Efficacy and safety of capivasertib-based combination therapy in PTEN-deficient advanced or metastatic prostate cancer: A systematic review and meta-analysis.

e17058 Background: In advanced and metastatic prostate cancer, PTEN loss is a frequent change that activates the PI3K–AKT pathway and causes resistance to conventional treatments. Capivasertib, a selective AKT inhibitor, was tested in conjunction with routine therapies to improve results in this molecularly characterized cohort. Methods: For adult patients with PTEN-deficient advanced or metastatic prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC) we conducted a systematic review and meta-analysis of randomized controlled trials comparing capivasertib-based combination therapy versus matched standard-of-care regimens without AKT inhibition. Abiraterone acetate (with or without prednisolone), enzalutamide, or docetaxel with prednisolone, were used as background treatments. Radiographic or Composite progression-free survival (PFS), overall survival (OS), Prostate Specific Antigen (PSA)-related outcomes, treatment termination due to adverse events (AEs), grade ≥3 diarrhea, and grade ≥3 exhaustion were the outcomes evaluated. Random-effects models were used to pool risk ratios (RRs) and hazard ratios (HRs). Results: There were three randomized studies. Capivasertib-based combination therapy improved PFS considerably compared to control (HR 0.83; 95% CI, 0.70-0.98; I² = 0%). A positive trend toward better OS was noted (HR 0.76; 95% CI, 0.57-1.00; I2= 47%). Capivasertib combinations also improved PSA-related outcomes (RR 0.78; 95% CI, 0.63-0.98; I2= 0%). Nevertheless, capivasertib was linked to an increased probability of discontinuing therapy due to adverse events (RR 3.21; 95% CI, 2.25-4.56; I2= 0%). While grade ≥3 fatigue was similar acrossgroups (RR 0.92; 95% CI, 0.71-1.19; I2= 0%), grade ≥3 diarrhea was numerically greater but extremely diverse among trials (RR 4.45; 95% CI, 0.37–54.04; I² = 92%). Conclusions: Capivasertib-based combination therapy offers a slight but noteworthy increase in PFS and PSA-related outcomes in patients with PTEN-deficient advanced or metastatic prostate cancer, with a signal toward OS benefit. Increased treatment dropout due to adverse events offsets these efficacy gains, emphasizing the significance of careful patient selection and toxicity management. AKT inhibition is a promising targeted therapy in this molecularly chosen population that should be further optimized in future trials.