Capivasertib in combination with fulvestrant: New treatment options for HR+/HER2− metastatic breast cancer

The identification and understanding of various signaling pathways involved in the pathogenesis of malignant neoplasms, particularly breast cancer (BC), have significantly transformed the therapeutic landscape of this disease. Hormone receptor-positive (HR + ) HER2-negative (HER2 − ) metastatic BC (mBC) is the most common but biologically heterogeneous subtype, which largely accounts for the variability in response to endocrine therapy. In patients without visceral crisis, endocrine therapy remains the preferred treatment option due to its higher efficacy and better tolerability compared with chemotherapy. Activation of the AKT signaling pathway promotes tumor cell growth, proliferation, and survival, leading to the development of endocrine resistance. PIK3CA and AKT mutations, as well as PTEN loss, are among the most frequent alterations, occurring in approximately 20–40% of patients with early-stage BC and in up to 40% of those with metastatic disease. As an AKT inhibitor, capivasertib has shown promising results in both preclinical studies and clinical trials, either as monotherapy or in combination with fulvestrant. The FAKTION trial demonstrated the efficacy and safety of capivasertib combined with fulvestrant, particularly in patients with alterations in the PI3K/AKT/PTEN signaling pathway. The CAPItello-291 study confirmed these findings, leading to the approval of this combination for the treatment of HR + /HER2 − breast cancer harboring PI3K/AKT/PTEN pathway alterations. Several clinical trials are currently underway to evaluate the efficacy of capivasertib, including that in the first-line treatment of patients with HR + /HER2 − mBC harboring PI3K/AKT/PTEN pathway alterations.