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.
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.
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.
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.
Annals of oncology : official journal of the European Society for Medical Oncology. 2025 Oct 19 [Epub ahead of print]
Karim Fizazi, Noel W Clarke, Maria De Santis, Hirotsugu Uemura, Andre P Fay, Nuri Karadurmus, Mariusz Kwiatkowski, Carlos Alvarez-Fernandez, Shusuan Jiang, Miguel Sotelo, Dominique Parslow, Niara Oliveira, Tae Gyun Kwon, Dingwei Ye, Steve Boudewijns, Pongwut Danchaivijitr, Claire Rooney, Christopher Gresty, Marc Yeste-Velasco, Jill Logan, Daniel J George, CAPItello-281 Study Group
Department of Cancer Medicine, Institut Gustave Roussy, Centre Oscar Lambret, University of Paris Saclay, Villejuif, France. Electronic address: ., The Christie and Salford Royal NHS Foundation Trusts, University of Manchester, Manchester, UK., Charite Universitätsmedizin Berlin, Berlin, Germany; Medical University of Vienna, Vienna, Austria., Kindai University Hospital, Osaka, Japan., Hospital Nora Teixeira and PUCRS School of Medicine, Porto Alegre, Brazil., SBU Gulhane Training and Research Hospital, Ankara, Turkey., Szpital Wojewódzki w Koszalinie, Koszalin, Poland., Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain., Hunan Cancer Hospital, Hunan, China., Hospital Maria Auxiliadora, Lima, Peru., Derriford Hospital, Plymouth, UK., Mater Hospital Brisbane, Mater Misericordiae Ltd, Brisbane, Australia; Mater Clinical Unit, School of Clinical Medicine, The University of Queensland, Brisbane, Australia., Kyungpook National University Chilgok Hospital, Daegu, South Korea., Fudan University Shanghai Cancer Center, Shanghai, China., Bravis Ziekenhuis, Roosendaal, Netherlands., Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand., AstraZeneca, Cambridge, UK., AstraZeneca, Barcelona, Spain., AstraZeneca, Gaithersburg, MD, USA., Duke University Cancer Institute, Durham, NC, USA.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41120017