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Published on: March 6, 2018
A Phase I Study of Capivasertib in Combination With Abiraterone Acetate in Patients With Metastatic
Neal Shore1, Begoña Mellado2, Satish Shah3
1Carolina Urologic Research Center, Myrtle Beach, SC.
Background:
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.
Methods:
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).
Results:
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.
Conclusion:
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.
Insights
Adding capivasertib to abiraterone acetate showed an acceptable safety profile in metastatic prostate cancer patients. This combination therapy warrants further investigation for advanced prostate cancer treatment.
Area of Science:
- Oncology
- Pharmacology
Background:
- Metastatic prostate cancer often develops resistance to androgen receptor-targeted agents.
- The PI3K/AKT/PTEN pathway is implicated in therapy resistance, suggesting pathway inhibitors as a potential treatment strategy.
- This study investigated the addition of capivasertib, an AKT inhibitor, to abiraterone acetate therapy.
Purpose of the Study:
- To evaluate the safety and tolerability of combining capivasertib with abiraterone acetate.
- To assess the pharmacokinetics (PK) of the combination therapy.
- To explore the preliminary clinical activity of this combination in metastatic prostate cancer.
Main Methods:
- An open-label phase Ib study was conducted.
- Twenty-seven patients with metastatic castration-resistant prostate cancer received abiraterone acetate plus prednisone and capivasertib on an intermittent schedule.
- Safety, tolerability, PK, and prostate-specific antigen (PSA) changes were monitored.
Main Results:
- No dose-limiting toxicities were observed.
- Common adverse events included diarrhea, anemia, asthenia, and nausea. Grade 3 or higher events included acute kidney injury and hyperglycemia.
- Nine participants (33%) achieved a ≥20% decrease in PSA. PK profiles were consistent with monotherapy.
Conclusions:
- The combination of capivasertib and abiraterone acetate demonstrated an acceptable tolerability profile.
- The safety profile was consistent with the known profiles of each individual agent.
- Further evaluation of this combination in advanced prostate cancer is supported by these findings.
