Pharmacodynamic and Clinical Results from a Phase I/II Study of the HSP90 Inhibitor Onalespib in Combination with Abiraterone Acetate in Prostate Cancer

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/m 2 once weekly for 3 of 4 weeks (regimen 1); or at 120 mg/m 2 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/m 2 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.

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…A second-generation of SSP90 inhibitors was developed and one of these compounds, Onmalespib, was found to be very active in preclinical models and was beneficial in prostate cancer models expressing AR-V7 [671]. However, in spite this promising preclinical background, Onalespib in combination with Abiraterone failed to show any significant clinical activity in CRPC patients in progression [672].…”

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants

“…Hsp90 is a molecular chaperone that is responsible for the folding and function of over 300 “client” proteins involved in prostate cancer development and progression; thus, targeting Hsp90 results in broad inhibition of critical signaling pathways (reviewed in [ 39 , 40 ]). Hsp90 has been extensively investigated as a target in prostate cancer both pre-clinically and clinically [ 41 ], but Hsp90 inhibitors such as 17-AAG and AUY922 have not yet been clinically approved despite continuing efforts [ 42 ]. 17-AAG was the first-in-class Hsp90 inhibitor, and it has far less potency than 2nd generation agents such as AUY922 [ 22 ].…”

Advances in the role of heat shock protein 90 in prostate cancer

“…Onalespib has been shown in basic studies to block AR nuclear translocation and inhibit its transcriptional activity, inhibiting PCa cell proliferation and tumour growth (Ferraldeschi et al, 2016). In a phase I/II clinical trial, including 48 prostate cancer patients, patients received Onalespib in a phase I/II trial, in which patients were treated with Onalespib in combination with abiraterone acetate, the results showed that no patient exhibited an objective or PSA response, declaring the combination to be unjustified (Slovin et al, 2019). Ganetespib reduced the expression of AKT, AR, IGFR‐1, EGFR, ERK, STAT3 in basic studies and had pro‐apoptotic and tumour growth inhibitory activity (He et al, 2013).…”