Evaluation of event-free survival as a surrogate for overall survival in genitourinary rhabdomyosarcoma.
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PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in pediatric patients. Due to rarity, treatment advancements are infrequent and randomized controlled trials (RCTs) are challenging to conduct and interpret. Surrogate endpoints are particularly useful in RCTs for rare diseases; however, they are not always accurate or effective. Event-free survival (EFS) is a common surrogate endpoint for overall survival (OS), but has never been validated in genitourinary (GU) RMS. METHODS: Data from three clinical trials were pooled, including 111 subjects with GU primary sites across low-, intermediate-, and high-risk RMS. These trials employed various chemotherapy regimens ± radiation, based on risk-group. The definitive endpoint was OS and the surrogate endpoint was EFS. A 2-stage meta-analytic copula modeling approach was selected to assess surrogacy. The Plackett model was chosen to estimate treatment effects. Sensitivity analyses included convergence testing, goodness-of-fit, and leave-one-out cross-validation. RESULTS: Of 111 subjects, 56 (50.5%) were randomized into control and 55 (49.5%) into treatment arms. Surrogacy analysis revealed a moderate to strong association between EFS and OS, with trial-level associations (Rtrial2 of 1.0) showing a stronger correlation than individual-level associations (Kendall's τ of 0.67). The surrogate threshold effect was 0.44. Robustness was limited by sample size due to disease and trial rarity. CONCLUSIONS: In GU RMS, EFS is a moderate to strong surrogate endpoint for OS. These findings support its use as a surrogate endpoint, and the strength of this surrogacy may enable future clinical trial design to utilize EFS with greater emphasis than in prior studies.