:
Letrozole-
matched
Placebo|Drug:
Palbociclib|Drug:
LHRH Agonist
Postmenopausal
The combination therapy is the
emerging treatment option for
patient suffering from breast
cancer.
Sanofi NCT04191382
Study of SAR439859 Versus
Letrozole in ER+, HER2- Pre-
operative Post-menopausal
Primary Breast Cancer
(AMEERA-4)
Breast Cancer
Drug:
SAR439859|Drug
: letrozole
Postmenopausal
, vs letrozole
The drug molecules are
showing favorable safety
profile with limited TRAEs
(treatment-related adverse
events).
17. Key Insight
Strategic Initiatives To Boost
Revenue
• Expansion of distribution channel in
the different geographical regions.
• Pricing strategy to capture major
market share.
• Strategic partnerships to increase
revenue generation.
• Increasing brand awareness among
healthcare professionals.
Clinical Insights
• Players are targeting on both the option:
monotherapy and combination therapies
for the patients with ER-positive, HER2-
negative, advanced or metastatic breast
cancer.
• Drug like “abemaciclib” which is
prescribed in combination with hormonal
therapy, including fulvestrant, the only
FDA-approved SERD, to treat patients
with ER-positive, HER2-negative
advanced or metastatic breast cancer
following endocrine therapy.
