title: Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable-Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen Deprivation Therapy: A Secondary Analysis of a Randomized Clinical Trial.
abstract: OBJECTIVE
  Several surrogates for prostate cancer-specific mortality satisfying the Prentice criteria exist, but whether these are surrogates for all-cause mortality, and how their performance compares, is unknown.
  
  
  OBJECTIVE
  To ascertain and compare the performance of 4 candidate surrogates (prostate-specific antigen [PSA] failure, PSA nadir >0.5 ng/mL, PSA doubling time <9 months, and interval to PSA failure <30 months) for all-cause mortality using the proportion of treatment-effect metric.
  
  
  METHODS
  For this randomized clinical trial, 206 men with unfavorable-risk prostate cancer who were seen at a Harvard-affiliated academic hospital or an associated community hospital between December 1, 1995, to April 15, 2001, were identified, randomized to radiation therapy alone or radiation therapy followed by 6 months of androgen deprivation therapy, and followed for a median 16.62 years. This analysis looks at the subgroup of 157 men with minimal comorbidities or no comorbidity (median follow-up, 16.49 months).
  
  
  METHODS
  Patients were previously randomized to receive radiation therapy or radiation and 6 months of androgen deprivation therapy.
  
  
  METHODS
  Risk of all-cause mortality.
  
  
  RESULTS
  Overall, a cohort of 157 men (median [interquartile range] age, 72.43 [68.75-75.53]) with unfavorable-risk prostate cancer and minimal or no comorbidities were selected for this study. Three tested metrics met all 4 Prentice criteria for surrogacy for the surrogate covariate in the adjusted model for all-cause mortality: PSA nadir greater than 0.5 ng/mL (adjusted hazard ratio [aHR], 1.72; 95% CI, 1.17-2.52; P = .01), PSA doubling time less than 9 months (aHR, 2.06; 95% CI, 1.29-3.28; P = .003), and interval to PSA failure less than 30 months (aHR, 1.76; 95% CI, 1.06-2.92; P = .03); while PSA failure did not. For the 3 successful surrogates, the proportion of treatment effect values were 103.86%, 43.09%, and 41.26%, respectively.
  
  
  CONCLUSIONS
  A PSA nadir value of greater than 0.5 ng/mL following radiation and androgen deprivation therapy appears to identify men prior to PSA failure who are at high-risk for death. This could be used to select men for entry at the time of PSA nadir onto randomized trials evaluating the impact on survival of salvage androgen deprivation therapy with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00116220.
authors.affiliation: Harvard Radiation Oncology Program, Brigham and Women's Hospital, Boston, Massachusetts2Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts3Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Royce
authors.affiliation: Department of Statistics, University of Connecticut, Storrs, Connecticut.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Department of Statistics, University of Connecticut, Storrs, Connecticut.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts3Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Marian
authors.initials: M
authors.lastname: Loffredo
authors.affiliation: Department of Pathology, Baptist Hospital, Miami, Florida.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Renshaw
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Institute, New York, New York.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Department of Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts3Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: D'Amico
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015415:Biomarkers; D017024:Chemotherapy, Adjuvant; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D060787:Neoplasm Grading; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D014481:United States / Q000453:epidemiology
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D017430:Prostate-Specific Antigen