Targeting the PI3K/AKT pathway in prostate cancer: the role of PTEN deficiency and biomarker-guided therapy

Loss of the PTEN tumor suppressor gene is a common molecular feature in advanced prostate cancer and is associated with activation of the PI3K/AKT signaling pathway, which controls cell growth and survival. Despite major advances in the treatment of metastatic castration-sensitive prostate cancer (mCSPC), patients with PTEN-deficient tumors represent an aggressive subgroup with poorer clinical outcomes and limited targeted therapeutic options. Capivasertib is a selective oral AKT inhibitor designed to suppress downstream signaling from PI3K pathway activation. We highlight the recent results from the Phase III CAPItello-281 trial (NCT04493853) demonstrating that the addition of capivasertib to abiraterone acetate and androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival in patients with PTEN-deficient mCSPC, leading to the FDA-approval of this regimen. Notable adverse events in the cabavisertib arm included hyperglycemia, diarrhea, and rash. CAPItello-281 addresses a significant unmet need for PTEN-deficient mCSPC, suggesting AKT inhibition as a potential new targeted treatment strategy for a sub-population with poor prognosis.