title: Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two randomised trials.
abstract: BACKGROUND
  Androgen suppression therapy and radiotherapy are used to treat locally advanced prostate cancer. 3 years of androgen suppression confers a small survival benefit compared with 6 months of therapy in this setting, but is associated with more toxic effects. Early identification of men in whom radiotherapy and 6 months of androgen suppression is insufficient for cure is important. Thus, we assessed whether prostate-specific antigen (PSA) values can act as an early surrogate for prostate cancer-specific mortality (PCSM).
  
  
  METHODS
  We systematically reviewed randomised controlled trials that showed improved overall and prostate cancer-specific survival with radiotherapy and 6 months of androgen suppression compared with radiotherapy alone and measured lowest PSA concentrations (PSA nadir) and those immediately after treatment (PSA end). We assessed a cohort of 734 men with localised or locally advanced prostate cancer from two eligible trials in the USA and Australasia that randomly allocated participants between Feb 2, 1996, and Dec 27, 2001. We used Prentice criteria to assess whether reported PSA nadir or PSA end concentrations of more than 0·5 ng/mL were surrogates for PCSM.
  
  
  RESULTS
  Men treated with radiotherapy and 6 months of androgen suppression in both trials were significantly less likely to have PSA end and PSA nadir values of more than 0·5 ng/mL than were those treated with radiotherapy alone (p<0·0001). Presence of candidate surrogates (ie, PSA end and PSA nadir values >0·5 ng/mL) alone and when assessed in conjunction with the randomised treatment group increased risk of PCSM in the US trial (PSA nadir p=0·0016; PSA end p=0·017) and Australasian trial (PSA nadir p<0·0001; PSA end p=0·0012). In both trials, the randomised treatment group was no longer associated with PCSM (p ≥ 0·20) when the candidate surrogates were included in the model. Therefore, both PSA metrics satisfied Prentice criteria for surrogacy.
  
  
  CONCLUSIONS
  After radiotherapy and 6 months of androgen suppression, men with PSA end values exceeding 0·5 ng/mL should be considered for long-term androgen suppression and those with localised or locally advanced prostate cancer with PSA nadir values exceeding 0·5 ng/mL should be considered for inclusion in randomised trials investigating the use of drugs that have extended survival in castration-resistant metastatic prostate cancer.
  
  
  BACKGROUND
  None.
authors: Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA. adamico@partners.org
authors: Anthony V
authors: AV
authors: D'Amico
authors: Ming-Hui
authors: MH
authors: Chen
authors: Mario
authors: M
authors: de Castro
authors: Marian
authors: M
authors: Loffredo
authors: David S
authors: DS
authors: Lamb
authors: Allison
authors: A
authors: Steigler
authors: Philip W
authors: PW
authors: Kantoff
authors: James W
authors: JW
authors: Denham
mesh_terms: D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001315:Australia; D015415:Biomarkers / Q000032:analysis; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000032:analysis*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy / Q000628:therapy*; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D014481:United States
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D017430:Prostate-Specific Antigen