Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer.
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Embargo End Date
ICR Authors
Authors
Slovin, S
Hussain, S
Saad, F
Garcia, J
Picus, J
Ferraldeschi, R
Crespo, M
Flohr, P
Riisnaes, R
Lin, C
Keer, H
Oganesian, A
Workman, P
de Bono, J
Hussain, S
Saad, F
Garcia, J
Picus, J
Ferraldeschi, R
Crespo, M
Flohr, P
Riisnaes, R
Lin, C
Keer, H
Oganesian, A
Workman, P
de Bono, J
Document Type
Journal Article
Date
2019-08-01
Date Accepted
2019-05-17
Abstract
PURPOSE: Onalespib is a potent, fragment-derived second-generation 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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (15), pp. 4624 - 4633
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group