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|Ref Type||Journal Article|
|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|
|Title||Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2019 Aug 01|
|Abstract Text||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 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.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.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.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||prostate cancer||no benefit||Abiraterone + Onalespib + Prednisone||Phase Ib/II||Actionable||In a Phase I/II trial, Onalespib (AT13387) in combination with Zytiga (abiraterone) and Adasone (prednisone) did not result in objective response or response in PSA in patients with advanced castration-resistant prostate cancer (PMID: 31113841; NCT01685268).||31113841|