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. fulvestrant alone in the
biomarker-altered population
AstraZeneca’s TRUQAP™ (capivasertib) in combination with
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 fulvestrant reduced the risk of
disease progression or death by 50% versus fulvestrant alone in
patients with tumors harboring PI3K/AKT/PTEN 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 tumors considered
HR-positive and HER2-low or HER2-negative.3 Collectively, mutations
in PIK3CA and 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 first-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 tumor 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/PTEN pathway in
HR-positive breast cancer and the critical need to test patients at
the time of diagnosis, as up to fifty percent have tumors 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
fulvestrant 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 fulvestrant is also under review by regulatory
authorities in Australia, Brazil, Canada, Israel, Singapore,
Switzerland and the UK.
Regulatory applications for TRUQAP in combination with
fulvestrant are also currently under review in China, the European
Union, Japan and several other countries.
IMPORTANT SAFETY INFORMATION ABOUT TRUQAP™
(capivasertib) tablets
TRUQAP is contraindicated in patients with severe
hypersensitivity to TRUQAP or any of its components.
Hyperglycemia
Severe hyperglycemia, associated with ketoacidosis, has occurred
in patients treated with TRUQAP. The safety of TRUQAP has not been
established in patients with Type I diabetes or diabetes requiring
insulin. Patients with insulin-dependent diabetes were excluded
from CAPItello-291.
Hyperglycemia occurred in 18% of patients treated with TRUQAP
(n=355). Grade 3 (insulin therapy initiated; hospitalization
indicated) or Grade 4 (life-threatening consequences; urgent
intervention indicated) hyperglycemia occurred in 2.8% of patients.
Diabetic ketoacidosis occurred in 0.3% of patients and diabetic
metabolic decompensation in 0.6% of patients. Dose reduction for
hyperglycemia was required in 0.6% and permanent discontinuation
was required in 0.6% of patients. The median time to first
occurrence of hyperglycemia was 15 days (range: 1 to 367).
In the 65 patients with hyperglycemia, 45% required treatment
with anti-hyperglycemic medication (insulin in 15% and metformin in
29%). Of the 29 patients who required anti-hyperglycemic medication
during treatment with TRUQAP, 66% (19/29) remained on these
medications at treatment discontinuation or last follow-up.
Evaluate fasting blood glucose (FG) and hemoglobin A1C (HbA1C)
and optimize blood glucose prior to treatment. Before initiating
TRUQAP, inform patients about TRUQAP’s potential to cause
hyperglycemia and to immediately contact their healthcare
professional if hyperglycemia symptoms occur (eg, excessive thirst,
urinating more often than usual or greater amount of urine than
usual, or increased appetite with weight loss). Evaluate FG at
least every two weeks during the first month and at least once a
month starting from the second month, prior to the scheduled dose
of TRUQAP. Monitor HbA1C every three months. Monitor FG more
frequently during treatment with TRUQAP in patients with a medical
history of diabetes mellitus and in patients with risk factors for
hyperglycemia such as obesity (BMI ≥ 30), elevated FG of >160
mg/dL (>8.9 mmol/L), HbA1C at or above the upper limit of
normal, use of concomitant systemic corticosteroids, or
intercurrent infections.
If a patient experiences hyperglycemia after initiating
treatment with TRUQAP, monitor FG as clinically indicated, and at
least twice weekly until FG decreases to normal levels. During
treatment with anti-hyperglycemic medication, continue monitoring
FG at least once a week for 8 weeks, followed by once every 2 weeks
and as clinically indicated. Consider consultation with a
healthcare practitioner with expertise in the treatment of
hyperglycemia and counsel patients on lifestyle changes. Withhold,
dose reduce, or permanently discontinue TRUQAP based on
severity.
Diarrhea
Severe diarrhea associated with dehydration occurred in patients
who received TRUQAP (n=355).
Diarrhea occurred in 72% of patients. Grade 3 or 4 diarrhea
occurred in 9% of patients. The median time to first occurrence was
8 days (range: 1 to 519). In the 257 patients with diarrhea, 59%
required antidiarrheal medications to manage symptoms. Dose
reductions were required in 8% of patients and 2% of patients
permanently discontinued TRUQAP due to diarrhea. In patients with
Grade ≥ 2 diarrhea (n=93) with at least 1 grade improvement (n=89),
median time to improvement from the first event was 4 days (range:
1 to 154).
Monitor patients for signs and symptoms of diarrhea. Advise
patients to increase oral fluids and start antidiarrheal treatment
at the first sign of diarrhea while taking TRUQAP. Withhold, reduce
dose, or permanently discontinue TRUQAP based on severity.
Cutaneous Adverse Reactions
Cutaneous adverse reactions, which can be severe, including
erythema multiforme (EM), palmar-plantar erythrodysesthesia, and
drug reaction with eosinophilia and systemic symptoms (DRESS),
occurred in patients who received TRUQAP (n=355).
Cutaneous adverse reactions occurred in 58% of patients. Grade 3
or 4 cutaneous adverse reactions occurred in 17% of patients
receiving TRUQAP. EM occurred in 1.7% of patients and DRESS
occurred in 0.3% of patients. Dose reduction was required in 7% of
patients and 7% of patients permanently discontinued TRUQAP due to
cutaneous adverse reactions.
Monitor patients for signs and symptoms of cutaneous adverse
reactions. Early consultation with a dermatologist is recommended.
Withhold, dose reduce, or permanently discontinue TRUQAP based on
severity.
Embryo-Fetal Toxicity
Based on findings from animals and mechanism of action, TRUQAP
can cause fetal harm when administered to a pregnant woman. Advise
pregnant women and females of reproductive potential of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with TRUQAP and for
1 month after the last dose. Advise male patients with female
partners of reproductive potential to use effective contraception
during treatment with TRUQAP and for 4 months after the last
dose.
TRUQAP is used in combination with fulvestrant. Refer to the
full Prescribing Information of fulvestrant for pregnancy and
contraception information.
ADVERSE REACTIONS
Among the 355 patients who received TRUQAP in CAPItello-291, the
most common (≥20%) adverse reactions, including laboratory
abnormalities, were diarrhea (72%), cutaneous adverse reactions
(58%), increased random glucose (57%), decreased lymphocytes (47%),
decreased hemoglobin (45%), increased fasting glucose (37%), nausea
and fatigue (35% each), decreased leukocytes (32%), increased
triglycerides (27%), decreased neutrophils (23%), increased
creatinine (22%), vomiting (21%), and stomatitis (20%).
In the 155 patients with PIK3CA/AKT1/PTEN alterations treated
with TRUQAP + fulvestrant, dose reductions due to adverse reactions
were reported in 21% of patients. Permanent TRUQAP discontinuation
due to an adverse reaction occurred in 10% of patients. Dose
interruptions of TRUQAP occurred in 39% of patients.
DRUG INTERACTIONS
Strong CYP3A Inhibitors: Avoid concomitant use with a
strong CYP3A inhibitor. If concomitant use cannot be avoided,
reduce the dose of TRUQAP and monitor patients for adverse
reactions.
Moderate CYP3A Inhibitors: When concomitantly used with a
moderate CYP3A inhibitor, reduce the dose of TRUQAP and monitor
patients for adverse reactions.
Strong or Moderate CYP3A Inducers: Avoid concomitant use
of TRUQAP with strong or moderate CYP3A inducers.
INDICATION AND USAGE
TRUQAP in combination with fulvestrant is indicated 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 with one or more
PIK3CA/AKT1/PTEN alteration as detected by an FDA-approved test
following progression on at least one endocrine-based regimen in
the metastatic setting or recurrence on or within 12 months of
completing adjuvant therapy.
Please see full Prescribing Information,
including Patient Information for TRUQAP.
Notes
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.
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 tumors considered HR-positive and HER2-low or
HER2-negative.3 Collectively, mutations in PIK3CA and 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), and endocrine 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 optimization 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, randomized trial
evaluating the efficacy of TRUQAP in combination with fulvestrant
versus placebo plus fulvestrant 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 PI3K/AKT/PTEN pathway (PIK3CA, AKT1 or PTEN genes). In the
trial, approximately 40% of tumors 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 tumor
types either as monotherapy or in combination with established
treatments. The ongoing clinical research program is focused on
tumors reliant on signaling via the PI3K/AKT/PTEN pathway, and in
tumors harboring 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).
Fulvestrant
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, fulvestrant 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. Fulvestrant
represents a hormonal treatment approach that helps to slow tumor
growth by blocking and degrading the estrogen receptor – a key
driver of disease progression.
Fulvestrant 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 tumor environment.
With fam-trastuzumab deruxtecan-nxki, 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 fulvestrant and 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 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, TRUQAP 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. Please visit
www.astrazeneca-us.com and follow us on social media
@AstraZeneca.
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.
US-82368 Last Updated 11/23
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