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Intermediate Clinical Endpoints for Surrogacy in Localised Prostate Cancer
TAKE-HOME MESSAGE
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The authors of this meta-analysis of 75 trials including over 50,000 patients evaluated the performance of intermediate clinical endpoints in randomised trials enrolling patients with localised prostate cancer. Metastasis-free survival correlated strongly with overall survival. Progression-free survival showed moderate correlation with overall survival. However, biochemical failure, biochemical failure–free survival, biochemical failure and clinical failure, and local failure all correlated poorly with overall survival.
- Among patients with localised prostate cancer, only metastasis-free survival was validated as a surrogate endpoint for overall survival.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised 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 randomised trials in localised prostate cancer.
METHODS
For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater.
FINDINGS
75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly.
INTERPRETATION
Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date.
Additional Info
Disclosure statements are available on the authors' profiles:
Intermediate Clinical Endpoints for Surrogacy in Localised Prostate Cancer: An Aggregate Meta-Analysis
Lancet Oncol 2021 Mar 01;22(3)402-410, LA Gharzai, R Jiang, D Wallington, G Jones, S Birer, N Jairath, EM Jaworski, MR McFarlane, BA Mahal, PL Nguyen, H Sandler, TM Morgan, ZR Reichert, JJ Alumkal, R Mehra, AU Kishan, K Fizazi, S Halabi, EM Schaeffer, FY Feng, D Elliott, RT Dess, WC Jackson, MJ Schipper, DE SprattFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Advanced Prostate Cancer
Prostate cancer requires long-term outcome analyses, and a variety of efforts have been made to improve upon the endpoints such that clinical trials could be expedited. In this study, 53,000 patients were included in the analysis covering 75 trials, with a median follow-up of 9.1 years. A variety of endpoints were studied, with a particular emphasis on how these intermediate endpoints might relate to overall survival, biochemical failure, clinical failure, local failure, progression-free survival, and metastasis-free survival within a group of patients with localized prostate cancer. Only metastasis-free survival was identified as a surrogate endpoint for overall survival in this comprehensive analysis.
These data are extensive but still not complete in my estimation. There was no analyses of testosterone levels, and important factors, such as secondary treatments, were not captured in a complete fashion. PSA recurrence is known to be problematic, but issues such as PSA doubling time are not addressed herein. Furthermore, cure rates are not clearly evaluated.
Taken together, despite the tremendous work of this group studying intermediate clinical endpoints, there is still more work to be done, and the deficiencies in our assessments remain substantial. More innovative studies are required in this area.