Wanling Xie1, Meredith M Regan1, Marc Buyse2, Susan Halabi3, Philip W Kantoff4, Oliver Sartor5, Howard Soule6, Donald Berry7, Noel Clarke8, Laurence Collette9, Anthony D'Amico10, Richard De Abreu Lourenco11, James Dignam12, Mario Eisenberger13, Nicholas James14, Karim Fizazi15, Silke Gillessen16, Yohann Loriot15, Nicolas Mottet17, Wendy Parulekar18, Howard Sandler19, Daniel E Spratt20, Matthew R Sydes21, Bertrand Tombal22, Scott Williams23, Christopher J Sweeney24. 1. Division of Biostatistics, Dana-Farber Cancer Institute, Boston, MA. 2. International Drug Development Institute, Louvain la Neuve, Belgium. 3. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC. 4. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. 5. Departments of Medicine & Urology, Tulane University, New Orleans, LA. 6. Prostate Cancer Foundation, Santa Monica, CA. 7. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX. 8. Urological Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. 9. European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium. 10. Department of Radiation Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA. 11. Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, NSW, Australia. 12. Department of Public Health Science, University of Chicago, Chicago, IL. 13. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD. 14. University Hospitals Birmingham, Birmingham, United Kingdom. 15. Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France. 16. Division of Cancer Sciences, University of Manchester and The Christie, Manchester, United Kingdom. 17. Urology Oncology, University Jean Monnet, St Etienne, France. 18. Canadian Cancer Trials Group, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada. 19. Radiation Oncology, Cedars Sinai Medical Center, Los Angeles, CA. 20. University of Michigan, Ann Arbor, MI. 21. Medical Research Council Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom. 22. Institut de Recherche Clinique, Université Catholique de Louvain, Brussels, Belgium. 23. Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. 24. Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA.
Abstract
PURPOSE: Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion. METHODS: EFS 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, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7. RESULTS: Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS. CONCLUSION: EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.
PURPOSE: Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion. METHODS: EFS 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, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7. RESULTS: Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS. CONCLUSION: EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.
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