title: Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer.
abstract: OBJECTIVE
  It is currently unclear if early prostate-specific antigen (PSA) or pain improvements are adequate surrogates for overall survival in men with metastatic hormone-refractory prostate cancer (HRPC). Here we examined various degrees of PSA decline and pain response as surrogates for the survival benefit observed in the TAX327 trial.
  
  
  METHODS
  In the TAX327 trial, 1,006 men with HRPC were randomly assigned to receive docetaxel in two schedules, or mitoxantrone, each with prednisone: 989 men provided data on 3-month PSA decline. Surrogacy was examined for post-treatment changes in PSA and pain response using Cox proportional hazards models to calculate the proportion of treatment effect (PTE) explained by each potential surrogate.
  
  
  RESULTS
  A > or = 30% PSA decline within 3 months of treatment initiation provides the highest degree of surrogacy, with a PTE of 0.66 (95% CI, 0.23 to 1.0), and was associated with a hazard ratio (HR) of 0.50 (95% CI, 0.43 to 0.58) for overall survival after adjusting for treatment effect. Introduction of a > or = 30% PSA decline is predictive of survival regardless of treatment arm. Other changes in PSA or PSA kinetics, PSA normalization, and pain responses were highly prognostic but weaker surrogates for survival.
  
  
  CONCLUSIONS
  In the TAX327 trial, a PSA decline of > or = 30% within 3 months of chemotherapy initiation had the highest degree of surrogacy for overall survival, confirming data from the Southwest Oncology Group 9916 trial. However, given the wide CIs around the estimate of this moderate surrogate effect, overall survival should remain the preferred end point for phase III trials of cytotoxic agents in HRPC.
authors.affiliation: Duke Comprehensive Cancer Center, Durham, NC 27710, USA. andrew.armstrong@duke.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Armstrong
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Ou Yang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Ian
authors.initials: I
authors.lastname: Tannock
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
authors.forename: Mario
authors.initials: M
authors.lastname: Eisenberger
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality / Q000556:secondary*; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary*; D015897:Comorbidity; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage; D010146:Pain / Q000145:classification / Q000453:epidemiology / Q000517:prevention & control*; D010147:Pain Measurement; D011241:Prednisone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D018931:Antineoplastic Agents, Hormonal; D043823:Taxoids; D000077143:Docetaxel; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; D011241:Prednisone