CAPItello-281 Trial Shows Capivasertib Plus Abiraterone Maintains Quality of Life in PTEN-Deficient Prostate Cancer
Key Insights
The Phase III CAPItello-281 trial demonstrated that adding capivasertib to abiraterone maintained overall health-related quality of life in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (search).
While the combination showed higher rates of manageable adverse events including diarrhea (51.9%), rash (35.4%), and hyperglycemia (38.0%), these toxicities occurred early and were effectively managed with supportive care.
The study enrolled 1,012 patients and showed no clinically meaningful differences between treatment arms in FACT-P total scores, with approximately 80% of patients able to continue treatment.
The Phase III CAPItello-281 trial has provided crucial insights into the patient experience of combining capivasertib with abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer (search), demonstrating that the targeted therapy maintains overall quality of life despite increased early adverse events. The findings, presented by Daniel J. George, MD, FASCO, of Duke Cancer Institute at the 2026 ASCO Genitourinary Cancers Symposium, offer important guidance for clinicians considering this first-in-class targeted approach.
Study Design and Patient Population
CAPItello-281 enrolled 1,012 patients with PTEN (search)-deficient de novo metastatic hormone-sensitive prostate cancer (search), defined as absence of specific cytoplasmic staining in ≥90% of viable malignant cells by immunohistochemistry. Patients were randomized 1:1 to receive either capivasertib plus abiraterone/prednisone or placebo plus abiraterone/prednisone, both administered with androgen deprivation therapy.
The study utilized an intermittent dosing schedule for capivasertib at 400 mg twice daily (4 days on, 3 days off), specifically selected to maintain efficacy while mitigating cumulative side effects. Of the enrolled patients, 503 in each treatment arm received at least one dose of study therapy, with median treatment durations of 13.6 months in the capivasertib arm and 14.9 months in the placebo arm.
Quality of Life Outcomes Remain Stable
Patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire, with completion rates of 60.9% in the capivasertib arm and 62.8% in the placebo arm. The analysis revealed no clinically meaningful differences between treatment arms in key quality of life measures.
For the FACT-P total score, the difference between treatment arms was only 0.4 points (95% CI −1.97 to 2.78), well below the predefined clinically meaningful threshold of ≥10 points. Similarly, physical wellbeing showed a difference of −0.4 points (95% CI −0.89 to 0.14), and functional wellbeing demonstrated a difference of −0.3 points (95% CI −1.01 to 0.37), both below the ≥3-point threshold for clinical significance.
However, time to deterioration in physical wellbeing occurred earlier in the capivasertib arm, with a hazard ratio of 1.43 (95% CI 1.15−1.78). This difference was primarily driven by symptomatic adverse events such as diarrhea and rash occurring early in treatment. Importantly, no differences were observed between treatment arms in time to deterioration for FACT-P total score (HR 1.10; 95% CI 0.89−1.37) or functional wellbeing (HR 1.06; 95% CI 0.86−1.32).
Manageable Toxicity Profile
The adverse event profile was consistent with known AKT (search) inhibitor toxicities, with the most common events being diarrhea, rash, and hyperglycemia. These on-target effects occurred early during treatment and were generally manageable with supportive care and dose modifications.
Diarrhea occurred in 51.9% of patients receiving capivasertib versus 8.0% with placebo, with a median time to onset of 12 days compared to 142 days in the placebo group. The toxicity led to dose reduction in 4.4% of patients, treatment interruption in 12.5%, and discontinuation in only 1.0%. Supportive therapy was required in 33.2% of patients, with 47.3% recovering or in recovery at the time of analysis.
Rash affected 35.4% of capivasertib patients versus 7.0% receiving placebo, with a median onset of 13 days. This toxicity more frequently required treatment modifications, including dose interruption in 16.9%, dose reduction in 8.5%, and discontinuation in 4.8% of patients. Supportive therapy was administered in 29.0% of cases.
Hyperglycemia was observed in 38.0% of the capivasertib arm compared with 12.9% in the placebo arm, with a median time to onset of 54 days versus 114 days. Treatment modifications included dose reduction in 6.6%, dose interruption in 10.9%, and discontinuation in 1.0%, with supportive therapy given to 25.2% of patients.
Clinical Implications
Despite the higher adverse event rates, approximately 80% of patients were able to continue treatment with the capivasertib combination. The early occurrence of toxicities corresponded with the timing of treatment discontinuations, with 63% of capivasertib discontinuations occurring within the first 3 months. After this initial period, discontinuation rates became more parallel between arms, suggesting that early toxicity management is crucial for treatment continuation.
The findings build upon previously reported efficacy data showing that capivasertib plus abiraterone extended median radiographic progression-free survival to 33.2 months compared to 25.7 months with placebo, representing a 7.5-month improvement (HR 0.81; P = .034). Post hoc analyses suggested that patients with higher levels of PTEN (search) deficiency may derive greater benefit from the combination.
These results support the incorporation of AKT (search) pathway inhibition into treatment strategies for molecularly defined prostate cancer (search) populations, offering a targeted approach for patients with PTEN (search) loss while preserving functional wellbeing during therapy. The combination represents a potential first-in-class targeted treatment for patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (search), with manageable toxicities that do not significantly compromise overall quality of life.