Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study☆
Issued Date
2025-01-01
Resource Type
ISSN
09237534
eISSN
15698041
Scopus ID
2-s2.0-105024661258
Pubmed ID
41120017
Journal Title
Annals of Oncology
Rights Holder(s)
SCOPUS
Bibliographic Citation
Annals of Oncology (2025)
Suggested Citation
Fizazi K., Clarke N.W., De Santis M., Uemura H., Fay A.P., Karadurmus N., Kwiatkowski M., Alvarez-Fernandez C., Jiang S., Sotelo M., Parslow D., Oliveira N., Kwon T.G., Ye D., Boudewijns S., Danchaivijitr P., Rooney C., Gresty C., Yeste-Velasco M., Logan J., George D.J. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study☆. Annals of Oncology (2025). doi:10.1016/j.annonc.2025.10.004 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113599
Title
Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study☆
Author's Affiliation
The University of Manchester
The University of Queensland
Duke University
Charité – Universitätsmedizin Berlin
Medizinische Universität Wien
Institut de Cancerologie Gustave Roussy
AstraZeneca
Pontifícia Universidade Católica do Rio Grande do Sul
Siriraj Hospital
Gülhane Eğitim ve Araştırma Hastanesi
Fudan University Shanghai Cancer Center
Hospital Universitario Central de Asturias
The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University
Derriford Hospital
Instituto de Investigación Sanitaria del Principado de Asturias
Kyungpook National University Chilgok Hospital
Kindai University Hospital
Mater Hospital Brisbane
Hospital María Auxiliadora
Bravis Ziekenhuis
Szpital Wojewodzki
The University of Queensland
Duke University
Charité – Universitätsmedizin Berlin
Medizinische Universität Wien
Institut de Cancerologie Gustave Roussy
AstraZeneca
Pontifícia Universidade Católica do Rio Grande do Sul
Siriraj Hospital
Gülhane Eğitim ve Araştırma Hastanesi
Fudan University Shanghai Cancer Center
Hospital Universitario Central de Asturias
The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University
Derriford Hospital
Instituto de Investigación Sanitaria del Principado de Asturias
Kyungpook National University Chilgok Hospital
Kindai University Hospital
Mater Hospital Brisbane
Hospital María Auxiliadora
Bravis Ziekenhuis
Szpital Wojewodzki
Corresponding Author(s)
Other Contributor(s)
Abstract
Background: In metastatic hormone-sensitive prostate cancer (mHSPC), phosphatase and tensin homolog (PTEN) deficiency results in phosphoinositide 3-kinase (PI3K)/protein kinase B (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). The 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% confidence interval (CI) 0.66-0.98, P = 0.034]. Post hoc rPFS analyses for loss of PTEN cut-offs of ≥95%, ≥99%, and 100% showed that the capivasertib plus abiraterone arm performed consistently across cut-offs, 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.