A phase II trial of ganetespib, a heat shock protein 90 Hsp90) inhibitor, in patients with docetaxel-pretreated metastatic castrate-resistant prostate cancer (CRPC)-a prostate cancer clinical trials consortium (PCCTC) study

Manish K. Thakur, Lance K. Heilbrun, Shijie Sheng, Mark Stein, Glenn Liu, Emmanuel S. Antonarakis, Ulka Vaishampayan, Sijana H. Dzinic, Xiaohua Li, Stacy Freeman, Daryn Smith, Elisabeth I. Heath

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. Methods Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m2 on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. Results Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. Conclusions Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

Original languageEnglish (US)
Pages (from-to)112-118
Number of pages7
JournalInvestigational New Drugs
Volume34
Issue number1
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
This study was partially supported by NIH Cancer Center Support Grant CA022453 (to Bepler, G), NIH grants (CA127735 and CA084176 to Sheng, S), Fund for Cancer Research (to Sheng, S and Heath, E), and the Ruth Sager Memorial Fund (to Sheng, S).

Funding Information:
This study was partially supported by NIH Cancer Center Support Grant CA022453 (to Bepler, G), NIH grants (CA127735 and CA084176 to Sheng, S), Fund for Cancer Research (to Sheng, S and Heath, E), and the Ruth Sager Memorial Fund (to Sheng, S).

Publisher Copyright:
© 2015 Springer Science+Business Media New York.

Keywords

  • Ganetespib
  • Heat shock protein
  • Prostate cancer

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