title: 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.
abstract: BACKGROUND
  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/m(2) 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.
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Thakur
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Lance K
authors.initials: LK
authors.lastname: Heilbrun
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Shijie
authors.initials: S
authors.lastname: Sheng
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stein
authors.affiliation: University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Liu
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Ulka
authors.initials: U
authors.lastname: Vaishampayan
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Sijana H
authors.initials: SH
authors.lastname: Dzinic
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Freeman
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
authors.forename: Daryn
authors.initials: D
authors.lastname: Smith
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. heathe@karmanos.org.
authors.forename: Elisabeth I
authors.initials: EI
authors.lastname: Heath
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D018572:Disease-Free Survival; D000077143:Docetaxel; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D043823:Taxoids; D014230:Triazoles; D000077143:Docetaxel
keywords: Ganetespib; Heat shock protein; Prostate cancer