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J Clin Oncol. 2017 Sep 20;35(27):3097-3104. doi: 10.1200/JCO.2017.73.9987. Epub 2017 Aug 10.

Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer.

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Wanling Xie, Meredith M. Regan, and Christopher J. Sweeney, Dana-Farber Cancer Institute, Boston, MA; Marc Buyse, International Drug Development Institute; Bertrand Tombal, Université Catholique de Louvain, Louvain-la-Neuve; Laurence Collette, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Susan Halabi, Duke University Medical Center, Durham, NC; Philip W. Kantoff, Memorial Sloan Kettering Cancer Center, New York, NY; Oliver Sartor, Tulane Medical School, New Orleans, LA; Howard Soule, Prostate Cancer Foundation, Santa Monica; Howard M. Sandler, Cedars-Sinai Medical Center, Los Angeles, CA; Noel W. Clarke, The Christie NHS Foundation Trust, Manchester; Matthew R. Sydes, University College London, London, United Kingdom; James J. Dignam, University of Chicago, Chicago, IL; Karim Fizazi, Institut Gustave-Roussy, Villejuif, France; Wendy R. Paruleker, Canadian Cancer Trials Group, Kingston, Ontario, Canada; and Scott G. Williams, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.


Purpose Adjuvant therapy for intermediate-risk and high-risk localized prostate cancer decreases the number of deaths from this disease. Surrogates for overall survival (OS) could expedite the evaluation of new adjuvant therapies. Methods By June 2013, 102 completed or ongoing randomized trials were identified and individual patient data were collected from 28 trials with 28,905 patients. Disease-free survival (DFS) and metastasis-free survival (MFS) were determined for 21,140 patients from 24 trials and 12,712 patients from 19 trials, respectively. We evaluated the surrogacy of DFS and MFS for OS by using a two-stage meta-analytic validation model by determining the correlation of an intermediate clinical end point with OS and the correlation of treatment effects on both the intermediate clinical end point and OS. Results Trials enrolled patients from 1987 to 2011. After a median follow-up of 10 years, 45% of 21,140 men and 45% of 12,712 men experienced a DFS and MFS event, respectively. For DFS and MFS, 61% and 90% of the patients, respectively, were from radiation trials, and 63% and 66%, respectively, had high-risk disease. At the patient level, Kendall's τ correlation with OS was 0.85 and 0.91 for DFS and MFS, respectively. At the trial level, R2 was 0.86 (95% CI, 0.78 to 0.90) and 0.83 (95% CI, 0.71 to 0.88) from weighted linear regression of 8-year OS rates versus 5-year DFS and MFS rates, respectively. Treatment effects-measured by log hazard ratios-for the surrogates and OS were well correlated ( R2, 0.73 [95% CI, 0.53 to 0.82] for DFS and 0.92 [95% CI, 0.81 to 0.95] for MFS). Conclusion MFS is a strong surrogate for OS for localized prostate cancer that is associated with a significant risk of death from prostate cancer.

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