In a meta-analysis reported in The Lancet Oncology, Gharzai et al found that commonly used intermediate clinical endpoints in clinical trials in localized prostate cancer do not correlate well with overall survival, apart from metastasis-free survival—supporting the establishment of metastasis-free survival as a surrogate for overall survival by the Intermediate Clinical Endpoints in Cancer of the Prostate working group.
As stated by the investigators, “The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localized prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomized trials in localized prostate cancer.”
Study Details
A literature search of studies reported between January 1970 and January 2020 identified 75 randomized trials in localized or biochemically recurrent prostate cancer published between March 1986 and January 2020 that reported overall survival and at least one intermediate clinical endpoint and had a population of 70 or more patients. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure–free survival, progression-free survival, and metastasis-free survival.
The adequacy of surrogacy for the endpoints was evaluated by assessing the correlation of the treatment effect of the endpoint and overall survival using R² weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The endpoint was considered to be a surrogate for overall survival if R² was ≥ 0.7.
“Intermediate clinical endpoints based on biochemical and local failure did not meet the meta-analytic criteria for surrogacy and are not surrogate endpoints for overall survival in localized prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date.”— Gharzai et al
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Key Findings
A total of 75 trials including 53,631 patients were included in the analysis. Median follow-up was 9.1 years (interquartile range [IQR] = 5.7–10.6 years).
Intermediate clinical endpoints that included biochemical failure exhibited poor correlation with overall survival, including biochemical failure (25 trials/17,086 patients; R² = 0.38, 95% confidence interval [CI] = 0.11–0.64); biochemical failure plus clinical failure (12 trials/11,396 patients; R² = 0.28, 95% CI = 0.0045–0.65), and biochemical failure–free survival (41 trials/ 28,528 patients; R² = 0.12, 95% CI = 0.0030–0.33). Correlation with overall survival was also poor for local failure (21 trials/13,753 patients; R² = 0.085, 95% CI = 0.00–0.37) and for distant metastasis not including death as an event (18 trials/13,623 patients; R² = 0.24, 95% CI = 0.012–0.56).
Correlation of progression-free survival with overall survival was moderate (29 trials/ 25,095 patients; R² = 0.46, 95% CI = 0.22–0.67). Metastasis-free survival exhibited the strongest correlation with overall survival among all intermediate endpoints examined (26 trials/16,620 patients; R² = 0.78, 95% CI = 0.59–0.89).
A total of 54 trials including 34,237 patients used primary radiotherapy in trial design, with a median follow-up of 8.5 years (IQR = 5.7–9.8 years). Findings in these trials were similar to those for overall surrogacy, with poor correlations with overall survival for biochemical failure (R2 = 0.21), biochemical failure–free survival (R2 = 0.21), distant metastases (R2 = 0.04), and local failure (R2 = 0.05). Progression-free survival exhibited good correlation (R2 = 0.72), and metastasis-free survival had the strongest correlation (R2 = 0.78).
The investigators concluded, “Intermediate clinical endpoints based on biochemical and local failure did not meet the meta-analytic criteria for surrogacy and are not surrogate endpoints for overall survival in localized prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date.”
Daniel E. Spratt, MD, of the Department of Radiation Oncology, University of Michigan, Ann Arbor, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Prostate Cancer Foundation and National Institutes of Health. For full disclosures of the study authors, visit thelancet.com.
