This
announcement contains inside information
26 February 2025
Camizestrant demonstrated
highly statistically significant and clinically meaningful
improvement in progression-free survival in 1st-line advanced
HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 Phase
III trial
First and only
next-generation oral SERD and complete ER antagonist to demonstrate
1st-line benefit in combination with widely approved CDK4/6
inhibitors
Positive high-level results from a planned interim
analysis of the SERENA-6 Phase III trial showed that AstraZeneca's
camizestrant in combination with a
cyclin-dependent kinase (CDK) 4/6 inhibitor
(palbociclib, ribociclib or abemaciclib) demonstrated a highly
statistically significant and clinically meaningful improvement in
the primary endpoint of progression-free survival (PFS). The trial
evaluated switching to the camizestrant
combination versus continuing standard-of-care treatment
with an aromatase inhibitor (AI) (anastrozole or letrozole) in
combination with a CDK4/6 inhibitor in the
1st-line treatment of patients with hormone receptor
(HR)-positive, HER2-negative advanced breast
cancer whose tumours have an emergent ESR1 mutation.
The key secondary endpoints of time to second disease
progression (PFS2) and overall survival (OS) were immature at the
time of this interim analysis. However, the camizestrant
combination demonstrated a trend toward improvement in PFS2. The
trial will continue as planned to further assess key secondary
endpoints.
SERENA-6 is the first global, double-blind,
registrational Phase III trial to use a circulating tumour DNA
(ctDNA)-guided approach to detect the emergence of endocrine
resistance and inform a switch in therapy before disease
progression. The novel trial design used ctDNA monitoring at the
time of routine tumour scan visits to identify patients for early
signs of endocrine resistance and the emergence of ESR1 mutations. Following detection of
an ESR1 mutation without
disease progression, the endocrine therapy of patients was switched
to camizestrant from ongoing treatment with an AI, while continuing
combination with the same CDK4/6 inhibitor.
François-Clément
Bidard, MD, PhD, Professor of
Medical Oncology at Institut Curie & UVSQ/Université Paris-Saclay, France, and
co-principal investigator for the trial, said: "Patients have an
urgent need for new treatments that delay disease progression on
1st-line endocrine-based therapies. The results from SERENA-6 show
that switching from an aromatase inhibitor to camizestrant in
combination with any of the three CDK4/6
inhibitors after emergence of an
ESR1 mutation delays
progression of disease and extends the benefit of 1st-line
treatment, representing an important step forward for patients, and
a potential shift in clinical practice."
Susan Galbraith, Executive Vice President,
Oncology Haematology R&D, AstraZeneca, said:
"These impressive results demonstrate the versatility of
camizestrant in combination with all the widely approved CDK4/6
inhibitors to provide a well-tolerated new potential treatment
option in the first-line setting for the one in three patients with
HR-positive, HER2-negative advanced breast cancer whose tumours
develop ESR1 mutations
during treatment with an aromatase inhibitor in combination with a
CDK4/6 inhibitor. This critical read-out moves us one step closer
to realising the potential of camizestrant to become a new
standard-of-care as we look to shift the treatment paradigm and
establish this new endocrine therapy backbone in HR-positive breast
cancer."
The safety profile
of camizestrant in combination with palbociclib,
ribociclib or abemaciclib in SERENA-6 was consistent with the known
safety profile of each medicine. No new safety concerns were
identified and discontinuations were very low and similar in both
arms.
Globally, approximately 200,000 patients with
HR-positive breast cancer are treated with a medicine in the
1st-line setting; most frequently with endocrine therapies
that target estrogen receptor (ER)-driven disease, which are often
paired with CDK4/6 inhibitors.1-3 However, resistance to
CDK4/6 inhibitors and current endocrine therapies develops in many
patients with advanced disease.3
Mutations in the ESR1 gene are a key driver of
endocrine resistance and are widely tested for in clinical
practice.4,5 These mutations develop during treatment of
the disease, becoming more prevalent as the disease progresses and
are associated with poor outcomes.4,5 Approximately 30%
of patients with endocrine sensitive HR-positive disease develop
ESR1 mutations during
1st-line treatment without disease progression.1
Data will be presented at a
forthcoming medical meeting and shared with global regulatory
authorities.
Notes
HR-positive breast
cancer
Breast cancer is the second most common cancer and
one of the leading causes of cancer-related deaths
worldwide.6 More than two million patients were
diagnosed with breast cancer in 2022, with more than 665,000 deaths
globally.6 While survival rates are high for those
diagnosed with early breast cancer, only about 30% of patients
diagnosed with or who progress to metastatic disease are expected
to live five years following diagnosis.7
HR-positive breast cancer, characterised by the
expression of estrogen or progesterone receptors, or both, is the
most common subtype of breast cancer with 70% of tumours considered
HR-positive and HER2-negative.7 ERs often drive the
growth of HR-positive breast cancer cells.8
Once resistance to the treatment of HR-positive
breast cancer with CDK4/6 inhibitors and current endocrine
therapies occurs, treatment options are limited and survival rates
are low with 35% of patients anticipated to live beyond five years
after diagnosis.3,7,9 The optimisation of endocrine
therapy and overcoming resistance to enable patients to continue
benefiting from these treatments, as well as identifying new
therapies for those who are less likely to benefit, are active
areas of focus for breast cancer research.
SERENA-6
SERENA-6 is a Phase III, double-blind, randomised
trial evaluating the efficacy and safety of camizestrant in
combination with a CDK4/6 inhibitor (palbociclib, ribociclib or
abemaciclib ) versus treatment with an AI (anastrozole or
letrozole) in combination with a CDK4/6 inhibitor (palbociclib,
ribociclib or abemaciclib) in patients with HR-positive,
HER2-negative advanced breast cancer (patients with either locally
advanced disease, or metastatic disease) whose tumours have an
emergent ESR1
mutation.
The global trial enrolled 315 adult patients with
histologically confirmed HR-positive, HER2-negative advanced breast
cancer, undergoing treatment with an AI in combination with a
CDK4/6 inhibitor as 1st-line treatment. The primary endpoint of the
SERENA-6 trial is PFS as assessed by investigator, with secondary
endpoints including OS, and PFS2 by investigator assessment.
Camizestrant
Camizestrant is an investigational, potent,
next-generation oral selective estrogen receptor degrader (SERD)
and complete ER antagonist that is currently in Phase III trials
for the treatment of HR-positive breast cancer.
AstraZeneca's broad, robust and innovative
clinical development programme, including the SERENA-6, SERENA-4,
CAMBRIA-1 and CAMBRIA-2 trials, is evaluating the safety and
efficacy of camizestrant when used as a monotherapy or in
combination with other agents to address a number of areas of unmet
need in this specific type of breast cancer.
Camizestrant has demonstrated anti-cancer activity
across a range of preclinical models, including those with
ER-activating mutations. In the SERENA-2 Phase II trial,
camizestrant demonstrated PFS benefit versus Faslodex (fulvestrant) irrespective of
ESR1 mutation status or
prior treatment with CDK4/6 inhibitors in patients with ER-positive
locally advanced or metastatic breast cancer, previously treated
with endocrine therapy. The SERENA-1 Phase I trial demonstrated
that camizestrant is well tolerated and has a promising anti-tumour
profile when administered alone or in combination with palbociclib,
ribociclib and abemaciclib; three widely used CDK4/6 inhibitors.
Combinations with other agents are ongoing in SERENA-1.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer
biology, AstraZeneca is challenging, and redefining, the current
clinical paradigm for how breast cancer is classified and treated
to deliver even more effective treatments to patients in need -
with the bold ambition to one day eliminate breast cancer as a
cause of death.
AstraZeneca has a comprehensive portfolio of
approved and promising compounds in development that leverage
different mechanisms of action to address the biologically diverse
breast cancer tumour environment.
With Enhertu (trastuzumab deruxtecan), a
HER2-directed ADC, AstraZeneca and Daiichi Sankyo are aiming to
improve outcomes in previously treated HER2-positive, HER2-low and
HER2-ultralow metastatic breast cancer, and are exploring its
potential in earlier lines of treatment and in new breast cancer
settings.
In HR-positive breast cancer, AstraZeneca
continues to improve outcomes with foundational medicines
Faslodex and Zoladex (goserelin) and aims to
reshape the HR-positive space with first-in-class AKT inhibitor,
Truqap (capivasertib), the
TROP-2-directed ADC, Datroway (datopotamab deruxtecan) and
next-generation oral SERD and potential new medicine
camizestrant.
PARP inhibitor Lynparza (olaparib) is a targeted
treatment option that has been studied in early and metastatic
breast cancer patients with an inherited BRCA mutation. AstraZeneca
with MSD (Merck & Co., Inc. in the US and Canada) continue to
research Lynparza in these
settings and to explore its potential in earlier disease.
AstraZeneca is also exploring the efficacy and safety of saruparib,
a potent and selective inhibitor of PARP1, in combination with
camizestrant in BRCA-mutated, HR-positive, HER2-negative advanced
breast cancer.
To bring much-needed treatment options to
patients with triple-negative breast cancer, an aggressive form of
breast cancer, AstraZeneca is collaborating with Daiichi Sankyo to
evaluate the potential of Datroway alone and in combination with
immunotherapy Imfinzi
(durvalumab).
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology
with the ambition to provide cures for cancer in every form,
following the science to understand cancer and all its complexities
to discover, develop and deliver life-changing medicines to
patients.
The Company's focus is on some of the most
challenging cancers. It is through persistent innovation that
AstraZeneca has built one of the most diverse portfolios and
pipelines in the industry, with the potential to catalyse changes
in the practice of medicine and transform the patient experience.
AstraZeneca has the vision to redefine cancer
care and, one day, eliminate cancer as a cause of death.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global,
science-led biopharmaceutical company that focuses on the
discovery, development, and commercialisation of prescription
medicines in Oncology, Rare Diseases, and BioPharmaceuticals,
including Cardiovascular, Renal & Metabolism, and Respiratory
& Immunology. Based in Cambridge, UK, AstraZeneca's innovative
medicines are sold in more than 125 countries and used by millions
of patients worldwide. Please visit astrazeneca.com and
follow the Company on social media
@AstraZeneca.
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References
1. Cerner CancerMPact database. Accessed February
2025.
2. Lin M, et al. Comparative Overall Survival of CDK4/6
Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for
Hormone receptor-positive, HER2-negative metastatic breast cancer.
J Cancer. 2020;
10.7150/jca.48944.
3. Lloyd M R, et al. Mechanisms of Resistance to CDK4/6 Blockade
in Advanced Hormone Receptor-positive, HER2-negative Breast Cancer
and Emerging Therapeutic Opportunities. Clin Cancer Res. 2022;
28(5):821-30.
4. Brett O, et al. ESR1 mutation as an emerging clinical
biomarker in metastatic hormone receptor‑positive breast cancer. Breast Cancer Res. 2021;
23:85.
5. Zundelevich, A, et al. ESR1 mutations are frequent in newly
diagnosed metastatic and loco-regional recurrence of
endocrine-treated breast cancer and carry worse prognosis.
Breast Cancer Res.
2020; 22:16.
6. Bray F, et al. Global
cancer statistics 2022: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi:
10.3322/caac.21834.
7. National Cancer
Institute. Cancer Stat facts: Female breast cancer subtypes.
Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed February 2025.
8. Scabia V, et al.
Estrogen receptor positive breast cancers have patient specific
hormone sensitivities and rely on progesterone receptor.
Nat Commun. 2022;
10.1038/s41467-022-30898-0.
9. National
Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology (NCCN Guidelines). Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.
Accessed February 2025.
Adrian Kemp
Company Secretary
AstraZeneca PLC
