Randomized Trial of p53 Targeted Adjuvant Therapy for Patients (pts) With Organ-Confined Node-Negative Urothelial Bladder Cancer (UBC) Authors: Stadler WM et al, ASCO Reviewed by: Dr. Lori Wood Abstract: 5017 Date posted: June 12, 2009

R Treatment A: Adjuvant MVAC x 3 Treatment B: Observation pT1-T2 N0M0 urothelial cancer, post cystectomy and PLND p53 positive n = 272 (p53 positive) n = 114 randomized primary endpoint = time to recurrence (goal: improvement by 20% at 3 years)

STUDY RATIONALE Previous small studies showed that p53 positive tumors had  probability of recurrence post resection in organ confined bladder cancer. Prior USC randomized trial of adjuvant chemotherapy versus observation showed improved outcome in p53 positive tumors. p53 positive cells may be more susceptible to chemotherapy agents that damage DNA. Hypothesis: p53 IHC is a valid biomarker p53 IHC is prognostic p53 IHC is predictive for benefit from DNA damaging chemotherapy Cole et al, Nature 1997; 385:123

RESULTS 521 patients registered 499 had successful p53 assessment 272 p53 positive (  10% nuclear reactivity) 158 refused randomization 114 randomized (only 42% of p53 positive) 56 observation 46 MVAC 12 refused

RESULTS (CONTINUED) n = 499; 5-year relapse-free survival = 80%. no difference if p53 positive or negative n = 114; 5-year relapse-free survival = 83%. no difference if MVAC or observation Therefore, p53 positivity was not of prognostic or predictive value.

STUDY COMMENTARY Study was halted early by DSMB after review of futility analysis. Only 42% of p53 positive patients were randomized. Lower than expected event rate and failure (i.e.: 15% recurrence rate at 3 years) and the a priori hypothesis was  50%; therefore, study very underpowered. Lower event rate probably because only pT1-T2 N0 disease and excluded pT3-T4 or N+ disease. p53 positivity not predictive or prognostic.

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS p53 as assessed by IHC will not help guide therapeutic decisions in resected bladder cancer at this point in time. The role of adjuvant chemotherapy in all stages of (pT1-T4 N0 or N+) resected bladder cancer is still very controversial and understudied.