29
April 2024
Truqap
plus
Faslodex recommended
for approval in the EU by CHMP for
patients
with advanced ER-positive breast
cancer
Recommendation
based on CAPItello-291 results which showed the Truqap combination
reduced the risk of disease progression or death by
50%
vs.
Faslodex standard of care in a biomarker-altered
population
AstraZeneca's
Truqap
(capivasertib)
in combination with
Faslodex (fulvestrant)
has
been recommended for
approval in the European Union (EU) for the treatment
of
adult patients with estrogen receptor (ER)-positive,
HER2‑negative
locally advanced or metastatic breast cancer with one or more
PIK3CA, AKT1, or PTEN-alterations following
recurrence or progression on or after an endocrine-based
regimen.
The
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) based its positive opinion
on the
results from the
CAPItello-291 Phase
III trial published
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 or PTEN
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).1
In
Europe, breast cancer remains the leading cause of cancer death,
with more than 140,000 deaths in 2022 and more than 550,000 new
patients diagnosed in the same year.2 HR-positive breast
cancer (expressing
estrogen or
progesterone receptors, or both), is
the most common subtype of breast cancer with 70% of tumours
considered HR-positive and HER2-low or
HER2-negative.3
More
than 97% of
HR-positive breast cancer tumours are
ER-positive.4,5 Collectively,
mutations in PIK3CA, AKT1 and alterations in PTEN occur frequently,
affecting approximately 50% of patients with advanced HR-positive
breast cancer.6-8
HR-positive breast cancer progression is often driven by estrogen
receptors, and endocrine therapies that target ER-driven disease
are widely used as 1st-line treatment in the advanced setting, and
often paired with CDK4/6 inhibitors.9-11 However,
resistance to these therapies develops in many patients with
advanced disease, and alternative approaches are needed to extend
the effectiveness of endocrine-based
therapies.10
Mafalda
Oliveira, MD, PhD,
Senior Consultant at the Department
of Medical Oncology, Vall d'Hebron University Hospital, and Senior
Clinical Investigator of the Vall d'Hebron Institute of Oncology's
(VHIO) Breast Cancer Group in Barcelona, Spain, said: "There is an
urgent need to extend the effectiveness of widely used endocrine
therapies in patients with advanced ER-positive breast cancer to
delay disease progression or resistance. With
this combination demonstrating a fifty per cent reduction in
disease progression or death in patients with tumours harbouring
PIK3CA, AKT1, or PTEN-alterations in the CAPItello-291
trial,
this positive recommendation marks an important step in providing a
much-needed new treatment option for approximately half of patients
in this setting with these specific tumour biomarkers."
Susan
Galbraith, Executive Vice President, Oncology R&D, AstraZeneca,
said: "Today's news reinforces the practice-changing potential
of
Truqap in
combination with
Faslodex to
extend the effectiveness of endocrine-based treatment approaches
for patients who experience tumour progression on, or resistance to
widely used endocrine-based therapies. This
recommendation recognises
the high unmet need in this biomarker-specific patient population,
and if approved, patients in Europe with
this specific type of disease may
be able to benefit from this first-in-class
treatment option."
In
the CAPItello-291 trial,
the safety profile of
Truqap plus
Faslodex was
similar to that observed in previous trials evaluating this
combination.1
Regulatory
applications are currently under review in China and several other
countries, and similar indications for
Truqap in
combination with
Faslodex are
already approved in
Japan, the
US and several other countries based on results from the
CAPItello-291 trial.
Notes
HR-positive breast cancer
In
Europe, breast cancer remains the leading cause of cancer death,
with more than 140,000 deaths in 2022 and more than 550,000 new
patients diagnosed in the same year.2
HR-positive
breast cancer (expressing
estrogen or
progesterone receptors, or both), is
the most common subtype of breast cancer with 70% of tumours
considered HR-positive and HER2-low or
HER2-negative.3
HR-positive
breast cancer progression is often driven by estrogen receptors,
and endocrine therapies that target ER-driven disease are widely
used as 1st-line treatment in the advanced setting, and often
paired with CDK4/6 inhibitors.9-11 However, resistance
to CDK4/6 inhibitors and current endocrine therapies develops in
many patients with advanced disease.10 Once this occurs, treatment options are
limited - with chemotherapy being the current standard of
care -
and
survival rates are low with approximately 35% of patients
anticipated to live beyond five years after
diagnosis.3,10,12
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 (ER-positive and ER-positive, progesterone
receptor-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
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
approved in Japan, the US and several other countries for the
treatment of adult patients with HR-positive, HER2-negative locally
advanced or metastatic breast cancer with one or more biomarker
alterations (PIK3CA, AKT1 or PTEN) following recurrence or
progression on or after an endocrine-based regimen based on the
results from the CAPItello-291 trial.
Truqap
is
currently being evaluated in Phase III trials for the treatment of
multiple subtypes of breast cancer and in other tumour types 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.
World Health Organization. GLOBOCAN Europe Fact Sheet. Available
at:
https://gco.iarc.who.int/media/globocan/factsheets/populations/908-europe-fact-sheet.pdf.
Accessed April 2024.
3.
National
Cancer Institute. Surveillance, Epidemiology and End Results
Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed April 2024.
4.
Bae
S, et al. Poor prognosis of single hormone receptor positive breast
cancer: similar outcome as triple-negative breast cancer.
BMC Cancer.
2015; 15:138.
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Cserni
G, et al. Estrogen Receptor Negative and Progesterone Receptor
Positive Breast Carcinomas-How Frequent are they?
Pathol. Oncol. Res. 2011;
17:663-668.
6.
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.
7.
Hortobagyi
G N, et al. Correlative
Analysis of Genetic Alterations and Everolimus Benefit in Hormone
Receptor-Positive, Human Epidermal Growth Factor Receptor
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BOLERO-2. J
Clin Oncol. 2016;
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Millis
S Z, et al. Landscape of phosphatidylinositol-3-kinase pathway
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9.
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.
10.
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.
11.
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.
12.
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
April 2024.
Adrian
Kemp
Company
Secretary
AstraZeneca
PLC