Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy.
Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off).
No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment.
The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.
Clinical genitourinary cancer. 2022 Nov 26 [Epub ahead of print]
Neal Shore, Begoña Mellado, Satish Shah, Ralph Hauke, Dan Costin, Nabil Adra, Marie Cullberg, Carlos Fernandez Teruel, Thomas Morris
Carolina Urologic Research Center, Myrtle Beach, SC. Electronic address: ., Medical Oncology Department Hospital Clinic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain., Gettysburg Cancer Center, Gettysburg, PA., Nebraska Cancer Specialists, Omaha, NE., White Plains Hospital Center for Cancer Care, White Plains, NY., Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN., R&D BioPharmaceuticals, AstraZeneca, Gothenburg, Sweden., R&D BioPharmaceuticals, AstraZeneca, Cambridge, UK., R&D Oncology, AstraZeneca, Cambridge, UK.