18 June 2024
Update on the CAPItello-290
Phase III trial for Truqap
plus chemotherapy
in advanced or metastatic
triple-negative breast cancer
The CAPItello-290 Phase III trial
for Truqap (capivasertib)
in combination with paclitaxel in patients with locally advanced
(inoperable) or metastatic triple-negative breast cancer (TNBC) did
not meet the dual primary endpoints of improvement in overall
survival (OS) versus paclitaxel in combination with placebo in
either the overall trial population or in a subgroup of patients
with tumours harbouring specific biomarker alterations (PIK3CA,
AKT1 or PTEN).
Breast cancer is the second most common cancer and
one of the leading causes of cancer-related deaths
worldwide.1 While some breast cancers may test positive
for estrogen receptors, progesterone receptors or overexpression of
human epidermal growth factor receptor 2 (HER2), TNBC is defined as
negative for all three.2 In the 1st-line setting,
approximately 59,000 patients with TNBC are treated with a
medicine.3 Collectively, mutations in PIK3CA, AKT1 and
alterations in PTEN affect approximately 35% of patients with
TNBC.4
Peter Schmid, MD, Barts Cancer
Institute, London, UK, and principal investigator for the trial
said: "Despite modest advances, triple-negative breast cancer remains one of the most
challenging forms of disease to treat due to the lack of known
actionable biomarker targets, and chemotherapy-based regimens
continue to be the mainstay of treatment. While the CAPItello-290
trial results have not shown what we hoped, they provide important
information to further understand this aggressive form of breast
cancer where patients are in urgent need of new
treatments."
Susan Galbraith, Executive Vice
President, Oncology R&D, AstraZeneca, said: "We are committed
to advancing science for patients in some of the most challenging
cancers, including this heterogeneous subtype of breast cancer.
While we are disappointed in the CAPItello-290 outcome, these
results will further our understanding of the role of the PI3K/AKT
pathway in breast cancer as we continue our clinical research
across the Truqap clinical
development programme and across our pipeline."
The safety profile of Truqap in combination with paclitaxel
in CAPItello-290 was broadly consistent with the known safety
profile of each medicine with no new safety concerns
identified. Data will be shared in due course.
Truqap is currently being
evaluated in Phase III trials for the treatment of breast cancer
(CAPItello-292) and prostate cancer (CAPItello-280 and
CAPItello-281) in combination with established
treatments.
Notes
Triple-negative
breast cancer
1st-line treatment for advanced or metastatic TNBC
usually consists of chemotherapy alone or in combination with an
immunotherapy - options generally associated with response rates
between 30 to 50%.2,5,6 Among patients with tumours that
do respond to initial treatment, disease progression is common and
rapid, often occurring within two years.2,6-8 The
average overall survival of patients living with advanced or
metastatic TNBC is 12 to 18 months, with only about 14% of patients
living five years following diagnosis.9,10
CAPItello-290
CAPItello-290 is a Phase III,
double-blind, randomised trial evaluating the efficacy and safety
of Truqap in
combination with paclitaxel versus placebo in combination with
paclitaxel in the 1st-line treatment of patients with locally
advanced (inoperable) or metastatic TNBC.
The global trial enrolled 923 adult
patients with histologically confirmed
locally advanced or metastatic TNBC. The trial has
dual primary endpoints of OS 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).
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 the US,
Japan 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 also approved in Australia
for the treatment of adult patients with HR-positive, HER2-negative
locally advanced or metastatic breast cancer following recurrence
or progression on or after an endocrine based regimen based on
these trial results.
Truqap is currently being
evaluated in Phase III trials for the treatment of breast cancer
(CAPItello-292) and prostate cancer (CAPItello-280 and
CAPItello-281) in combination with established
treatments.
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).
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), 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
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@AstraZeneca.
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References
1. Bray F, et al. Global
cancer statistics 2022: GLOBOCAN estimates of incidence and
mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 Apr 4. doi:
10.3322/caac.21834.
2. O'Reilly D, et al. Overview of recent advances in metastatic
triple negative breast cancer. World J Clin Oncol. 2021;
12(3):164-182.
3. Cerner CancerMPact database. Accessed May 2024.
4. Cocco S, et al. Biomarkers in Triple-Negative Breast Cancer:
State-of-the-Art and Future Perspectives. Int J Mol Sci. 2020; 21(13):
4579.
5. Bergin A, et al. Triple-negative breast cancer: recent
treatment advances. F1000Res. 2019;
8:10.12688/f1000research.18888.1.
6. Zhang Y, et al. Genomic features of rapid versus late relapse
in triple negative breast cancer. BMC Cancer. 2021; 21(568).
7. Cortes J, et al. Pembrolizumab plus Chemotherapy in Advanced
Triple -Negative Breast
Cancer. N Engl J Med. 2022; 387:217-226.
10.1056/NEJMoa2202809.
8. Emans L, et al. Atezolizumab and nab-Paclitaxel in Advanced
Triple-Negative Breast Cancer: Biomarker Evaluation of the
IMpassion130 Study. J Natl Cancer
Inst. 2021; 113(8): Djab004.
9. National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available
at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed June 2024.
10. Sharma P, et al. Biology and Management of Patients with
Triple-Negative Breast Cancer. Oncologist.
2016; 21(9);1050-62. 10.1634/theoncologist.2016-0067.
Adrian Kemp
Company Secretary
AstraZeneca PLC