(UroToday.com) The 2023 American Urological Association (AUA) annual meeting held in Chicago, IL between April 28 and May 1st, 2023, was host to a non-invasive bladder cancer moderated poster session. Dr. Michele Marchioni presented a study evaluating progression-free survival (PFS) as a surrogate outcome of overall survival (OS) in a cohort of high-risk non-muscle invasive bladder (HR-NMIBC) cancer patients, using results from a machine learning-based analysis of a large multi-institutional database.
PFS is commonly used as a surrogate endpoint in clinical trials of treatment effectiveness in patients with HR-NMIBC. However, the validity of PFS as a surrogate endpoint for OS has yet to be formally evaluated in such a cohort of patients. This is further complicated by studies demonstrating PFS improvements, in the absence of corresponding OS benefits. This study aimed to evaluate the surrogacy of PFS for OS in a large cohort of HR-NMIBC patients treated with intravesical BCG.
This cohort included patients with de novo T1 HR-NMIBC, included at the time of the first TURBT. Patients were recruited from 18 tertiary care centers between 2002 and 2012. Progression-free survival was defined as the time from diagnosis of HR-NMIBC to the development/diagnosis of muscle-invasive bladder cancer (MIBC), with all such patients subsequently undergoing a radical cystectomy +/- neoadjuvant chemotherapy. A machine learning-based approach, utilizing a random survival forest (RSF), was used to rank evaluable covariates based on their ability to predict OS. Thereafter, the survival tree data mining technique was used to define classes based on time-to-progression rates. Finally, Cox-regression models were used to evaluate the predictive ability, measured in hazard ratios, for each of the variables, including PFS.
This analysis included 1,510 patients, with a median follow-up of 49 months. Overall, 485 patients progressed to MIBC, and 163 patient experienced any-cause death. The median time to MIBC progression was 82 months. Using RSF, time-to-progression, and age were the two variables that were most significantly predictive of OS. The concordance (“C”) index was 0.814 in the training set and 0.726 in the testing/validation cohort. Survival trees including these two covariates led to the generation of 5 risk groups with progressively increasing hazards of OS:
1. PFS of 62.5 months and age < 77.5 years (referent group)
2. PFS of 62.5 months and age of 77.5 years (HR: 9.0, p<0.001)
3. PFS between 10.5 and 62.5 months and age < 79.5 years (HR: 14.3, p<0.001)
4. PFS <10.5 months and age <79.5 (HR: 44.9, p<0.001)
5. PFS < 62.5 months and age of 79.5 years (HR: 58.7, p<0.001)
On subsequent multivariable Cox regression analysis accounting for progression, status operationalized as a time-dependent covariate, longer PFS (operationalized as a continuous variable), was associated with longer OS (HR: 0.9, p<0.001). Results were consistent after PFS stratification:
- PFS= 10.5 months as reference
- PFS between 10.5 and 62.5 months (HR: 0.4, p<0.001)
- PFS =62.5 months (HR: 0.2, p<0.001).
The results of this study suggest that PFS is a promising surrogate endpoint for OS. Based on these results, the authors suggested that future studies of efficacy in the HR-NMIBC disease space can “safely rely on PFS as a surrogate of OS”.
Presented by: Michele Marchioni, MD, PhD, Associate Professor of Urology, University of Studies "G. d'Annunzio" - Chieti and Pescara, Chieti, Italy
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023