AstraZeneca recently announced positive top-line results from the Phase 3 CAPItello-291 trial. This global, double-blind, randomized Phase 3 study forms part of a large-scale clinical program focused on capivasertib (AZD5363), a potential first-in-class, orally active pan-AKT (serine/threonine kinase) inhibitor that potently inhibits all three AKT isoforms (AKT1/2/3).
Capivasertib is an oral small-molecule AKT inhibitor. As a potent and selective ATP-competitive inhibitor, it exerts strong inhibitory activity against all three AKT isoforms (AKT1/2/3).
The CAPItello-291 trial is evaluating capivasertib plus Faslodex (fulvestrant) versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or negative breast cancer.
This global trial enrolled a total of 708 adult patients with histologically confirmed HR+, HER2-low or negative locally advanced (inoperable) or metastatic breast cancer, whose disease had relapsed or progressed during or after treatment with an aromatase inhibitor (with or without a CDK4/6 inhibitor), and who had received up to one prior chemotherapy regimen for advanced disease. The trial had two primary endpoints: progression-free survival (PFS) in the overall patient population and in a subgroup of patients with tumors harboring PIK3CA, AKT1, or PTEN gene alterations. Approximately 40% of patients in the trial had tumors with PI3K/AKT/PTEN gene alterations.
Results showed that the trial met both primary PFS endpoints: the capivasertib plus Faslodex combination improved PFS in both the overall patient population and the biomarker subgroup compared with placebo plus Faslodex. Although overall survival (OS) data were immature at the time of analysis, early findings were encouraging. The trial will continue to evaluate OS as a key secondary endpoint. The safety profile of capivasertib in combination with Faslodex in this trial was consistent with that observed in previous studies evaluating this regimen.
Data from the CAPItello-291 trial will be presented at an upcoming medical congress and shared with regulatory authorities worldwide. The above results in the all-comers population indicate that capivasertib, an AKT inhibitor, has the potential to offer a novel first-in-class treatment option for patients with HR+ breast cancer regardless of their biomarker status. Patients with HR+ breast cancer frequently experience disease progression or develop resistance to existing endocrine therapies for advanced disease, creating an urgent need for new treatments to expand the efficacy of endocrine-based approaches.
Capivasertib is currently being evaluated in combination with existing therapies for tumors with alterations in the PI3K/AKT/PTEN signaling pathway and those dependent on this pathway for survival. It is administered on an intermittent dosing schedule (4 days on, 3 days off), selected based on tolerability and target inhibition observed in early trials. Phase 3 trials are also underway for multiple subtypes of breast and prostate cancer, along with a Phase 2 trial for hematologic malignancies.
