ctDNA Testing Is Poised to Reshape Risk Assessment and Treatment Decision-Making in Bladder Cancer

Circulating tumor DNA (ctDNA) could be used to inform risk assessment and treatment decisions in genitourinary malignancies such as bladder cancer, although widespread adoption into routine clinical practice is predicated upon further validation, technical standardization, and prospective evidence, according to experts who participated in a recent OncLive Peer Exchange®.

During the discussion, which was filmed at the American Society of Clinical Oncology 2026 Genitourinary Cancers Symposium (ASCO GU), the panelists discussed how they are currently using ctDNA and other testing approaches to inform their practice and highlighted notable data in bladder cancer from ASCO GU that could further inform the integration of these testing modalities.

How are ctDNA and liquid biopsies currently used in the clinic?

The panelists began by discussing individual applications of ctDNA testing in their respective practices. “[It feels as if] clinical, pathologic, and genomic features are almost obsolete, and we are using ctDNA more in the adjuvant setting,” Pooja Ghatalia, MD, noted. “Granted, the neoadjuvant space has completely changed.”

Jean Hoffman-Censits, MD, and Arnab Basu, MBBS, MPH, FACP, noted that at their institutions, ctDNA testing via the tumor-informed Signatera assay is used routinely. Data on perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in bladder cancer may affect the use of ctDNA technology, but it will still be useful for disease monitoring, Noah Richardson, MD, added.

“I’ve been ordering [ctDNA testing] before patients start chemoradiotherapy for patients with muscle-invasive bladder cancer [MIBC] fairly routinely,” Steven Seyedin, MD, said. “[In terms of which patients] need ctDNA [testing], approximately 30% of patients with T2/N0 bladder cancer have a positive minimal residual disease [MRD] assay. This tells us that we can’t use clinical features alone to detect [MRD]. [Interestingly, ctDNA] is more predictive of metastasis-free survival [MFS] rather than local relapse. We don't know exactly how we should change management [to incorporate it], necessarily, but [ctDNA testing can be used to] guide our patients and [detect metastases and recurrence] earlier than before.”

What data presented during ASCO GU could inform the ideal use of ctDNA testing and liquid biopsy?

The panelists then shifted gears to discuss data presented during ASCO GU that could influence the use of ctDNA testing and liquid biopsy in the clinic. They began by highlighting data from an analysis of the phase 3 NIAGARA trial (NCT03732677), which examined urinary tumor DNA (utDNA) and ctDNA in patients with MIBC who received perioperative durvalumab (Imfinzi).¹

In March 2025, the FDA approved durvalumab in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by durvalumab monotherapy as adjuvant treatment, after radical cystectomy for adult patients with MIBC. The regulatory decision was supported by data from the NIAGARA trial.²

Findings from the analysis presented at ASCO GU demonstrated that patients in the durvalumab (n = 52) and comparator (n = 48) arms achieved utDNA clearance at rates of 38.5% and 27.1%, respectively. In the overall population, patients with utDNA clearance (n = 33) experienced a significant benefit in terms of event-free survival (EFS) vs those with persistent utDNA positivity (n = 67; HR, 0.24; 95% CI, 0.09-0.62). Additionally, patients who were utDNA negative prior to radical cystectomy (n = 76) achieved a pathologic complete response (pCR) rate of 72%. Among those with utDNA positivity prior to radical cystectomy (n = 96), the pCR rate was 18%. Patients with ctDNA- and utDNA-negative disease prior to cystectomy (n = 74) achieved a significant benefit in terms of 24-month EFS compared with those who were ctDNA negative and utDNA positive (HR, 0.46; 95% CI, 0.23-0.89) and those who were ctDNA and utDNA positive (n = 34; HR, 0.25; 95% CI, 0.12-0.49).¹

“utDNA, by itself, may not be the full answer,” Basu said. “In NIAGARA, [28%] of patients were [utDNA] negative and still didn't have a pCR. We need imaging or artificial intelligence–based algorithms to help us bridge that gap. There's also a gap in the utilization [of utDNA] in other disease types, [such as] penile cancer or urethral cancers of the upper tract. We need to be able to target MRD across the disease spectrum in all diseases.”

In an exploratory analysis of the phase 3 IMvigor011 study (NCT04660344) presented at ASCO GU, investigators examined how serial ctDNA testing can be used to differentiate patients at high vs low risk of disease recurrence to avoid unnecessary treatment.³ The trial examined atezolizumab (Tecentriq) in patients with MIBC who were ctDNA positive at any time point up to 1 year after cystectomy. ctDNA testing was performed using a personalized, tumor-informed, 16-plex multiplex polymerase chain reaction next-generation sequencing assay.

“Data from IMvigor011 have shown us [how to utilize] this technology, [considering] the ongoing changes with enfortumab vedotin plus pembrolizumab in the perioperative setting. I believe this will continue to change, but we certainly use ctDNA for monitoring,” Richardson commented.

Findings from the exploratory analysis demonstrated that ctDNA-negative patients (n = 357) experienced 6-, 12-, and 24-month DFS rates of 98.0%, 95.4%, and 88.4%, respectively. Those who were ctDNA positive at the time of the initial test (n = 126) achieved 6-, 12-, and 24-month DFS rates of 49.9%, 19.2%, and 8.2%, respectively. These respective rates were 89.1%, 43.8%, and 22.3% among patients who were ctDNA positive at a subsequent test (n = 86).³

Patients who were ctDNA negative had 6-, 12-, and 24-month overall survival (OS) rates of 100%, 100%, and 97.1%, respectively. The 6-, 12-, and 24-month OS rates were 96.4%, 87.4%, and 48.5%, respectively, among patients who were ctDNA positive at the time of the initial test. Those who were ctDNA positive at a subsequent test experienced 6-, 12-, and 24-month OS rates of 98.8%, 98.8%, and 71.8%, respectively.³

Patients with a maximum of 0.1 mean tumor molecules per mL (MTM/mL; n = 56) experienced 6-, 12-, and 24-month disease-free survival (DFS) rates of 82.1%, 53.4%, and 28.4%, respectively. The respective OS rates at these time points were 100%, 100%, and 67.4%. Among patients with more than 0.1 MTM/mL to a maximum of 3 MTM/mL (n = 99), the DFS rates at 6, 12, and 24 months were 71.2%, 26.6%, and 13.2%, respectively; the respective OS rates were 97.2%, 95.0%, and 60.1%. In those with more than 3 MTM/mL (n = 57), the 6-month DFS rate was 44.0%, the 12-month DFS rate was 9.4%, and the 24-month DFS rate was 0.0%; the OS rates at 6, 12, and 24 months were 95.2%, 76.0%, and 42.6%, respectively.³

“The evidence for improving outcomes with immunotherapy post cystectomy for patients who are ctDNA positive really comes from the IMvigor011 data showing that patients could be salvaged if they were ctDNA positive post cystectomy, but those patients did not receive neoadjuvant immunotherapy,” Richardson noted. “Patients who receive enfortumab vedotin/pembrolizumab [who are] ctDNA positive post cystectomy are likely [to be] at a high risk for recurrence, but we don't currently have level 1 evidence [indicating] the best [approach] at that point. For many patients, we'd likely be following phase 3 trials and continuing enfortumab vedotin/pembrolizumab, but these patients are at risk for relapse. Future trials may reevaluate how to intensify therapy. One of those trials, the [phase 2/3] MODERN trial [NCT05987241], is looking at postcystectomy ctDNA [levels] to intensify or de-escalate adjuvant therapy based on their ctDNA profile.”

Two phase 2 studies evaluated the use of ctDNA testing to guide response-adapted bladder preservation strategies in patients with MIBC: RETAIN (NCT02710734) and RETAIN-2 (NCT04506554).⁴ These trials included patients with MIBC who were treated with AMVAC (accelerated methotrexate, vinblastine, doxorubicin [Adriamycin], and cisplatin) and AMVAC plus nivolumab (Opdivo), respectively. The primary end point in RETAIN-2 was 2-year MFS in the intention-to-treat (ITT) population.

Results from an integrated analysis of RETAIN and RETAIN-2 were presented during ASCO GU. At a median follow-up of 32.3 months, the 2-year MFS rate in the ITT population was 83.5% (95% CI, 75.0%-92.9%). The 2-year MFS rate among patients who underwent active surveillance (n = 22) was 85.2% (95% CI, 70.9%-100%). These data met the primary end point of RETAIN-2.

Additional data from the pooled analysis of the RETAIN data sets (n = 111) showed that 42.3% of patients were ctDNA positive at baseline and that 13.6% were ctDNA positive after treatment. The overall ctDNA clearance rate from baseline positive to posttreatment negative was 72.7% (n = 32/44). The clearance rates in the active surveillance (n = 18) and intervention (n = 26) arms were 83.3% and 65.4%, respectively.

ctDNA positivity at baseline (HR, 12.62; 95% CI, 3.74-42.57; P < .0001) and post neoadjuvant therapy (HR, 10.73; 95% CI, 4.76-24.21; P < .0001) were found to be strongly prognostic of MFS benefit. Similar outcomes were observed for MFS (HR, 13.29; 95% CI, 4.66-37.93; P < .0001) and OS (HR, 5.0; 95% CI, 1.67-14.98; P = .004) among ctDNA-negative patients, regardless of active surveillance or cystectomy.

However, ctDNA status after neoadjuvant therapy was found to be predictive of metastatic control but not local control among patients who received active surveillance (n = 44). The 24-month MFS rate in these patients was 82.6%, but the 24-month recurrence-free survival rate was 51.4%.

“[Data from] RETAIN [showed that] following ctDNA for patients with upper tract [disease] who might be getting adjuvant therapy is not great at picking up MIBC recurrences,” Hoffman-Censits explained. “Those patients still need that guideline-endorsed cystoscopy. Those patients [don’t just need] lab scans and follow-up, but urology-directed cystoscopies. [These are] important things to remember for that patient population. ctDNA is at a place where it can be informative, but it doesn't give us every answer for every patient all the time. We need to use all our clinical tools to make decisions.”

References

1. Van Der Heijden MS, Galsky MD, Joshi R, et al. Urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) in patients (pts) with muscle-invasive bladder cancer (MIBC) who received perioperative durvalumab (D) in NIAGARA. J Clin Oncol. 2026;44(suppl 7):636. doi:10.1200/JCO.2026.44.7_suppl.636
2. FDA approves durvalumab for muscle invasive bladder cancer. FDA. Updated March 28, 2025. Accessed April 6, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
3. Powles T, Grindheim J, Yilmaz M, et al. Circulating tumor (ct)DNA-guided adjuvant atezolizumab (atezo) in muscle-invasive bladder cancer (MIBC): exploratory analysis of ctDNA dynamics in the IMvigor011 trial. J Clin Oncol. 2026;44(suppl 7):633. doi:10.1200/JCO.2026.44.7_suppl.633
4. Mellema JJ, Stockem C, Herberts C, et al. Induction ipilimumab plus nivolumab followed by consolidating chemoradiotherapy as bladder-sparing treatment in stage II/III urothelial carcinoma of the bladder: the phase 2 Indi-Blade trial. J Clin Oncol. 2026;44(suppl 7):LBA637. doi:10.1200/JCO.2026.44.7_suppl.LBA637