Why ctDNA serves as a rule-out in NeoBLAST's response assessment

Determining clinical complete response in muscle-invasive bladder cancer without the ability to perform a pathologic examination requires a multimodal approach—and NeoBLAST¹ (NCT06537154) has assembled one of the most comprehensive response assessment frameworks yet used in this setting, according to Marie-Pier St-Laurent, MD, FRCSC.

Because the trial's central hypothesis is that definitive bladder treatment can be safely deferred in patients who respond deeply to neoadjuvant therapy, the accuracy of clinical complete response determination is foundational.

"We cannot get a pathological CR—the goal is to try to avoid cystectomy," Dr. St-Laurent said. The NeoBLAST definition requires negativity across all the following: conventional cross-sectional imaging, bladder MRI with VI-RADS classification, transurethral resection of bladder tumor (TURBT) with template and mapping bladder, and circulating tumor DNA. Urine-derived tumor DNA is being collected exploratorily but does not currently contribute to the clinical complete response definition.

"utDNA is quite promising, but it's not there yet—those tests need to be further refined," St-Laurent said, noting that future data from collected specimens may eventually allow its inclusion.

The role of each modality is distinct. Conventional CT confirms absence of metastatic or progressive disease. Bladder MRI improves local bladder detection sensitivity. TURBT with template biopsy provides histologic assessment of the bladder. ctDNA assess metastatic/micro-metastatic disease and serves primarily as a rule-out: A positive result excludes complete response regardless of other findings, whereas a negative result does not confirm it.

"If ctDNA is positive, clearly you're not a CR," St-Laurent said.

The phase 2 feasibility threshold—requiring at least 25% of patients with clinical complete response to accept randomization—was set with input from investigators and trialists and reflects the inherent challenge of randomly assigning patients between definitive treatment and surveillance in a curative-intent setting. Since opening in Vancouver in August 2025, the trial has been accruing faster than projected, and St-Laurent indicated that although the target enrollment number has not yet been reached, the rate of accrual suggests the feasibility end point is within reach. Enrollment is expected to accelerate further as enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) became available in Canada following Health Canada approval for cisplatin-ineligible patients in June. The higher complete response rates anticipated with that regimen, and the expanded pool of neoadjuvant-eligible patients, should support both feasibility and the pace of enrollment toward the phase 3 threshold.

If the phase 3 trial ultimately demonstrates non-inferiority of active surveillance—with a prespecified margin of 10% for metastasis-free survival at 2 years—the implications for practice would be significant.

"It will really change our guidelines and how our algorithm works," St-Laurent said. Cystectomy would retain its role for patients who do not achieve complete response, but those who do would have a validated alternative pathway.

"If a patient is willing to accept this non-inferiority margin and they want to try to save their bladder, they can take that as an option." Surveillance in that pathway would include cystoscopy, cytology, ctDNA, and conventional imaging, with definitive treatment initiated at recurrence.

REFERENCE

1. St-Laurent M-P, Eigl BJ, Tyldesley S, et al. NeoBLAST: A pilot randomized controlled trial of active surveillance versus definitive bladder treatment following clinical complete response to neoadjuvant therapy in muscle-invasive bladder cancer - study protocol. Eur Urol Oncol. 2026 Aug 7:S2588-9311(26)00198-7. doi:10.1016/j.euo.2026.07.008