title: Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens.
abstract: OBJECTIVE
  Patients previously treated with ketoconazole were excluded from phase III trials of abiraterone acetate due to potential overlapping mechanism of action. The purpose of this study was to determine the clinical utility of abiraterone and its impact on circulating androgens following ketoconazole.
  
  
  METHODS
  Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. The primary endpoint was the proportion of patients with PSA response, defined as ≥30% PSA decline at 12 weeks. H0 = 0.30 versus H1 = 0.50 (α = 0.05, power = 0.83). Circulating androgen levels were measured using liquid chromatography tandem mass spectrometry.
  
  
  RESULTS
  Thirty-nine patients were included in the final analysis. Twenty (51%; 95% confidence interval, 36%-66%) patients had ≥30% PSA decline; the null hypothesis was rejected. Sixteen (41%) had ≥50% PSA decline. Median PFS (progression-free survival) was 16 weeks; median radiographic PFS (rPFS) was 36 weeks. Samples for measurement of baseline androgens were available in 37 patients. The PSA response proportion was 59% in 29 patients with DHEA ≥ limit of quantitation (LOQ), compared with 13% in 8 patients with DHEA < LOQ (P = 0.042). Median PFS was 6 and 16 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P = 0.017); median rPFS was 14 and 36 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P < 0.001).
  
  
  CONCLUSIONS
  Abiraterone demonstrates modest clinical efficacy in mCRPC patients previously treated with ketoconazole. Patients with DHEA ≥ LOQ were more likely to demonstrate PSA responses and longer PFS. Analysis of circulating androgens merits further investigation as a biomarker for response to androgen synthesis inhibitor therapy.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. won.kim@ucsf.edu.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicine, PK/PD Core Resource, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: John H
authors.initials: JH
authors.lastname: Wilton
authors.affiliation: Department of Medicine, PK/PD Core Resource, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.affiliation: Department of Urology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Vivian
authors.initials: V
authors.lastname: Weinberg
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Allison
authors.initials: A
authors.lastname: Morse
authors.affiliation: Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Russell Z
authors.initials: RZ
authors.lastname: Szmulewitz
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Terence W
authors.initials: TW
authors.lastname: Friedlander
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Lin
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Harzstark
authors.affiliation: Janssen Research and Development, Menlo Park, California.
authors.forename: Arturo
authors.initials: A
authors.lastname: Molina
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
mesh_terms: D000069501:Abiraterone Acetate; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000097:blood*; D000736:Androstenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019233:Retreatment; D065088:Steroid Synthesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000728:Androgens; D000736:Androstenes; D065088:Steroid Synthesis Inhibitors; D000069501:Abiraterone Acetate; D007654:Ketoconazole