TIDMAZN
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 Phase III trial published
earlier this year in The New England Journal of Medicine . (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 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 and follow the
Company on Social Media @ AstraZeneca .
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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 . 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 . 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
. Accessed November 2023.
Dr. Jhaveri has financial interests related to AstraZeneca.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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