AUA 2022: Surrogate Endpoints as Predictors of Survival in Metastatic Urothelial Cancer Trials

( The 2022 Annual Meeting of the American Urological Association was host to a moderated poster session for non-invasive bladder cancer. Dr. Fady Ghali presented the results of his group’s systematic review evaluating the association between surrogate endpoints and overall survival in metastatic urothelial cancer trials.

Due to various reasons such as low statistical power and limited follow-up, clinically relevant endpoints such as progression-free survival (PFS) and objective response rate (ORR) are utilized as surrogate endpoints in clinical trials. It is assumed that patients with improvements in such surrogates would likely see concordant overall survival outcomes benefits, however the association between these surrogate endpoints and the “hard outcome” of OS has not been formally evaluated. To address this knowledge gap, the authors evaluated trial-level data assessing the statistical relationship between surrogate endpoints and OS.

A systematic literature search to identify all phase II/III trials in metastatic urothelial cancer published in English, had at least two treatment arms, and reported median PFS and/or ORR and OS was conducted. Recorded variables included publication year, class of drug/intervention, presence/absence of industry funding, and median PFS/ORR and OS. The correlation between PFS/ORR and OS was evaluated using the coefficient of determination (R2), surrogate threshold effect (STE), and linear regression analysis.

Of 3,254 trials initially identified, 57 studies and 62 comparisons met the pre-determined inclusion criteria. The median year of publication was 2016 [IQR 2006, 2020]; the average number of participants per study was 128 [IQR 85, 370]; and the median follow-up was 25.30 [IQR 16.40, 41.20] months.  

The median observed changes in the surrogate endpoints *(i.e. treatment arm – control arm) of PFS and ORR were 0.20 months (IQR: -1.50 – 1.40) and 2.5% (IQR: -8.93% - 10.40%). Median OS change was 0.60 months (IQR: -1.20 – 2.60). 

Linear regression analysis demonstrated a wide scatter between PFS/ORR and OS.

The correlation coefficient R2 between PFS and OS was 0.122 and 0.097 between ORR and OS.


  AUA22_Fady Ghali  


STE analysis determined that a PFS of 13.4 months provided 95% confidence for a positive OS. No included trials met this threshold. STE for ORR was >100%, with none of the trials meeting this threshold.

The authors concluded that the surrogate endpoints of PFS and ORR are weakly correlated with OS in metastatic UC. Trials demonstrating a 13.4-month improvement in PFS can claim an OS benefit with 95% confidence, while ORR is not a reliable surrogate. The take home message is that caution should be exercised when using surrogate endpoints in lieu of OS in metastatic urothelial cancer trials.

Presented by: Fady Ghali, MD, SUO Fellow, University of Washington, Seattle, WA

Written by: Rashid Sayyid, MD, MSc – Urology Chief Resident, Augusta University/Medical College of Georgia, @rksayyid on Twitter during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.


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