ESMO Congress 2026

In prostate cancer, PTEN deficiency activates the PI3K/AKT pathway, constituting an independent proliferative drive that androgen receptor pathway inhibitors cannot suppress, and is associated with worse outcomes ^[1]. Capivasertib is an oral selective AKT inhibitor designed to suppress downstream signaling from PI3K pathway activation ^[4]. The pivotal phase III CAPItello-281 study (NCT04493853) enrolled patients with PTEN-deficient mHSPC (diagnostic cutoff: ≥90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining), who received capivasertib or placebo (1:1) plus abiraterone, prednisone/prednisolone, and ADT; the primary endpoint was investigator-assessed rPFS, with OS as a key secondary endpoint. The primary analysis showed a statistically significant rPFS improvement and led to FDA approval of this regimen ^[1][4]. At screening, 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors ^[1], and notable adverse events included hyperglycemia, diarrhea, and rash ^[4].

At ESMO 2026, the updated survival analysis of CAPItello-281 was reported as a concomitant paper in Annals of Oncology, presented by Karim Fizazi. The phase III trial enrolled 1012 patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer; both arms received ADT, and this update adds 17 months of follow-up beyond the prior analysis. Median OS was 57.4 vs 46.5 months, HR 0.82 (95% CI 0.68–0.99), p=0.044; median rPFS was 35.5 vs 26.0 months, HR 0.83 (95% CI 0.70–0.99), p=0.033; and median SSE-FS was 43.8 vs 35.9 months, HR 0.83 (95% CI 0.69–0.99), p=0.044. Safety was consistent with the primary analysis, with diarrhea, hyperglycemia, and rash prominent; however, OS was a descriptive analysis and, despite a nominal p=0.044, did not cross the pre-specified statistical significance threshold.

Relative to prior knowledge, this update moves the evidence from rPFS toward longer-term survival: after 17 additional months of follow-up, OS shows a numerical improvement (57.4 vs 46.5 months) with an HR of 0.82, an encouraging trend, and the rPFS benefit is sustained. This has a clear reference point in the current first-line mHSPC landscape, where pooled comparative evidence on first-line combination therapies was specifically limited to all-comer randomized trials, with targeted and biomarker-driven strategies reviewed as a separate category ^[5]; PTEN loss itself is an established adverse feature in the ARPI plus ADT setting ^[6]. By selecting this population via immunohistochemistry and combining AKT inhibition with AR-pathway inhibition, CAPItello-281 adds continuing supportive evidence for a biomarker-selected first-line strategy ^[1].

Limitations: OS did not cross the pre-specified significance threshold at this analysis and remains descriptive, requiring longer follow-up; the strategy depends on PTEN immunohistochemistry screening ^[1], and adverse events such as diarrhea, hyperglycemia, and rash still require management in the combination setting ^[4].