Northwestern University, Chicago, IL
Laila A Gharzai , Ralph Jiang , Elizabeth Jaworski , Krystal A Morales , Robert Timothy Dess , William C. Jackson , Holly Hartman , Rohit Mehra , Amar Upadhyaya Kishan , Abhishek A Solanki , Edward M. Schaeffer , Felix Y Feng , Nicholas George Zaorsky , Alejandro Berlin , Lee Evan Ponsky , Jonathan Evan Shoag , Yilun Sun , Matthew J. Schipper , Jorge A. Garcia , Daniel Eidelberg Spratt
Background: The Intermediate Clinical Endpoints (ICEs) in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate endpoint for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate endpoints for OS exist in advanced prostate cancer. Methods: In this meta-analysis, PubMed was searched for trials in advanced prostate cancer, defined as node positive (N1M0), metastatic castration-sensitive (mCSPC), non-metastatic (M0CRPC), or metastatic castration-resistant prostate cancer (mCRPC). Eligible randomized trials were required to report OS and ≥1 intermediate clinical endpoint (ICE). ICEs included biochemical-failure (BF), clinical failure (CF), BF-free survival (BFS), progression-free survival (PFS), radiographic PFS (radiographic +/- other study defined endpoints). Candidacy for surrogacy was assessed using the second condition of the meta-analytic approach, correlation of the treatment effect of the ICE and OS, using R2 weighted by the inverse variance of the log ICE hazard ratio and defined as an R2> 0.70. Results: A total of 143 randomized trials (n = 75,601 patients) were included. No candidate endpoints met criteria for surrogacy; R2 BF (n = 28,922) 0.42 (95%CI 0.18-0.64), BFS (n = 25,741) 0.57 (95%CI 0.37-0.73), CF (n = 22,616) 0.31 (95%CI 0.0075-0.56), PFS (n = 52,639) 0.50 (95%CI 0.35-0.63), and radiographic PFS (n = 52,548) 0.50 (95%CI 0.35-0.63). Within preplanned subgroups by castration sensitive or resistant disease, or by treatment type, neither BFS nor PFS met criteria for surrogacy. When assessing radiographically-defined progression (exclusive or with clinical progression), PFS for the overall group and by castration status did not meet criteria for surrogacy. Sensitivity analyses demonstrated that candidacy for surrogacy of all endpoints tested did not change over time. Conclusions: Our aggregate screening method for surrogate endpoints in advanced prostate cancer demonstrated commonly used clinical endpoints are not valid surrogate endpoints for OS, and further composite endpoint construction is necessary.
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