Minimal Residual Disease Detection with Urine-derived DNA Is Prognostic for Recurrence-free Survival in Bacillus Calmette-Guérin–unresponsive Non–muscle-invasive Bladder Cancer Treated with Nadofaragene Firadenovec

In patients with bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer, urine DNA profiling identifies those with the greatest likelihood of benefitting from nadofaragene firadenovec treatment. Longitudinal testing before and after treatment best identifies those likely to have positive treatment outcomes. Urinary tumor DNA (utDNA) profiling identifies mutations associated with urothelial carcinoma and can be used to detect minimal residual disease (MRD). We evaluate the utility of utDNA profiling to predict treatment failure in bacillus Calmette-Guérin–unresponsive high-grade (HG) non–muscle-invasive bladder cancer (NMIBC) treated with nadofaragene firadenovec. Urine was collected from participants prior to induction (n = 32) and at their 3-mo evaluation (n = 18) in the parallel-arm, phase 2 study (NCT01687244) of nadofaragene firadenovec. The UroAmp MRD assay (Convergent Genomics, South San Francisco, CA, USA) was used to perform utDNA testing. Risk of HG NMIBC recurrence was determined using two algorithm versions, and recurrence-free survival (RFS) was assessed using a Kaplan-Meier analysis. TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were the most prevalently mutated genes. With pretreatment urine, the validated MRD algorithm resulted in 12-mo RFS of 56% for negative and 22% for positive patients (p = 0.097). The experimental, enhanced algorithm classified two additional patients as positive, giving RFS of 71% for negative and 20% for positive patients (p = 0.012). With 3-mo urine, both algorithms gave RFS of 100% for negative and 38% for positive patients (p = 0.038). Longitudinal utDNA testing classified patients as negative (7%), complete responders (13%), partial responders (27%), unresponsive (20%), and expanding (33%). Urinary MRD testing after nadofaragene firadenovec induction provided statistically significant prognostication of recurrence among phase 2 trial participants. By analyzing urine-borne tumor DNA, we can help determine which patients with high-grade non–muscle-invasive bladder cancer are at the greatest risk of recurrence when receiving second-line therapy.