title: Changes in PSA kinetics predict metastasis- free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of 4 phase II trials.
abstract: BACKGROUND
  Several phase II trials in men with noncastrate PSA-recurrent prostate cancer have assessed the impact of novel nonhormonal agents on PSA kinetics. However, it is unknown whether changes in PSA kinetics influence metastasis-free survival (MFS).
  
  
  METHODS
  We performed a retrospective post hoc analysis of 146 men treated in 4 phase II trials examining the investigational agents marimastat (a matrix metalloproteinase inhibitor; n = 39), imatinib (a tyrosine kinase inhibitor; n = 25), ATN-224 (a copper/zinc-superoxide dismutase inhibitor; n = 22), and lenalidomide (an antiangiogenic/immunomodulatory drug; n = 60). We investigated factors influencing MFS, including within-subject changes in PSA kinetics (PSA slope, doubling time, and velocity) before and after treatment initiation.
  
  
  RESULTS
  After a median follow-up of 16.8 months, 70 patients (47.9%) developed metastases. In multivariable Cox regression models, factors that were independently predictive of MFS after adjusting for age and other clinical prognostic variables were baseline PSA doubling time (PSADT) (P = .05), baseline PSA slope (P = .01), on-study change in PSADT (P = .02), and on-study change in PSA slope (P = .03). In a landmark Kaplan-Meier analysis, median MFS was 63.5 months (95% confidence interval [CI], 34.6-not reached) and 28.9 months (95% CI, 13.5-68.0) for men with or without any decrease in PSA slope by 6 months after treatment, respectively.
  
  
  CONCLUSIONS
  This hypothesis generating analysis suggests that within-subject changes in PSADT and PSA slope after initiation of experimental therapy may correlate with MFS in men with biochemically recurrent prostate cancer. If validated in prospective trials, changes in PSA kinetics may represent a reasonable intermediate end point for screening new agents in these patients.
authors.affiliation: Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, CRB1-1M45, 1650 Orleans Street, Baltimore, MD 21231, USA. eantona1@jhmi.edu
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
authors.forename: Marianna L
authors.initials: ML
authors.lastname: Zahurak
authors.forename: Jianqing
authors.initials: J
authors.lastname: Lin
authors.forename: Daniel
authors.initials: D
authors.lastname: Keizman
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012189:Retrospective Studies
chemical_list: D017430:Prostate-Specific Antigen