A phase I study of abiraterone acetate combined with BEZ235, a dual PI3K/mTOR inhibitor, in metastatic castration resistant prostate cancer

Xiao X. Wei, Andrew C. Hsieh, Won Kim, Terence Friedlander, Amy M. Lin, Mirela Louttit, Charles J. Ryan

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background. Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance. Methods. This phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy. Results. Six patients (n=6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3+3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed. Conclusion. The combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile.

Original languageEnglish (US)
Pages (from-to)503-e43
JournalOncologist
Volume22
Issue number5
DOIs
StatePublished - May 2017
Externally publishedYes

Bibliographical note

Funding Information:
Novartis Pharmaceuticals provided financial support for this study. The authors thank all patients who participated in this study and their families.

Publisher Copyright:
© AlphaMed Press 2017.

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