Pharmacodynamic and clinical results from a Phase I/II study of the hsp90 inhibitor onalespib in combination with abiraterone acetate in prostate cancer

Susan Slovin, Syed Hussain, Fred Saad, Jorge Garcia, Joel Picus, Roberta Ferraldeschi, Mateus Crespo, Penelope Flohr, Ruth Riisnaes, Chihche Lin, Harold Keer, Aram Oganesian, Paul Workman, Johann De Bono

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9 Scopus citations

Abstract

Purpose: Onalespib is a potent, fragment-derived secondgeneration HSP90 inhibitor with preclinical activity in castration- resistant prostate cancer (CPRC) models. This phase I/II trial evaluated onalespib in combination with abiraterone acetate (AA) and either prednisone or prednisolone (P) in men with CRPC progressing on AA/P. Patients and Methods: Patients with progressing CRPC were randomly assigned to receive 1 of 2 regimens of onalespib combined with AA/P. Onalespib was administered as intravenous 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 (CTC) 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 and 160 mg/m2 for regimens 1 and 2, respectively. Transient decreases in CTC counts and AR expression in CTC were observed in both regimens. HSP72 was significantly upregulated following onalespib treatment, but only a modest decrease in AR and GR was shown in paired pre- and posttreatment tumor biopsy samples. No patients 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.

Original languageEnglish
Pages (from-to)4624-4633
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number15
DOIs
StatePublished - Aug 1 2019

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