Introduction: Addressing the Challenge of PTEN-Deficient Prostate Cancer
The landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has undergone a rapid transformation over the last decade. The standard of care has shifted from androgen deprivation therapy (ADT) alone to intensification strategies involving androgen receptor pathway inhibitors (ARPIs), docetaxel, or triplet therapies. However, despite these advances, a significant subset of patients experiences early progression and poor long-term outcomes. One of the most critical drivers of this resistance is the loss of the phosphatase and tensin homolog (PTEN) tumor suppressor.
PTEN deficiency occurs in approximately 25% to 30% of patients with mHSPC. Loss of PTEN leads to the constitutive activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. This pathway provides an independent survival and proliferative signal to cancer cells, effectively bypassing the blockade of the androgen receptor (AR) pathway. Historically, patients with PTEN-deficient mHSPC have had a worse prognosis and a shorter duration of response to conventional ARPIs. The CAPItello-281 study (NCT04493853) was designed to address this unmet need by evaluating whether the addition of capivasertib, a potent and selective pan-AKT inhibitor, to abiraterone could overcome this resistance.
