Citation: Clin Cancer Res. 2019 May 21 [Epub ahead of print]
Author: Slovin SF, Hussain S, Saad F, Garcia JA, Picus J, Ferraldeschi R, Crespo M, Flohr PR, Riisnaes R, Lin C, Keer H, Oganesian A, Workman P, de Bono JS.
Abstract: Onalespib is a potent, fragment-derived second-generation HSP90 inhibitor with preclinical activity in castration-resistant prostate cancer (CPRC) models. This Phase 1/2 trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P Experimental Design: Subjects with progressing CRPC were randomized to receive one of two regimens of onalespib combined with AA/P. Onalespib was administered as intravenous (IV) infusion starting at 220 mg/m2 once weekly for 3 of 4 weeks (Regimen 1); or at 120 mg/m2 on Day 1 and Day 2 weekly for 3 of 4 weeks (Regimen 2). Primary endpoints were response rate and safety. Secondary endpoints included evaluation of androgen receptor (AR) depletion in circulating tumor cells (CTCs) and in fresh tumor tissue biopsies Results: Forty-eight patients were treated with onalespib in combination with AA/P. The most common ≥ Grade 3 toxicities related to onalespib included diarrhea (21%) and fatigue (13%). Diarrhea was dose-limiting at 260 mg/m2 and 160 mg/m2 for Regimen 1 and Regimen 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly up-regulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and post-treatment tumor biopsy samples. No subjects showed an objective or PSA response Conclusions:Onalespib in combination with AA/P, showed mild evidence of some biological effect, however this effect did not translate into clinical activity, hence further exploration of this combination was not justified.
Copyright ©2019, American Association for Cancer Research.
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