Updated CAPItello-281 data show numerical OS benefit with capivasertib in PTEN-deficient mHSPC

Adding the AKT inhibitor capivasertib (Truqap) to abiraterone acetate and androgen deprivation therapy (ADT) was associated with an approximately 11-month difference in median overall survival (OS) in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC). This finding comes from an updated, descriptive analysis of the phase 3 CAPItello-281 trial (NCT04493853) presented at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.¹

The data add survival context to a regimen the FDA approved in June 2026 on the basis of radiographic progression-free survival (rPFS).

“Patients with metastatic hormone-sensitive disease and de novo presentation have really poor outcomes,” said presenting author Karim Fizazi, MD, PhD, during the presentation at ESMO. “For these patients, dual inhibitions of the PI3K and AKT pathway on top of the androgen receptor pathway might be needed to address the key drivers of disease.”

Trial design

CAPItello-281 is a global, double-blind, multicenter phase 3 trial. It enrolled patients with de novo mHSPC whose tumors were PTEN deficient, defined as at least 90% of viable malignant cells showing no specific cytoplasmic PTEN staining by immunohistochemistry. In total, 1012 patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily on an intermittent schedule (4 days on, 3 days off), or placebo. Both arms also received abiraterone 1000 mg daily with prednisone or prednisolone plus ADT. Randomization was stratified by disease volume and visceral metastases and by geography.

The primary end point was investigator-assessed rPFS. At the primary data cutoff (October 7, 2024), median rPFS was 33.2 months with capivasertib compared with 25.7 months with placebo (HR, 0.81; 95% CI, 0.66 to 0.98; P = .034).² At that point, OS was only 26% mature.

Updated efficacy findings

The ad hoc data cutoff (March 9, 2026) added approximately 17 months of follow-up and captured 421 deaths. Deaths occurred in 38.5% of the capivasertib arm and 44.8% of the placebo arm. The OS curves began to separate after approximately 1 year. At 42% OS maturity, median OS was 57.4 months with capivasertib plus abiraterone compared with 46.5 months with placebo plus abiraterone (HR, 0.82; 95% CI, 0.68 to 0.99; P = .044).

Rates of subsequent anticancer therapy were similar between arms (38.7% vs 40.8%), although subsequent chemotherapy was somewhat less frequent in the capivasertib arm (25.6% vs 30.5%).

Point estimates for OS favored capivasertib across disease-volume subgroups. The HR was 0.74 (95% CI, 0.49 to 1.11) in patients with high-volume disease with visceral metastases, 0.89 (95% CI, 0.70 to 1.14) in those with high-volume disease without visceral metastases, and 0.70 (95% CI, 0.42 to 1.15) in those with low-volume disease.

The updated rPFS results were consistent with the primary analysis. Median rPFS was 35.5 months in the treatment arm compared with 26.0 months in the control arm (HR, 0.83; 95% CI, 0.70 to 0.99; nominal P = .033), representing a 9.5 month difference. Symptomatic skeletal event-free survival (SSE-FS) also favored capivasertib, with a median of 43.8 months compared with 35.9 months (HR, 0.83; 95% CI, 0.69 to 0.99; nominal P = .044).

PTEN cutoff analyses

In post hoc exploratory analyses, the OS hazard ratio moved further toward benefit as the PTEN-loss threshold increased. Among patients with at least 95% PTEN loss, the HR was 0.76 (95% CI, 0.61 to 0.93), with median OS of 57.4 months compared with 41.1 months. The HR was 0.75 (95% CI, 0.56 to 1.02) at a 99% threshold and 0.74 (95% CI, 0.53 to 1.02) in patients with complete PTEN loss.

This mirrors the rPFS pattern reported in the primary publication. In that analysis, the control arm performed progressively worse as the PTEN-loss cutoff increased, translating into a numerically improved treatment effect.²

“Of course, this is post hoc analysis. We need to be very cautious,” Fizazi cautioned.

Safety

The safety profile was consistent with the primary analysis. The most common adverse events (AEs) with capivasertib compared with placebo were diarrhea (52.7% vs 9.5%), hyperglycemia (40.4% vs 13.9%), and rash (36.4% vs 8.0%). Grade 3 or higher AEs in the capivasertib arm included hyperglycemia in 11.3%, rash in 12.7%, and diarrhea in 6.4% of patients.

In the primary publication, deaths associated with an AE occurred in 7.2% and 5.2% of patients, respectively.²

Fizazi concluded, “We believe that these results support capivasertib, ADT, and abiraterone as a first-in-class treatment for the PTEN-deficient mCSPC population with an adverse prognosis, and this applies to both populations, high-volume and low-volume [disease].”

__________

REFERENCES

1. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN-deficient metastatic hormonesensitive prostate cancer (mHSPC): Updated overall survival (OS) from CAPItello-281. Presented at: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. LBA56. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/LBA56.html.pdf

2. Fizazi K, Clarke NW, Santis MD, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004