In a study reported in the Journal of Clinical Oncology, Xie et al found that event-free survival including prostate-specific antigen biochemical failure as an event is not an adequate surrogate for overall survival in men receiving radiotherapy as primary therapy for localized prostate cancer.
“Event-free survival is a weak surrogate for overall survival and is not suitable for use as an intermediate clinical endpoint to substitute for overall survival to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy–based trials.”— Xie et al
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Study Details
The study involved analysis of patient-level and trial-level data from 10,350 patients in 15 radiation therapy–based trials with enrollment between 1987 to 2011 within the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) database, with a median follow-up of 10 years. Event-free survival was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause. Correlation between event-free survival and overall survival using patient-level data was quantified using Kendall’s tau (range = 0–1). Correlation using trial-level data was assessed using hazard ratios for event-free survival and overall survival, with clinically relevant surrogacy defined as an R2 ≥ 0.7.
Key Findings
Kaplan-Meier estimates of event-free, metastasis-free, and overall survival at 5 years were 56%, 80%, and 84%.
At the patient level, the Kendall’s tau value for correlation of event-free survival and overall survival over the entire follow-up was 0.43 (95% confidence interval [CI] = 0.42–0.44) and the correlation with metastasis-free survival was 0.51 (95% CI = 0.49–0.52). When non–prostate cancer deaths were excluded from analysis, the correlation between time to event and disease-specific survival was 0.52 (95% CI = 0.50–0.54) and the correlation between time to event and time to metastasis was 0.53 (95% CI = 0.51–0.55).
At the trial level, the overall R2 for event-free survival vs overall survival was 0.35 (95% CI = 0.01–0.60). For 8-year overall survival according to 5-year event-free survival, the value was 0.55 (95% CI = 0.26–0.70) and the value for 8-year metastasis-free survival according to 5-year event-free survival was 0.63 (95% CI = 0.31–0.76). Values for 5-year overall survival and metastasis-free survival vs 3-year event-free survival were 0.61 (95% CI = 0.35–0.73) and 0.73 (95% CI = 0.48–0.82), respectively. In analysis excluding non–prostate cancer deaths, R2 values were 0.45 (95% CI = 0.15–0.63) for the 8-year disease-specific survival rate vs 5-year time-to-event rate and 0.44 (95% CI = 0.17–0.62) for 5-year vs 3-year rates.
The investigators concluded, “Event-free survival is a weak surrogate for overall survival and is not suitable for use as an intermediate clinical endpoint to substitute for overall survival to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy–based trials.”
Christopher J. Sweeney, MBBS, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Prostate Cancer Foundation and by grants from Astellas/Pfizer, Janssen, Takeda, Sotio, Sanofi, Bayer, and Dendreon. For full disclosures of the study authors, visit ascopubs.org.
