RNS Number : 0638J
08 December 2022
8 December 2022 13:30 GMT
Capivasertib plus Faslodex reduced the risk of disease
death by 40% versus Faslodex in advanced HR-positive breast
CAP Itello-291 Phase III trial results presented at SABCS
show potential of capivasertib as first-in-class AKT
Detailed results from the CAPItello-291 Phase III trial showed
AstraZeneca's capivasertib in combination with Faslodex
(fulvestrant) demonstrated a statistically significant and
clinically meaningful improvement in progression-free survival
(PFS) versus placebo plus Faslodex in patients with hormone
receptor (HR)-positive, HER2-low or negative, loca lly advanced or
metastatic breast cancer, following recurrence or progression on,
or after, endocrine therapy (with or without a CDK4/6
inhibitor).(1) Results will be presented today in an oral
presentation at the 2022 San Antonio Breast Cancer Symposium
Results showed capivasertib in combination with Faslodex
demonstrated a 40% reduction in the risk of disease progression or
death versus placebo plus Faslodex in the overall trial population
(based on a hazard ratio [HR] of 0.60, 95% confidence interval [CI]
0.51-0.71; p=<0.001; median 7.2 versus 3.6 months).(1) In the
AKT pathway biomarker-altered population, capivasertib plus
Faslodex reduced the risk of disease progression or death by 50%
versus placebo plus Faslodex (HR of 0.50, 95% CI 0.38-0.65; p=
<0.001; median 7.3 v ersus 3.1 months).(1) Alterations within
the AKT pathway (PI3K/AKT/PTEN) occur frequently in breast cancer,
affecting up to 50% of patients with advanced HR-positive breast
Nicholas Turner, MD, PhD, Professor of Molecular Oncology at The
Institute of Cancer Research, London, and The Royal Marsden NHS
Foundation Trust, London, UK, and principal investigator in the
CAPItello-291 Phase III trial, said: "These data demonstrate the
practice-changing potential of capivasertib as a new treatment
option for patients with advanced HR-positive breast cancer.
Critically, this potentially first-in-class treatment has shown it
delays disease progression for those who have progressed on, or
become resistant to, endocrine therapies and CDK4/6
S usan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: "Capivasertib brings important progress to an
area with persistent treatment gaps as the first therapy of its
kind shown to be effective in a Phase III trial in patients with
advanced HR-positive, HER2-low or negative breast cancer. We
believe these results which showed benefit in all-comers and
biomarker positive populations can reshape HR-positive breast
cancer treatment, and that capivasertib can become an important new
option for patients."
Summary of results: CAPItello-291(1)
Capivasertib plus Placebo plus Faslodex
Median PFS in overall
population (months) 7.2 3.6
HR (95% CI) 0.60 (0.51-0.71)
Median PFS in the biomarker-altered
population (months) 7.3 3.1
HR (95% CI) 0.50 (0.38-0.65)
ORR in overall population 22.9% 12.2%
ORR in biomarker-altered
population 28.8% 9.7%
HR, hazard ratio; CI, confidence interval; PFS, progression-free
survival; ORR, objective response rate
Confirmed objective response rate (ORR) was 22.9% for the
capivasertib plus Faslodex arm versus 12.2% for the placebo plus
Faslodex arm in the overall trial population, and 28.8% versus
9.7%, respectively, in the biomarker-altered population.(1)
Although the overall survival (OS) data were immature at the time
of the analysis, early data are encouraging.(1) The trial will
continue to assess OS as a key secondary endpoint.
The safety profile of capivasertib plus Faslodex was similar to
that observed in previous trials evaluating this combination.(1) In
the overall trial population, the most frequent any grade adverse
events (AEs) with capivasertib plus Faslodex occurring in 20% or
more of patients were diarrhoea (72.4%), nausea (34.6%), rash (
group term including rash, rash macular, maculo-papular rash, rash
papular and rash pruritic ; 38%) fatigue (20.8%) and vomiting
(20.6%).(1) The most frequent Grade 3 or higher AEs occurring in 5%
or more of patients were diarrhoea (9.3%) and rash (12.1%).(1)
HR-positive breast cancer
Breast cancer is the most common cancer and is one of the
leading causes of cancer-related deaths worldwide.(5) More than two
million patients were diagnosed with breast cancer in 2020, with
nearly 685,000 deaths globally.(5)
HR-positive breast cancer (expressing estrogen or progesterone
receptors, or both), is the most common subtype of breast cancer
with approximately 70% of breast cancer tumours considered
HR-positive and HER2-low or negative.(6)
The growth of HR-positive breast cancer cells is often driven by
estrogen receptors (ER),(7) andendocrine therapies that target
ER-driven disease are widely used as 1st-line treatment in the
advanced setting, and often paired with cyclin-dependent kinase
(CDK) 4/6 inhibitors.(8,9) 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(9) - with chemotherapy being the current standard of
care(10) - and survival rates are low with 30% of patients
anticipated to live beyond five years after diagnosis.(6)
Optimising endocrine therapy and overcoming resistance for
patients with ER-driven disease at all stages of treatment as well
as identifying new therapies for those who no longer have ER-driven
disease are active areas of focus for breast cancer research.
CAPItello-291 is a Phase III, double-blind, randomised trial
that is part of a larger clinical programme focused on
capivasertib, an investigational AKT (serine/threonine kinase)
inhibitor. CAPItello-291 is evaluating the efficacy of capivasertib
in combination with Faslodex versus placebo plus Faslodex for the
treatment of locally advanced (inoperable) or metastatic
HR-positive, HER2-low or 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 AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial,
approximately 40% of tumours had these alterations.
Capivasertib is an investigational oral treatment currently in
Phase III trials for the treatment of multiple subtypes of breast
cancer, prostate cancer and a Phase II trial for haematologic
malignancies. A potent, selective adenosine triphosphate
(ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3),
capivasertib is being evaluated as a monotherapy and in combination
with existing therapies in tumours harbouring alterations in the
AKT pathway (PI3K/AKT/PTEN), and in tumours reliant on signalling
via this pathway for survival. Capivasertib 400 mg 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.
The capivasertib clinical research programme is investigating
the safety and efficacy of capivasertib when used alone and in
combination with established treatment regimens.
Capivasertib was discovered by AstraZeneca subsequent to a
collaboration with Astex Therapeutics (and its collaboration with
the Institute of Cancer Research and Cancer Research Technology
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 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 (fulvestrant) and
Zoladex (goserelin) and aims to reshape the HR-positive space with
next-generation SERD and potential new medicine camizestrant as
well as a potential first-in-class AKT kinase inhibitor,
capivasertib. 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
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),
capivasertib in combination with chemotherapy, and Imfinzi in
combination with other oncology medicines, including Lynparza and
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 (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
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1. Turner, et al. Capivasertib and fulvestrant for patients with
aromatase inhibitor-resistant hormone receptor-positive/human
epidermal growth factor receptor 2-negative advanced breast cancer:
results from the Phase III CAPItello-291 trial. Presented at: San
Antonio Breast Cancer Symposium, 6-10 December 2022, San Antonio,
2. 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.
3. 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.
4. Millis S Z, et al. Landscape of phosphatidylinositol-3-kinase
pathway alterations across 19784 diverse solid tumors. JAMA Oncol.
5. 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.
6. National Cancer Institute. Surveillance, Epidemiology and End Results Program. https://seer.cancer.gov/statfacts/html/breast-subtypes.html . Accessed December 2022.
7. Scabia V, et al. Estrogen receptor positive breast cancers
have patient specific hormone sensitivities and rely on
progesterone receptor. Nat Commun. 2022;
8. 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.
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.
10. National Comprehensive Cancer Network. Clinical Practice
Guidelines in Oncology (NCCN Guidelines). Available at:
. Accessed December 2022.
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December 08, 2022 08:30 ET (13:30 GMT)
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