Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer
| Autor: | Fred Saad, Aram Oganesian, Harold N. Keer, Susan F. Slovin, Ruth Riisnaes, Penelope Flohr, Johann S. de Bono, Mateus Crespo, Roberta Ferraldeschi, Chihche Lin, Joel Picus, Syed A. Hussain, Paul Workman, Jorge A. Garcia |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cancer Research medicine.medical_specialty Prednisolone Abiraterone Acetate Isoindoles Gastroenterology Article 03 medical and health sciences chemistry.chemical_compound Prostate cancer 0302 clinical medicine Circulating tumor cell Prednisone Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Tissue Distribution HSP90 Heat-Shock Proteins Survival rate Aged Aged 80 and over business.industry Abiraterone acetate Middle Aged medicine.disease Survival Rate Regimen Prostatic Neoplasms Castration-Resistant 030104 developmental biology Treatment Outcome Oncology chemistry 030220 oncology & carcinogenesis Pharmacodynamics Benzamides Patient Safety business medicine.drug |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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