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Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study
Fizazi, K. Clarke, N. W. De Santis, M. Uemura, H. Fay, A. P. Karadurmus, N. Kwiatkowski, M. Alvarez-Fernandez, C. Jiang, S. Sotelo, M.
Fizazi, K.
Clarke, N. W.
De Santis, M.
Uemura, H.
Fay, A. P.
Karadurmus, N.
Kwiatkowski, M.
Alvarez-Fernandez, C.
Jiang, S.
Sotelo, M.
Abstract
BACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC), PTEN deficiency results in PI3K/AKT pathway activation, providing an independent proliferative drive, which cannot be suppressed by androgen receptor pathway inhibitors (ARPIs), resulting in worse outcomes. Dual inhibition of PI3K/AKT and AR pathways with capivasertib and abiraterone may delay progression and improve disease outcomes. PATIENTS AND METHODS: In CAPItello-281 (NCT04493853), patients with PTEN-deficient mHSPC (diagnostic cut-off: ≥90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining) received capivasertib or placebo (1:1) plus abiraterone, prednisone/prednisolone and androgen deprivation therapy (ADT). Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS); overall survival (OS) was a key secondary endpoint. Post-hoc exploratory subgroups at increasing PTEN cut-off thresholds were also assessed. RESULTS: 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors. In the randomized PTEN-deficient population, a statistically significant improvement in rPFS was observed with capivasertib plus abiraterone (n=507, median 33.2 months) versus placebo plus abiraterone (n=505, 25.7 months; Hazard Ratio [HR] 0.81, 95% CI 0.66-0.98, P=0.034). Post-hoc rPFS analyses for loss of PTEN cut-offs of ≥95%, ≥99%, and 100% showed the capivasertib plus abiraterone arm performed consistently across cutoffs, but the placebo plus abiraterone arm performed progressively worse as the cut-off for the degree of PTEN loss was increased, resulting in a numerically improved treatment effect. In the overall population studied, the HR for OS (26.4% maturity) was 0.90, 95% CI 0.71-1.15, P=0.401. The most common adverse events (AEs) for capivasertib plus abiraterone were diarrhea (51.9%; 8.0% placebo plus abiraterone), hyperglycemia (38.0%; 12.9%) and rash (35.4%; 7.0%). Deaths associated with an AE were reported in 36 (7.2%) and 26 (5.2%) patients in the capivasertib plus abiraterone and placebo plus abiraterone arms, respectively. CONCLUSIONS: Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone.
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Date
2025
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Article
Citation
Fizazi K, Clarke NW, De Santis M, Uemura H, Fay AP, Karadurmus N, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study. Annals of oncology : official journal of the European Society for Medical Oncology. 2025 Oct 19. PubMed PMID: 41120017. Epub 2025/10/22. eng.