Is Capivasertib Effective in Treatment?

Capivasertib is an investigational serine/threonine kinase (AKT) inhibitor.

Is Capivasertib Effective in Treatment?

The CAPItello-291 study is a phase III, double-blind, randomized controlled clinical trial, which is part of a large-scale clinical development program centered on capivasertib. This study aims to evaluate the efficacy of capivasertib combined with fulvestrant versus placebo combined with fulvestrant in the treatment of patients with locally advanced (unresectable) or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low or negative (defined as immunohistochemistry (IHC) score 0 or 1+, or IHC 2+/in situ hybridization (ISH) negative) breast cancer.

This global clinical trial enrolled a total of 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer. All enrolled patients experienced disease recurrence or progression during or after aromatase inhibitor therapy; among them, some had previously received cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment while others had not. In addition, all patients had received no more than one chemotherapy regimen for advanced disease.

Which Tests Are Required to Identify Eligible Patients?

Prior to the initiation of capivasertib treatment, genetic testing is recommended to identify specific mutations that can predict treatment efficacy. Key genetic tests include the following:

1. PIK3CA mutation testing: Detecting PIK3CA gene mutations is critical because capivasertib targets the PI3K/AKT pathway. It has been demonstrated that patients harboring PIK3CA mutations derive greater benefits from therapies targeting this pathway.

2. AKT1 mutation testing: Identifying AKT1 gene mutations is essential given that capivasertib directly inhibits AKT, a key protein in this pathway.

3. PTEN deletion or mutation testing: PTEN is a tumor suppressor gene that negatively regulates the PI3K/AKT pathway. Deletion or mutation of PTEN can lead to activation of this pathway, making patients more likely to respond to capivasertib.

Pharmacodynamics of Capivasertib

In in vitro experiments, capivasertib inhibits the growth of breast cancer cell lines, including those harboring relevant PIK3CA or AKT1 mutations or PTEN alterations. In in vivo experiments, capivasertib, either as monotherapy or in combination with fulvestrant, inhibits tumor growth in mouse xenograft models, including estrogen receptor-positive breast cancer models with PIK3CA, AKT1 and PTEN alterations.

The exposure-response relationship and the time course of pharmacodynamic effects associated with capivasertib efficacy have not been fully elucidated. Within the dose range of 80 to 800 mg (equivalent to 0.2 to 2 times the approved recommended dose), an exposure-response relationship was observed for diarrhea (Common Terminology Criteria for Adverse Events [CTCAE] grades 2–4), rash (CTCAE grades 2–4) and hyperglycemia (CTCAE grades 3 or 4).

At the recommended dose, no mean prolongation of the QTc interval exceeding 20 milliseconds was observed.