title: Prospective evaluation of low-dose ketoconazole plus hydrocortisone in docetaxel pre-treated castration-resistant prostate cancer patients.
abstract: BACKGROUND
  Ketoconazole is a well-known CYP17-targeted systemic treatment for castration-resistant prostate cancer (CRPC). However, most of the published data has been in the pre-chemotherapy setting; its efficacy in the post-chemotherapy setting has not been as widely described. Chemotherapy-naïve patients treated with attenuated doses of ketoconazole (200-300 mg three times daily) had PSA response rate (>50% decline) of 21-62%. We hypothesized that low-dose ketoconazole would likewise possess efficacy and tolerability in the CRPC post-chemotherapy state.
  
  
  METHODS
  Men with CRPC and performance status 0-3, adequate organ function and who had received prior docetaxel were treated with low-dose ketoconazole (200 mg orally three times daily) and hydrocortisone (20 mg PO qAM and 10 mg PO qPM) until disease progression. Primary endpoint was PSA response rate (>50% reduction from baseline) where a rate of 25% was to be considered promising for further study (versus a null rate of <5%); 25 patients were required. Secondary endpoints included PSA response >30% from baseline, progression-free survival (PFS), duration of stable disease and evaluation of adverse events (AEs).
  
  
  RESULTS
  Thirty patients were accrued with median age of 72 years (range 55-86) and median pre-treatment PSA of 73 ng ml(-1) (range 7-11,420). Twenty-nine patients were evaluable for response and toxicity. PSA response (>50% reduction) was seen in 48% of patients; PSA response (>30% reduction) was seen in 59%. Median PFS was 138 days; median duration of stable disease was 123 days. Twelve patients experienced grade 3 or 4 AEs. Of the 17 grade 3 AEs, only 3 were attributed to treatment. None of the two grade 4 AEs were considered related to treatment.
  
  
  CONCLUSIONS
  In docetaxel pre-treated CRPC patients, low-dose ketoconazole and hydrocortisone is a well-tolerated, relatively inexpensive and clinically active treatment option. PSA response to low-dose ketoconazole appears historically comparable to that of abiraterone in this patient context. A prospective, randomized study of available post-chemotherapy options is warranted to assess comparative efficacy.
authors: Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors: E N
authors: EN
authors: Lo
authors: Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors: L A
authors: LA
authors: Beckett
authors: 1] Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA [2] VA Northern California Health Care System, Mather, CA, USA.
authors: C X
authors: CX
authors: Pan
authors: Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors: D
authors: D
authors: Robles
authors: Kaiser-Permanente Medical Center, Vallejo, CA, USA.
authors: J M
authors: JM
authors: Suga
authors: Lahey Hospital and Medical Center, Burlington, MA, USA.
authors: J M
authors: JM
authors: Sands
authors: Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors: P N
authors: PN
authors: Lara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage*; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen; D007654:Ketoconazole; D006854:Hydrocortisone