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 tumours 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 tumour 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 (https://www.astrazeneca.com/media-centre/press-releases/2022/capivasertib-pfs-in-hr-positive-breast-cancer.html) Phase III trial presented at the 2022 San Antonio Breast Cancer Symposium and recently published online in The New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2214131).[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.

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 tumours 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]

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
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 (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 AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours 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 haematologic 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 tumours harbouring alterations in the AKT pathway (PI3K/AKT/PTEN), and in tumours reliant on signalling 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 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 Limited).

Faslodex
Faslodex is an endocrine therapy indicated for the treatment of oestrogen 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-oestrogen therapy, or disease progression on anti-oestrogen 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 oestrogen 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 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 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 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), capivasertib 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 (http://www.astrazeneca.com/) and follow the Company on Twitter @AstraZeneca (https://twitter.com/AstraZeneca).

Contacts
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References

1. FDA. Priority Review. Available at: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review. Accessed June 2023.
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. 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.
4. National Cancer Institute. Surveillance, Epidemiology and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed June 2023. 
5. 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.
6. 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.
7. Turner N, et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. NEJM. 2023; 388:2058-70.
8. 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.
9. 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.