CAPItello-281, presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU 2026), evaluated patient-reported outcomes (PROs) and tolerability of capivasertib plus abiraterone compared with placebo plus abiraterone in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC).
The Phase III study investigates the clinical impact of targeting the AKT signaling pathway, which is frequently activated in prostate cancer with PTEN loss. Alongside previously reported improvements in radiographic progression-free survival, this analysis provides important data on health-related quality of life and treatment-related adverse events, helping to clarify the patient experience associated with capivasertib-based therapy in this molecularly defined population.
Background
Loss of the PTEN tumor suppressor gene is one of the most common molecular alterations in advanced prostate cancer and is associated with activation of the PI3K/AKT signaling pathway, promoting tumor growth and resistance to androgen-targeted therapies. Despite major advances in the treatment of metastatic hormone-sensitive prostate cancer (mHSPC), including androgen deprivation therapy (ADT) combined with androgen receptor–targeted agents such as abiraterone, patients with PTEN-deficient tumors continue to represent a biologically aggressive subgroup with limited targeted therapeutic options. Capivasertib is a selective oral AKT inhibitor designed to suppress downstream signaling from PI3K pathway activation.
The Phase III CAPItello-281 trial (NCT04493853) evaluated whether adding capivasertib to abiraterone could improve outcomes in patients with PTEN-deficient de novo mHSPC. Previous analyses demonstrated that the combination significantly improved radiographic progression-free survival (rPFS) compared with placebo plus abiraterone.
Methods and Study Design
CAPItello-281 evaluated health-related quality of life (HRQoL) and treatment tolerability in patients receiving capivasertib plus abiraterone compared with placebo plus abiraterone, both administered with standard androgen deprivation therapy (ADT) and prednisone or prednisolone. Patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire, a validated instrument that evaluates multiple dimensions of quality of life in patients with prostate cancer.
The FACT-P questionnaire includes a total score and several domain-specific subscales, including physical wellbeing (PWB) and functional wellbeing (FWB). Clinically meaningful changes were predefined as:
- ≥10-point change in the FACT-P total score
- ≥3-point change in PWB or FWB subscales
Time to deterioration (TTD) analyses were performed to evaluate the time until a clinically meaningful worsening in these measures. In addition, adverse events commonly associated with AKT inhibition, including diarrhea, rash, and hyperglycemia, were assessed descriptively, with attention to their time of onset, need for treatment modification, and recovery.
CAPItello-281 is a Phase III, randomized, double-blind, placebo-controlled trial enrolling patients with PTEN-deficient metastatic hormone-sensitive prostate cancer. PTEN deficiency was defined by immunohistochemistry as absence of specific cytoplasmic staining in ≥90% of viable malignant cells.
A total of 1,012 patients were randomized in a 1:1 ratio to receive:
- Capivasertib + abiraterone + prednisone/prednisolone + ADT (n = 507)
- Placebo + abiraterone + prednisone/prednisolone + ADT (n = 505)
Of these, 503 patients in each treatment arm received at least one dose of study therapy.
The median treatment duration was:
- 13.6 months (range 0.1–46.6) in the capivasertib arm
- 14.9 months (range 0.1–47.1) in the placebo arm
At the time of analysis, 47.5% of patients in the capivasertib group and 53.5% in the placebo group remained on treatment.
Completion of the FACT-P questionnaire occurred in 60.9% of patients in the capivasertib arm and 62.8% in the placebo arm, providing evaluable patient-reported outcome data.
Results
Across the study population, overall health-related quality of life was generally maintained with the addition of capivasertib to abiraterone.There were no clinically meaningful differences between treatment arms in the change from baseline for key HRQoL measures.
- For the FACT-P total score, the difference between treatment arms was 0.4 points (95% CI −1.97 to 2.78)
- For the physical wellbeing (PWB) subscale, the difference was −0.4 points (95% CI −0.89 to 0.14)
- For the functional wellbeing (FWB) subscale, the difference was −0.3 points (95% CI −1.01 to 0.37)
These findings indicate that the addition of capivasertib did not significantly worsen overall quality of life or functional status compared with standard therapy.
However, time to deterioration in physical wellbeing occurred earlier in the capivasertib arm, with:
HR 1.43 (95% CI 1.15–1.78)
This difference was likely driven by symptomatic adverse events such as diarrhea and rash.
In contrast, 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)
- Functional wellbeing: HR 1.06 (95% CI 0.86–1.32)
These findings suggest that while certain physical symptoms were more frequent with capivasertib, overall functional quality of life remained stable.Adverse events associated with capivasertib were generally consistent with the known toxicity profile of AKT inhibitors and occurred early during treatment.
The most common events included diarrhea, rash, and hyperglycemia.
Diarrhea
- Occurred in 51.9% of patients receiving capivasertib versus 8.0% with placebo
- Median time to onset: 12 days (IQR 3–43) with capivasertib vs 142 days (IQR 28–339) with placebo
- Led to dose reduction in 4.4% of patients
- Led to treatment interruption in 12.5%
- Led to treatment discontinuation in 1.0%
Supportive therapy was required in 33.2% of patients, and 47.3% recovered or were recovering at the time of analysis.
Rash
- Occurred in 35.4% of patients receiving capivasertib vs 7.0% with placebo
- Median time to onset: 13 days (IQR 11–43) with capivasertib vs 78 days with placebo
Treatment modifications included:
- Dose reduction in 8.5%
- Dose interruption in 16.9%
- Treatment discontinuation in 4.8%
- Supportive therapy was administered in 29.0% of patients.
Hyperglycemia
- Observed in 38.0% of patients in the capivasertib arm compared with 12.9% in the placebo arm
- Median time to onset: 54 days vs 114 days
Treatment modifications included:
- Dose reduction in 6.6%
- Dose interruption in 10.9%
- Treatment discontinuation in 1.0%
- Supportive therapy was given in 25.2% of patients.
Overall, these toxicities were manageable with supportive treatment and dose modifications.
Conclusion
The Phase III CAPItello-281 trial provides important evidence supporting the use of capivasertib plus abiraterone in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer. The combination improves disease control while maintaining overall patient-reported quality of life, despite higher rates of manageable early adverse events. These findings suggest that AKT pathway inhibition can be incorporated into treatment strategies for molecularly defined prostate cancer populations, offering a targeted approach for patients with PTEN loss while preserving functional wellbeing during therapy.