REG - AstraZeneca PLC - Camizestrant improved PFS in 1L HR+ breast cancer

AstraZenecaAnnouncement

26/02/2025 07:15

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RNS Number : 4461Y  AstraZeneca PLC  26 February 2025

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 (http://www.astrazeneca.com/)  and follow the
Company on social media @AstraZeneca
(https://www.linkedin.com/company/astrazeneca) .

Contacts
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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.
(https://seer.cancer.gov/statfacts/html/breast-subtypes.html.%20Accessed%20January%202025)
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
(https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf) . Accessed
February 2025.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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