TY - JOUR
T1 - Intermediate clinical endpoints for surrogacy in localised prostate cancer
T2 - an aggregate meta-analysis
AU - Gharzai, Laila A.
AU - Jiang, Ralph
AU - Wallington, David
AU - Jones, Gavin
AU - Birer, Samuel
AU - Jairath, Neil
AU - Jaworski, Elizabeth M.
AU - McFarlane, Matthew R.
AU - Mahal, Brandon A.
AU - Nguyen, Paul L.
AU - Sandler, Howard
AU - Morgan, Todd M.
AU - Reichert, Zachery R.
AU - Alumkal, Joshi J.
AU - Mehra, Rohit
AU - Kishan, Amar U.
AU - Fizazi, Karim
AU - Halabi, Susan
AU - Schaeffer, Edward M.
AU - Feng, Felix Y.
AU - Elliott, David
AU - Dess, Robert T.
AU - Jackson, William C.
AU - Schipper, Matthew J.
AU - Spratt, Daniel E.
N1 - Funding Information:
EMS declares consulting fees from Janssen and Pfizer, outside of the submitted work. DE is a board member, owner, and co-founder of Retractor (a medical device company that makes a device for prostate radiation). JJA declares research funding to their institution from Zenith Epigenetics, Astellas, Aragon, Janssen, and Gilead; consulting fees from Janssen, Merck, and Dendreon; and speaker's fees from Astellas; all outside of the submitted work. HS is a member of a clinical trial steering committee for Janssen; and has stock from Radiogel for an inactive role on medical advisory board; all outside of the submitted work. AUK reports funding from ViewRay and Intelligent Automation; personal fees from Varian and Janssen; and research support from the American Society for Radiation Oncology (ASTRO) and the Prostate Cancer Foundation; all outside of the submitted work. BAM reports grants from the Prostate Cancer Foundation, ASTRO, and the US Department of Defense; and personal fees from Prostate Health Education Network, The Exeter Group, and Novavax; all outside of the submitted work. PLN declares consulting fees and research grants from Bayer, Astellas, Janssen, and Blue Earth; and consulting fees from Ferring, Augmenix, Boston Scientific, Dendreon, and Cota; all outside of the submitted work. KF declares participation in advisory boards and honoraria to their institution from Amgen, Astellas, AstraZeneca, Bayer, Clovis, Curevac, ESSA, Genentech, Janssen, MSD, Novartis, Orion, and Sanofi, outside of the submitted work. MJS declares consultancy fees from Innovative Analytics, outside of the submitted work. DES declares personal fees from Janssen, AstraZeneca, and BlueEarth, outside of the submitted work. All other authors declare no competing interests.
Funding Information:
We thank Christopher Sweeney (Dana Farber Cancer Institute, Boston, MA, USA) for review of the report. This study was funded in part by the Prostate Cancer Foundation and the National Institutes for Health (grant numbers P50 CA186786 and R01 CA240991-05).
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/3
Y1 - 2021/3
N2 - Background: 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. Funding: Prostate Cancer Foundation and National Institutes of Health.
AB - Background: 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. Funding: Prostate Cancer Foundation and National Institutes of Health.
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U2 - 10.1016/S1470-2045(20)30730-0
DO - 10.1016/S1470-2045(20)30730-0
M3 - Article
C2 - 33662287
AN - SCOPUS:85101690808
VL - 22
SP - 402
EP - 410
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 3
ER -
