REG - AstraZeneca PLC - Truqap approved in US for HR+ breast cancer

AstraZenecaAnnouncement

17/11/2023 07:00

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RNS Number : 8160T  AstraZeneca PLC  17 November 2023

17 November 2023

 

Truqap (capivasertib) plus Faslodex approved in the US for patients with
advanced HR-positive breast cancer

 

First-in-class AKT inhibitor has potential to reshape treatment for breast
cancer patients with specific biomarker alterations (PIK3CA, AKT1 or PTEN)

 

Approval based on CAPItello-291 results which showed this combination reduced
the risk of disease progression or death by 50% vs. Faslodex alone in the
biomarker-altered population

 

AstraZeneca's Truqap (capivasertib) in combination with Faslodex (fulvestrant)
has been approved in the US for the treatment of adult patients with hormone
receptor (HR)-positive, HER2-negative locally advanced or metastatic breast
cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN). Eligible
patients will have progressed on at least one endocrine-based regimen in the
metastatic setting or experienced recurrence on or within 12 months of
completing adjuvant therapy.

 

The approval by the Food and Drug Administration (FDA) was based on the
results from the CAPItello-291
(https://www.astrazeneca.com/media-centre/press-releases/2022/capivasertib-pfs-in-hr-positive-breast-cancer.html)
Phase III trial published earlier this year in The New England Journal of
Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2214131) .(1) In the
trial, Truqap in combination with Faslodex reduced the risk of disease
progression or death by 50% versus Faslodex alone in patients with tumours
harbouring PI3K/AKT pathway biomarker alterations (based on hazard ratio of
0.50, 95% confidence interval 0.38-0.65; p=<0.001; median progression-free
survival (PFS) 7.3 versus 3.1 months).

 

Breast cancer is the most common cancer and one of the leading causes of
cancer-related death worldwide.(2) HR-positive breast cancer (expressing
estrogen or progesterone receptors, or both), is the most common subtype, with
more than 65% of tumours considered HR-positive and HER2-low or
HER2-negative.(3) Collectively, mutations in PIK3CA, AKT1 and alterations in
PTEN occur frequently, affecting up to 50% of patients with advanced
HR-positive breast cancer.(4-6) Endocrine therapies are widely used in this
setting, but many patients develop resistance to 1st-line cyclin-dependent
kinase (CDK) 4/6 inhibitors and estrogen receptor-targeting therapies,
underscoring the need for additional endocrine therapy-based options.(7)

( )

Komal Jhaveri, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center
(MSK), US, said: "Patients with advanced HR-positive breast cancer typically
experience tumour progression or resistance with widely used first-line
endocrine therapies and there is an urgent need to extend the effectiveness of
these approaches. The combination of capivasertib and fulvestrant, a
first-of-its-kind combination, provides a much-needed new treatment option for
up to half of patients in this setting with these specific biomarkers,
offering the potential to delay disease progression and provide more time with
their disease under control."

 

Dave Fredrickson, Executive Vice President, Oncology Business Unit,
AstraZeneca, said: "The rapid US approval of Truqap reinforces the important
role of the PI3K/AKT pathway in HR-positive breast cancer and the critical
need to test patients at the time of diagnosis, as up to fifty per cent have
tumours with these alterations. As a first-in-class medicine, this approval
provides a critical new option for patients in the US with this specific type
of disease and we look forward to bringing Truqap to the many breast cancer
patients who can benefit across the globe."

 

In the CAPItello-291 trial, the safety profile of Truqap plus Faslodex was
similar to that observed in previous trials evaluating this combination.(1)

 

Concurrently with this approval, the FDA also approved a companion diagnostic
test to detect relevant alterations (PIK3CA, AKT1 and PTEN).

 

The US regulatory submission was granted Priority Review
(https://www.astrazeneca.com/media-centre/press-releases/2023/capivasertib-in-combination-with-faslodex-granted-priority-review-in-the-us.html)
and reviewed under Project Orbis, which provides a framework for concurrent
submission and review of oncology medicines among participating international
partners. As part of Project Orbis, Truqap plus Faslodex is also under review
by regulatory authorities in Australia, Brazil, Canada, Israel, Singapore,
Switzerland and the UK.

 

Regulatory applications for Truqap in combination with Faslodex are also
currently under review in China, the European Union, Japan and several other
countries.

 

Financial considerations

Following this approval in the US, Astex Therapeutics is eligible to receive a
milestone payment from AstraZeneca on first commercial sale of the drug in the
US as well as royalties on future sales in line with the agreement between the
two companies.

 

Notes

 

HR-positive breast cancer

Breast cancer is the most common cancer and one of the leading causes of
cancer-related death worldwide.(2) More than two million patients were
diagnosed with breast cancer in 2020, with nearly 685,000 deaths globally.(2)
In the US, more than 290,000 patients are expected to be diagnosed in 2023,
with more than 43,000 deaths.(8)

 

HR-positive breast cancer (expressing estrogen or progesterone receptors, or
both), is the most common subtype of breast cancer with more than 65% of
tumours considered HR-positive and HER2-low or HER2-negative.(3) Collectively,
mutations in PIK3CA, AKT1 and alterations in PTEN occur frequently, affecting
up to 50% of patients with advanced HR-positive breast cancer.(4-6)

 

The growth of HR-positive breast cancer cells is often driven by estrogen
receptors (ER), andendocrine therapies that target ER-driven disease are
widely used as first-line treatment in the advanced setting, and often paired
with CDK4/6 inhibitors.(7,9,10) However, resistance to CDK4/6 inhibitors and
current endocrine therapies develops in many patients with advanced
disease.(9) Once this occurs, treatment options are limited - with
chemotherapy being the current standard of care - and survival rates are low
with 30% of patients anticipated to live beyond five years after
diagnosis.(3,9,11)

 

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.

 

CAPItello-291

CAPItello-291 is a Phase III, double-blind, randomised trial evaluating the
efficacy of Truqap in combination with Faslodex versus placebo plus Faslodex
for the treatment of locally advanced (inoperable) or metastatic HR-positive,
HER2-low or negative (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ
hybridisation (ISH)-negative) breast cancer.

 

The global trial enrolled 708 adult patients with histologically confirmed
HR-positive, HER2-low or negative breast cancer whose disease has recurred or
progressed during or after aromatase inhibitor therapy, with or without a
CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The
trial has dual primary endpoints of PFS in the overall patient population and
in a population of patients whose tumours have qualifying alterations in the
PI3K/AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40%
of tumours had these alterations and approximately 70% of patients received a
prior CDK4/6 inhibitor.

 

Truqap

Truqap (capivasertib) is a first-in-class, potent, adenosine triphosphate
(ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg
is administered twice daily according to an intermittent dosing schedule of
four days on and three days off. This was chosen in early phase trials based
on tolerability and the degree of target inhibition.

 

Truqap is currently being evaluated in Phase III trials for the treatment of
multiple subtypes of breast cancer and in other tumour types either as
monotherapy or in combination with established treatments. The ongoing
clinical research programme is focused on tumours reliant on signalling via
the PI3K/AKT pathway, and in tumours harbouring biomarker alterations in this
pathway.

 

Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex
Therapeutics (and its collaboration with the Institute of Cancer Research and
Cancer Research Technology Limited).

 

Faslodex

Faslodex is an endocrine therapy indicated for the treatment of estrogen
receptor-positive, locally advanced or metastatic breast cancer in
postmenopausal women not previously treated with endocrine therapy, or with
disease relapse on or after adjuvant anti-estrogen therapy, or disease
progression on anti-estrogen therapy.

 

In the US, EU and Japan, Faslodex is also approved in combination with CDK4/6
inhibitors for the treatment of women with HR-positive, HER2-negative advanced
or metastatic breast cancer, whose cancer has progressed after endocrine
medicine. Faslodex represents a hormonal treatment approach that helps to slow
tumour growth by blocking and degrading the estrogen receptor - a key driver
of disease progression.

 

Faslodex is approved as monotherapy or in combination with medicines from
various drug classes including CDK4/6, PI3K and AKT inhibitors for the
treatment of patients with HR-positive advanced breast cancer and is being
evaluated in combination with medicines from other drug classes.

 

AstraZeneca in breast cancer

Driven by a growing understanding of breast cancer biology, AstraZeneca is
starting to challenge, and redefine, 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 antibody drug conjugate
(ADC), AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in
previously treated HER2-positive and HER2-low 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, and
next-generation SERD and potential new medicine camizestrant. AstraZeneca is
also collaborating with Daiichi Sankyo to explore the potential of
TROP2-directed ADC, datopotamab deruxtecan, in this setting.

 

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.

 

To bring much-needed treatment options to patients with triple-negative breast
cancer, an aggressive form of breast cancer, AstraZeneca is evaluating the
potential of datopotamab deruxtecan alone and in combination with
immunotherapy Imfinzi (durvalumab), Truqap in combination with chemotherapy,
and Imfinzi in combination with other oncology medicines, including Lynparza
and Enhertu.

 

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 operates in over 100 countries
and its innovative medicines are 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
For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

References

1.   Turner N, et al. Capivasertib in Hormone Receptor-Positive Advanced
Breast Cancer. NEJM. 2023; 388:2058-70.

2.   Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J
Clin. 2021; 10.3322/caac.21660.

3.   National Cancer Institute. Surveillance, Epidemiology and End Results
Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html
(https://seer.cancer.gov/statfacts/html/breast-subtypes.html) . Accessed
November 2023.

4.   Howell S J, et al. Fulvestrant plus capivasertib versus placebo after
relapse or progression on an aromatase inhibitor in metastatic, oestrogen
receptor-positive, HER2-negative breast cancer (FAKTION). J Clin
Oncol. 2022; 23:851-64.

5.   Hortobagyi G N, et al. Correlative Analysis of Genetic Alterations and
Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor
Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. J Clin
Oncol. 2016; 34:419-26.

6.   Millis S Z, et al. Landscape of phosphatidylinositol-3-kinase pathway
alterations across 19784 diverse solid tumors. JAMA
Oncol. 2016;2(12):1565-73.

7.   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.

8.   American Cancer Society. Key Statistics for Breast Cancer. Available
at:
https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html
(https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html)
. Accessed November 2023.

9.   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.

10.  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.

11.  National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology (NCCN Guidelines). Available at:
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419
(https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419) .
Accessed November 2023.

 

Dr. Jhaveri has financial interests related to AstraZeneca.

 

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

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