Meta-Analysis of Candidate Surrogate End Points in Advanced Prostate Cancer
METHODS: We searched for trials in advanced prostate cancer, defined as node-positive, metastatic castration-sensitive, nonmetastatic, or metastatic castration-resistant prostate cancer. Eligible randomized trials reported OS and one or more intermediate clinical end points, including biochemical failure (BF), clinical failure, biochemical failure–free survival (BFS), progression-free survival (PFS), and radiographic PFS. Candidacy for surrogacy was assessed by using the second condition of the meta-analytic approach; R2 was weighted by the inverse variance of the log intermediate clinical end point hazard ratio and defined as R2>0.70.
RESULTS: A total of 143 randomized trials (n=75,601 patients) were included. No candidate end points met the criteria for surrogacy (R2 BF [n=28,922], 0.42 [95% confidence interval (CI), 0.18 to 0.64]; BFS [n=25,741], 0.57 [95% CI, 0.37 to 0.73]; clinical failure [n=22,616], 0.31 [95% CI, 0.075 to 0.56]; PFS [n=52,639], 0.50 [95% CI, 0.35 to 0.63]; and radiographic PFS [n=52,548], 0.50 [95% CI, 0.35 to 0.63]). Within preplanned subgroups according to castration-sensitive or castration-resistant disease or according to treatment type, neither BFS nor PFS consistently met criteria for surrogacy. Sensitivity analyses showed that candidacy for surrogacy of all end points tested did not change over time.
CONCLUSIONS: Our aggregate screening method for surrogate end points in advanced prostate cancer showed that commonly used clinical end points are not clear valid surrogate end points for OS. (Funded by the Prostate Cancer Foundation and the National Cancer Institute.)
Laila A. Gharzai, M.D., LL.M., Ralph Jiang, M.S., Elizabeth M. Jaworski, M.D., Krystal Morales Rivera, M.D., Ph.D., Robert T. Dess, M.D., William C. Jackson, M.D., Holly E. Hartman, Ph.D., Rohit Mehra, M.D., Amar U. Kishan, M.D., Abhishek A. Solanki, M.D., Edward M. Schaeffer, M.D., Ph.D., Felix Y. Feng, M.D., Nicholas G. Zaorsky, M.D., M.S., Alejandro Berlin, M.D., Lee Ponsky, M.D., Jonathan Shoag, M.D., Yilun Sun, Ph.D., Matthew J. Schipper, Ph.D., Jorge Garcia, M.D., and Daniel E. Spratt, M.D.
Department of Radiation Oncology, Northwestern University, Chicago; Department of Biostatistics, University of Michigan, Ann Arbor; Department of Radiation Oncology, University of Michigan, Ann Arbor; Department of Population and Quantitative Health Sciences, Case Western Reserve, Cleveland, OH; Department of Pathology, University of Michigan, Ann Arbor; Department of Radiation Oncology, University of California, Los Angeles, Los Angeles; Department of Radiation Oncology, Stritch School of Medicine, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL; Department of Urology, Northwestern University, Chicago; Department of Radiation Oncology, University of California, San Francisco, San Francisco; Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve, Cleveland, OH; Department of Radiation Oncology, University of Toronto; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON; Department of Urology, University Hospitals Cleveland Medical Center, Case Western Reserve, Cleveland, OH; Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve, Cleveland, OH.
Source: Gharzai LA, Jiang R, Jaworski EM et al. Meta-Analysis of Candidate Surrogate End Points in Advanced Prostate Cancer. NEJM Evidence. 2023. DOI: 10.1056/EVIDoa2200195.