Time to Biochemical Failure as Surrogate Endpoint in Locally Advanced Prostate Cancer
As reported in the Journal of Clinical Oncology by Dignam et al, analysis of outcomes in the phase III NRG/RTOG 9202 trial indicates that the time interval to biochemical failure (IBF) could serve as a surrogate endpoint for clinical outcomes in patients receiving radiotherapy plus long-term androgen deprivation (AD) for locally advanced prostate cancer.
Study Details
The study involved data from patients in the trial randomly assigned to radiotherapy plus short-term AD (4 months; STAD, n = 762) or long-term AD (28 months; LTAD, n = 758). IBF was assessed in relation to prostate cancer–specific survival and overall survival. Survival modeling and landmark analysis methods were used to assess LTAD benefit on IBF and clinical endpoints, association between IBF and clinical endpoints, and the mediating effect of IBF on LTAD benefits (surrogacy measure).
Performance of IBF as Surrogate Marker
The trial showed that LTAD was superior to STAD for both biochemical failure (on the Phoenix definition of a rise by 2 ng/mL or more above nadir prostate-specific antigen) and clinical endpoints. Among all patients, those remaining free of BF for 3 years had relative risk reductions of 39% for overall survival and 73% for prostate cancer–specific survival. Analysis accounting for 3-year IBF status reduced the LTAD vs STAD overall survival benefit from 12% (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.79–0.98) to 6% (HR = 0.94, 95% CI = 0.83–1.07) and the LTAD prostate cancer–specific survival benefit from 30% (HR = 0.70, 95% CI = 0.52–0.82) to 6% (HR = 0.94, 95% CI = 0.72–1.22). Overall, the proportion of treatment effect explained by 3-year IBF status was 52% for overall survival and 85% for prostate cancer–specific survival. Among men experiencing BF in the first 3 years, 50% of subsequent deaths by 12 years were attributed to prostate cancer. Among those with no BF by 3 years, 19% of subsequent deaths were attributed to prostate cancer.
The investigators concluded, “The IBF satisfied surrogacy criteria and identified the benefit of LTAD on disease-specific survival and [overall survival]. The IBF may serve as a valid endpoint in clinical trials and may also aid in risk monitoring after initial treatment.”
James J. Dignam, PhD, of the Department of Public Health Sciences, University of Chicago, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. The study authors’ full disclosures can be found at jco.ascopubs.org.
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