Urinary MRD Detection Predicts Recurrence in BCG-Unresponsive NMIBC, Quantifies Response to Nadofaragene Firadenovec

Urinary measurable residual disease (uMRD) enables quantitative assessment of molecular response to nadofaragene firadenovec for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC), according to new research presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium.

uMRD profiling identifies mutations associated with urothelial carcinoma and can be used to predict recurrence and assess response to therapy. Nadofaragene firadenovec is an intravesical therapy approved for patients with BCG-unresponsive NMIBC.

Vikram M. Narayan, MD, and colleagues designed an analysis aimed at evaluating the utility of uMRD to identify molecular response to nadofaragene firadenovec in patients with high-grade BCG-refractory or relapsed NMIBC. The open-label, multicenter, parallel-arm, phase 2 study included 43 patients, 35 of whom were evaluable with initial pathological stages of Ta (n=3), T1 (n=9), and Tis (n=23). Concomitant carcinoma in situ was noted in 6 patients.

Urine samples were collected prior to induction and at 3 months. Researchers used the UroAmp MRD assay, which identifies single-nucleotide variants, copy-number variants (CNVs), insertion-deletions, copy-neutral loss of heterozygosity, microsatellite instability, and aneuploidy.

The primary end point of the study was 12-month high-grade recurrence-free survival (RFS).

In pretreatment urine, TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3, and ERBB2 were among the most prevalently mutated genes. Most CNVs occurred in SOX4 and NIT1, and uMRD identified patients with high (72%) and low (28%) recurrence risk in both pre- and postinduction collections.

After 12 months, the postinduction RFS rate was 100% for low-risk and 38% for high-risk patients (P=.038), whereas preinduction RFS was 56% and 22%, respectively (P=.097).

By using matched pre- and postinduction urine, Dr. Narayan and colleagues measured quantitative drug response and categorized patients as MRD negative (75%), MRD complete responder (13%), MRD partial responder (27%), MRD stable (20%), or MRD refractory (33%). They found that recurrence correlated broadly with response groups; the MRD negative and complete responder groups did not recur on study, while 7 of 12 patients in the other groups recurred.

“uMRD enables quantitative assessment of molecular response to drug treatment,” researchers concluded as a result of their study. “uMRD-determined pretreatment disease burden assessment can support stratification of control and intervention arms in future treatment trials.”