Decision based on CAPItello-291 Phase III
trial results which showed the combination reduced the risk of
disease progression or death by 40% vs. FASLODEX alone
Potential first-in-class AKT inhibitor being
reviewed under Project Orbis
AstraZeneca’s New Drug Application (NDA) for capivasertib in
combination with FASLODEX® (fulvestrant) has been accepted and
granted Priority Review in the US for the treatment of adult
patients with hormone receptor (HR)-positive, human epidermal
growth factor receptor 2 (HER2)-negative locally advanced or
metastatic breast cancer following recurrence or progression on or
after an endocrine-based regimen.
The Food and Drug Administration (FDA) grants Priority Review to
applications for medicines that, if approved, would offer
significant improvements over available options by demonstrating
safety or efficacy improvements, preventing serious conditions, or
enhancing patient compliance.1 The Prescription Drug User Fee Act
date, the FDA action date for their regulatory decision, is during
the fourth quarter of 2023.
The NDA is also being reviewed under Project Orbis, an
initiative of the FDA which provides a framework for concurrent
submission and review of oncology medicines among participating
international partners to expedite approval for patients around the
world.
Breast cancer is the most common cancer worldwide, with an
estimated 2.3 million patients diagnosed each year.2 In the US,
more than 290,000 patients are expected to be diagnosed in 2023,
with more than 43,000 deaths.3 More than 65% of breast cancer
tumors are considered HR-positive and HER2-low or negative.4
Endocrine therapies are widely used for the treatment of
HR-positive breast cancer, but many patients with advanced disease
develop resistance to 1st-line CDK4/6 inhibitors and endocrine
therapies, underscoring the need for additional options.5,6
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “This Priority Review decision underscores the
potential of capivasertib to extend the effectiveness of
endocrine-based treatment approaches for patients with HR-positive
breast cancer who experience tumor progression on, or resistance to
these widely used therapies. We look forward to working with the
FDA to bring this potential first-in-class AKT inhibitor to
patients as quickly as possible.”
The NDA is based on data from the CAPItello-291 Phase III trial
presented at the 2022 San Antonio Breast Cancer Symposium and
recently published online in The New England Journal of
Medicine.7
In the trial, 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 hazard ratio [HR] of 0.60, 95% confidence interval [CI]
0.51-0.71; p=<0.001; median progression-free survival (PFS) 7.2
versus 3.6 months).7 Although the overall survival (OS) data were
immature at the time of the analysis, early data are encouraging.
The trial continues 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.7
In January 2023, capivasertib was granted Fast Track Designation
by the FDA in this setting for this patient population.
Important Safety Information About FASLODEX® (fulvestrant)
injection
Contraindications
- FASLODEX is contraindicated in patients with known
hypersensitivity to the drug or to any of its components.
Hypersensitivity reactions, including urticaria and angioedema,
have been reported in association with FASLODEX
Warnings and Precautions
Risk of Bleeding
- Because FASLODEX is administered intramuscularly, it should be
used with caution in patients with bleeding diatheses,
thrombocytopenia, or anticoagulant use
Hepatic Impairment
- FASLODEX is metabolized primarily in the liver. A 250 mg dose
is recommended in patients with moderate hepatic impairment
(Child-Pugh class B). FASLODEX has not been evaluated in patients
with severe hepatic impairment (Child-Pugh class C)
Injection Site Reaction
- Use caution while administering FASLODEX at the dorsogluteal
injection site due to the proximity of the underlying sciatic
nerve. Injection site-related events, including sciatica,
neuralgia, neuropathic pain, and peripheral neuropathy, have been
reported with FASLODEX injection
Embryo-Fetal Toxicity and Lactation
- Pregnancy testing is recommended for females of reproductive
potential within seven days prior to initiating FASLODEX
- Advise pregnant women of the potential risk to a fetus. Advise
women of reproductive potential to use effective contraception
during FASLODEX treatment and for 1 year after the last dose.
Advise lactating women not to breastfeed during treatment with
FASLODEX and for 1 year after the final dose because of the
potential risk to the infant
Immunoassay Measurement of Serum Estradiol
- Due to structural similarity of fulvestrant and estradiol,
FASLODEX can interfere with estradiol measurement by immunoassay,
resulting in falsely elevated estradiol levels
Adverse Reactions Monotherapy
- The most common adverse reactions occurring in ≥5% of patients
receiving FASLODEX 500 mg were injection site pain, nausea, bone
pain, arthralgia, headache, back pain, fatigue, pain in extremity,
hot flash, myalgia, vomiting, anorexia, diarrhea, asthenia,
musculoskeletal pain, cough, dyspnea, and constipation
- Increased hepatic enzymes (ALT, AST, ALP) occurred in >15%
of FASLODEX patients and were not dose-dependent
Combination Therapy – FASLODEX plus ribociclib
- The most frequently reported (≥5%) Grade 3 or 4 adverse
reactions in patients receiving FASLODEX plus ribociclib in
descending frequency were neutropenia, leukopenia, infections, and
abnormal liver function tests
- The most common adverse reactions (≥20%) of any grade reported
in patients receiving FASLODEX 500 mg plus ribociclib 600 mg/day
were neutropenia, infections, leukopenia, cough, nausea, diarrhea,
vomiting, constipation, pruritus, and rash
- Additional adverse reactions in patients receiving FASLODEX
plus ribociclib included asthenia, dyspepsia, thrombocytopenia, dry
skin, dysgeusia, electrocardiogram QT prolonged, dry mouth,
vertigo, dry eye, lacrimation increased, erythema, hypocalcemia,
blood bilirubin increased, and syncope
Combination Therapy—FASLODEX plus palbociclib
- The most frequently reported Grade ≥3 adverse reactions in
patients receiving FASLODEX plus palbociclib in descending
frequency were neutropenia and leukopenia
- Adverse reactions (≥10%) of any grade reported in patients
receiving FASLODEX 500 mg plus palbociclib 125 mg/day by descending
frequency were neutropenia, leukopenia, infections, fatigue,
nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting,
alopecia, rash, decreased appetite, and pyrexia
- Additional adverse reactions occurring at an overall incidence
of <10% of patients receiving FASLODEX plus palbociclib included
asthenia, aspartate aminotransferase increased, dysgeusia,
epistaxis, lacrimation increased, dry skin, alanine
aminotransferase increased, vision blurred, dry eye, and febrile
neutropenia
Combination Therapy—FASLODEX plus abemaciclib
- The most frequently reported (≥5%) Grade 3 or 4 adverse
reactions in patients receiving FASLODEX plus abemaciclib were
neutropenia, diarrhea, leukopenia, anemia, and infections
- The most common adverse reactions (≥20%) of any grade reported
in patients receiving FASLODEX 500 mg plus abemaciclib 150 mg twice
daily were diarrhea, fatigue, neutropenia, nausea, infections,
abdominal pain, anemia, leukopenia, decreased appetite, vomiting,
and headache
Indications for FASLODEX
Monotherapy FASLODEX is an estrogen receptor antagonist
indicated for the treatment of:
- Hormone receptor (HR)-positive, human epidermal growth factor
receptor 2 (HER2)-negative advanced breast cancer in postmenopausal
women not previously treated with endocrine therapy
- HR-positive advanced breast cancer in postmenopausal women with
disease progression following endocrine therapy
Combination Therapy FASLODEX is indicated for the treatment
of:
- HR-positive, HER2-negative advanced or metastatic breast cancer
in postmenopausal women in combination with ribociclib as initial
endocrine-based therapy or following disease progression on
endocrine therapy
- HR-positive, HER2-negative advanced or metastatic breast cancer
in combination with palbociclib or abemaciclib in women with
disease progression after endocrine therapy
Please see full Prescribing Information for
FASLODEX with Patient Information
Notes
HR-positive breast cancer Breast cancer is the most
common cancer and is one of the leading causes of cancer-related
deaths worldwide.2 More than two million patients were diagnosed
with breast cancer in 2020, with nearly 685,000 deaths
globally.2
HR-positive breast cancer (expressing estrogen or progesterone
receptors, or both), is the most common subtype of breast cancer
with more than 65% of breast cancer tumors considered HR-positive
and HER2-low or negative.4
The growth of HR-positive breast cancer cells is often driven by
estrogen receptors (ER), and endocrine 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.5,6,8 However, resistance to CDK4/6 inhibitors
and current endocrine therapies develops in many patients with
advanced disease.6 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.4,6,9
Optimizing 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 CAPItello-291 is a Phase III, double-blind,
randomized trial that is part of a larger clinical program 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 (immunohistochemistry (IHC) 0 or
1+, or IHC 2+/in-situ hybridization (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 tumors have qualifying alterations in
the AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial,
approximately 40% of tumors had these alterations.
Capivasertib 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 hematologic malignancies. A potent, adenosine
triphosphate (ATP)-competitive inhibitor of all three AKT isoforms
(AKT1/2/3), capivasertib is being evaluated in combination with
existing therapies in tumors harboring alterations in the AKT
pathway (PI3K/AKT/PTEN), and in tumors reliant on signaling via
this pathway for survival. Capivasertib 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.
The capivasertib clinical research program 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
Limited).
FASLODEX FASLODEX® (fulvestrant) 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 tumor
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 and PI3K
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 tumor environment.
With fam-trastuzumab deruxtecan-nxki, 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 and 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 olaparib is a targeted treatment option that has
been studied in early and metastatic breast cancer patients with an
inherited BRCA mutation. AstraZeneca with Merck & Co., Inc.,
known as MSD outside the US and Canada, continue to research
olaparib 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 durvalumab,
capivasertib in combination with chemotherapy, and durvalumab in
combination with other oncology medicines, including olaparib and
fam-trastuzumab deruxtecan-nxki.
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 catalyze 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.
About AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialization 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. For more information, please visit
www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.
References
- FDA. Priority Review. Available at:
https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review.
Accessed June 2023.
- 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.
- 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 June 2023.
- National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed June 2023.
- 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.
- 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.
- Turner N, et al. Capivasertib in Hormone Receptor–Positive
Advanced Breast Cancer. NEJM. 2023; 388:2058–70.
- 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.
- 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 June 2023.
US-76393 Last Updated 06/23
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Media Inquiries Brendan McEvoy +1 302 885 2677 Jillian
Gonzales +1 302 885 2677
US Media Mailbox: usmediateam@astrazeneca.com
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