AstraZeneca's First-in-Class Pan-AKT Inhibitor Capivasertib Shows Significant Efficacy in Phase III Trial for HR+ Breast Cancer

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October 26, 2022 /BioValleyBIOON/ -- AstraZeneca recently announced positive high-level results from the CAPItello-291 Phase III trial. This is a global, double-blind, randomized Phase III trial and part of a large-scale clinical program focused on researchingCapivasertib (AZD5363), a potential first-in-class, orally available pan-AKT (serine/threonine kinase) inhibitor, exhibits potent inhibitory activity against all three AKT isoforms (AKT1/2/3).

CAPItello-291 trial is evaluatingCapivasertib in combination with Faslodex (fulvestrant), Placebo combined with Faslodex forTreatment of locally advanced (inoperable) or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) low expression or negativeBreast Cancer。

This global trial enrolled 708 adult patients with histologically confirmed HR+, HER2-low or negative locally advanced (inoperable) or metastatic breast cancer, whose disease had recurred or progressed during or after treatment with aromatase inhibitors (with or without CDK4/6 inhibitors), and who had received up to one chemotherapy regimen for advanced disease. The trial includedTwo primary endpoints: Progression-Free Survival (PFS) in the overall patient population and in patient subgroups (tumors with PIK3CA, AKT1, or PTEN gene alterations)In the trial, approximately 40% of patients had tumors with PI3K/AKT/PTEN gene alterations.

The results showed,The trial met two primary endpoints of PFS: compared with placebo + Faslodex, the combination regimen of capivasertib + Faslodex improved PFS in the overall patient population and patient subgroups.Although the overall survival (OS) data were not yet mature at the time of analysis, early results are encouraging. The trial will continue to evaluate OS as a key secondary endpoint. In this trial, the safety profile of capivasertib in combination with Faslodex was consistent with what has been observed in previous trials assessing this combination.

Data from the CAPItello-291 trial will be presented at an upcoming medical conference and shared with regulatory authorities worldwide.Results from the all-comers population indicate that, as an AKT inhibitor, capivasertib has the potential to offer a novel first-in-class treatment option for patients with HR+ breast cancer, regardless of their biomarker status.HR+ breast cancer patients often experience disease progression or develop resistance to existing endocrine therapies when treated for advanced disease, creating an urgent need for new therapies to extend the effectiveness of endocrine-based treatment approaches.

Chemical Structure of Capivasertib (Source: chemsrc.com)

HR-positive (HR+) breast cancer (expressing estrogen or progesterone receptors, or both) is the most common subtype of breast cancer.，The growth of HR+ breast cancer cells is typically driven by estrogen receptors (ER).Endocrine therapies targeting ER-driven diseases are widely used as first-line treatments for advanced breast cancer, often in combination with cyclin-dependent kinase (CDK) 4/6 inhibitors. However, many patients with advanced disease develop resistance to CDK4/6 inhibitors and current endocrine therapies, leaving limited treatment options. Optimizing endocrine therapy and overcoming resistance in all treatment phases for patients with ER-driven breast cancer remains a key focus of breast cancer research.

Capivasertib is an orally administered small-molecule AKT inhibitor, acting as a potent and selective adenosine triphosphate (ATP)-competitive inhibitor, with strong inhibitory effects on all three AKT isoforms (AKT1/2/3).Currently, capivasertib is being evaluated in combination with existing therapies,For the treatment of tumors with alterations in the PI3K/AKT/PTEN signaling pathway and tumors dependent on the survival of this signaling pathway.Capivasertib is administered according to an intermittent dosing regimen (4 days on, 3 days off), which was selected based on the tolerability and degree of target inhibition observed in earlier trials.

Capivasertib was discovered by AstraZeneca following a collaboration with Astex Therapeutics. Capivasertib is an investigational oral medication currently in Phase 3 trials for the treatment of multiple subtypes of breast and prostate cancer, as well as in Phase 2 trials for the treatment of hematologic malignancies. (Bioon.com)

Source of the original text:Capivasertib plus Faslodex significantly improved progression-free survival vs. Faslodex in CAPItello-291 Phase III trial in advanced HR-positive breast cancer