ctDNA Insights Stand at the Forefront of Data-Driven, Individualized MIBC Management

Rapid advances in systemic therapy, perioperative treatment strategies, and biomarker science are reshaping muscle-invasive bladder cancer (MIBC) management, with circulating tumor DNA (ctDNA) emerging as a pivotal tool for guiding treatment and predicting outcomes.

“MIBC [management is] changing quickly, and ctDNA does have a role to play,” Thomas Powles, MD, MRCP, MBBS, said in a recent OncLive® Peer Exchange. “It’s going to revolutionize the outcome of our patients. We're going to cure more patients, and I hope you see that in your clinics as well.”

During the panel discussion, bladder cancer experts discussed the strengths and limitations of current standards of care (SOCs) for patients with MIBC across the neoadjuvant, adjuvant, and perioperative settings. They contextualized these standards in light of updates to the treatment paradigm, which were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.

What up-front regimen should patients with MIBC receive in the neoadjuvant setting?

“[In] the current treatment paradigm for MIBC, it’s still the case that one needs to look at platinum eligibility to start with in the neoadjuvant setting,” Powles said. “For those eligible for platinum-based chemotherapy, the [phase 3] NIAGARA [trial (NCT03732677)] approach is a SOC.”

NIAGARA showed that the addition of durvalumab (Imfinzi) to neoadjuvant gemcitabine and cisplatin, followed by radical cystectomy and adjuvant durvalumab, significantly improved event-free survival (EFS; HR, 0.68; 95% CI, 0.56-0.82; P < .0001) and overall survival (OS; HR, 0.75; 95% CI, 0.59-0.93; 2-sided P = .0106) compared with gemcitabine and cisplatin alone in the neoadjuvant setting, followed by radical cystectomy and no adjuvant treatment in patients with cisplatin-eligible MIBC.1 Based on these data, in March 2025, the FDA approved perioperative durvalumab plus chemotherapy for this indication.

What do the SunRISe trials show about the expanded potential for gemcitabine intravesical systems in bladder cancer management?

The panelists were quick to highlight that although NIAGARA has reshaped the current MIBC treatment arsenal, innovations beyond immunotherapy are fast approaching, particularly in the neoadjuvant setting. A recent notable development for non-MIBC (NMIBC) hints at what may come for MIBC down the line. In September 2025, the FDA approved the gemcitabine intravesical system (formerly TAR-200; Inlexzo) for the treatment of adult patients with Bacillus Calmette-Guérin–unresponsive NMIBC with carcinoma in situ with or without papillary tumors.2 This regulatory decision was supported by findings from the phase 2b SunRISe-1 trial (NCT04640623).

The phase 2 SunRISe-4 study (NCT04919512) evaluated the efficacy and safety of the gemcitabine intravesical system plus cetrelimab in patients with cisplatin-ineligible MIBC. Data presented at ESMO 2025 showed that patients who received the combination (n = 88) achieved a pathologic complete response (pCR) rate of 38% (95% CI, 28%-49%) vs 28% (95% CI, 16%-44%) with cetrelimab monotherapy (n = 46).3 The 12-month recurrence-free survival (RFS) rates were 77% (95% CI, 67%-85%) and 64% (95% CI, 47%-77%), respectively.

“It's an interesting approach, and…the response rate is really high,” Joaquim Bellmunt, MD, PhD, said. “It's a good device. The paradigm is now crowded, and it's going to be difficult to decide the best way to go.”

Exploratory analyses also showed that urinary tumor DNA (utDNA) and ctDNA may be effective biomarkers for detecting residual disease after neoadjuvant therapy. utDNA-positive minimal residual disease (MRD) rates decreased after 12 weeks of neoadjuvant therapy across both arms. In particular, in the gemcitabine intravesical system arm, this rate dropped from 77.8% at baseline to 50.0% at week 12. utDNA MRD negativity at week 12 was associated with pCR, and ctDNA MRD negativity was linked with longer RFS.

“When it comes to muscle-invasive disease, the big question is: Can [the intravesical gemcitabine device] contribute to a potential increase in pCR rate if it's given in the context of even more effective systemic therapies?” Petros Grivas, MD, PhD, said. “SunRISe-4 is interesting and hypothesis-generating, but my sense is that the systemic therapy was probably not adequate in the context of what we see from the NIAGARA regimen and recent data from [the phase 3 KEYNOTE-905 trial (NCT03924895)] with enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda]. But I can see a future where [the gemcitabine intravesical system] could be investigated to boost pCR rates in the context of more effective systemic therapies. Could we select patients with durable clinical CRs who can keep their bladders? I can see the future there to be tested in clinical trials with [the gemcitabine intravesical system] in muscle-invasive disease.”

What perioperative regimens are gaining ground in cisplatin-ineligible MIBC?

The panelists noted that the management of cisplatin-ineligible MIBC is also evolving based on data from KEYNOTE-905. In the trial, patients who received enfortumab vedotin plus pembrolizumab followed by radical cystectomy and standard pelvic lymph node dissection (RC + PLND; n = 170) achieved a median EFS that was not reached (NR; 95% CI, 37.3-NR) compared with 15.7 months (95% CI, 10.3-20.5) with RC + PLND followed by observation alone (n = 174; HR, 0.40; 95% CI, 0.28-0.57; 1-sided P < .0001).4 The respective pCR rates were 57.1% (95% CI, 49.3%-64.6%) and 8.6% (95% CI, 4.9%-13.8%).

What do data show about the effect of ctDNA status on survival outcomes in MIBC?

Shifting to the core of the discussion, the experts took on the topic of ctDNA’s growing role in bladder cancer treatment decision-making. They provided context by spotlighting findings from the ctDNA analysis of the phase 3 IMvigor010 trial (NCT02450331) of adjuvant atezolizumab (Tecentriq) vs observation in patients with MIBC. In this trial, among patients who were ctDNA positive, treatment with atezolizumab was associated with an OS benefit vs observation (HR, 0.59; 95% CI, 0.42-0.83).5 Furthermore, greater levels of ctDNA clearance with atezolizumab correlated with longer OS.

“IMvigor010 started all the excitement with ctDNA in basically all of genitourinary oncology,” Alan Tan, MD, said. “[It is] compelling that if [a patient is] ctDNA positive, [they] are destined to recur. These are the patients who need to [receive] intensified [treatment].”

The IMvigor010 findings were validated in updated data from the phase 3 CheckMate 274 trial (NCT02632409) of adjuvant nivolumab (Opdivo) vs placebo in patients with high-risk MIBC, which were presented at ESMO 2025 (Table 1).6 The ctDNA analysis—though the panelists cautioned about the relatively small sample size—showed that baseline undetectable ctDNA status (n = 79) was associated with improved survival outcomes vs detectable ctDNA status (n = 54). Among all patients with ctDNA-undetectable disease, the median disease-free survival (DFS) was 52.1 months (95% CI, 19.4-not evaluable [NE]) vs 5.0 months (95% CI, 2.8-6.5) among those with detectable ctDNA (HR, 0.30; 95% CI, 0.18-0.48). The respective median OS values were NR (95% CI, 62.0 months-NE) and 28.2 months (95% CI, 19.4-36.1; HR, 0.44; 95% CI, 0.25-0.76).

However, trends toward improved DFS and OS outcomes were observed with nivolumab vs placebo, regardless of ctDNA status. Among patients with ctDNA-detectable disease, the median DFS with nivolumab (n = 27) was 7.4 months (95% CI, 2.8-19.2) vs 2.8 months (95% CI, 2.4-5.0) with placebo (n = 27; HR, 0.35; 95% CI, 0.18-0.66). The median DFS values among patients in these respective arms with ctDNA-undetectable disease were 91.9 months (95% CI, 19.2-NE; n = 50) and 52.2 months (95% CI, 16.9-NE; n = 29; HR, 0.99; 95% CI, 0.51-1.93). The median OS among patients with ctDNA-detectable disease was 36.2 months (95% CI, 23.0-NE) with nivolumab vs 19.3 months (95% CI, 8.1-28.2) with placebo (HR, 0.41; 95% CI, 0.20-0.83). The median OS values among patients in these respective arms with ctDNA-undetectable disease were NR (95% CI, 62.0 months-NE) and NR (95% CI, 40.7 months-NE; HR, 0.87; 95% CI, 0.41-1.84).

The panelists explained that the hypothesis regarding the use of ctDNA testing in bladder cancer was further confirmed in IMvigor011 (NCT04660344), which they later elaborated on in the context of growing evidence supporting ctDNA testing in MIBC.

What are some of the recent advances in systemic therapy, unmet needs, and the importance of ctDNA testing in MIBC?

“Patients with bladder cancer die of metastatic disease, not local disease,” Powles said. “The purpose of surgery is to catch the cancer early enough before the cancer spreads. If it's later than that, and the cancer has already spread, the role of surgery becomes somewhat academic. In the end, the MRD—the disease that's already spread—is going to define the outcome of the patients, and the question will be: Have you given systemic therapy [that is] effective to cure those patients? What are the early features after cystectomy that can tell you whether the patient is going to relapse?”

Powles opened the floor to a larger discussion about the role of ctDNA testing in bladder cancer and when it is best predictive of disease recurrence, calling for insights on both the benefits and limitations of this method for choosing optimal treatment strategies.

“We live in an era where we have an emergence of new, more effective systemic therapies that aim not only to [target] the primary tumor but also the micrometastases, which are the invisible enemy,” Grivas said. “The more effective systemic therapies may enable us to try to cure more patients, especially [those] with localized disease, and maybe a few with advanced metastatic disease. [They may] also, down the road, enable us to do more bladder preservation.”

Grivas noted the efficacy of immune checkpoint inhibition that the NIAGARA data uphold, as well as the increasing relevance of antibody-drug conjugates exemplified in KEYNOTE-905, explaining that “checkpoint inhibition by itself is probably not as effective in the context of combination therapy but may have a role in the adjuvant setting, and ctDNA [testing] can help refine that discussion.”

The panelists unanimously acknowledged that, although several advances have been made in the systemic management of MIBC, patient outcomes still need improvement, and MRD remains an area of largely untapped potential.

“We need biomarkers, and we need better drugs, so we need a combination of MRD and a biomarker that predicts the activity of the drug,” Guru P. Sonpavde, MD, said. “In my mind, MRD is still a biomarker for microscopic disease.”

Tan explained the promise of treatment response monitoring, which allows for a close look at how disease may be progressing in a patient, noting that “with treatment response monitoring, we have insight into the ctDNA kinetics of the tumor and when resistance starts to develop if [a patient does not] clear ctDNA. This is an avenue that needs to be explored further.”

He emphasized that implementing adaptive treatment approaches based on ctDNA levels and biomarker expression following completion of standard regimens, such as enfortumab vedotin plus pembrolizumab, may be the next step in helping patients live longer.

“We need to recognize the heterogeneity of this disease,” Tan said. “We're helping a lot of patients, but we need better biomarker recognition and MRD treatment response monitoring to raise that tail of the curve that we're already seeing.”

How do the IMvigor011 trial data begin to add to the conversation about the role of ctDNA testing in MIBC?

The phase 3 IMvigor011 trial prospectively evaluated ctDNA-guided treatment outcomes with adjuvant atezolizumab vs placebo in patients with MIBC. Data presented at ESMO 2025 showed that patients who tested ctDNA positive at any time point through ctDNA testing had improved DFS and OS with atezolizumab vs placebo.7 The median DFS was 9.9 months (95% CI, 7.2-12.7) with atezolizumab (n = 167) vs 4.8 months (95% CI, 4.1-8.3) with placebo (n = 83; HR, 0.64; 95% CI, 0.47-0.87; stratified P = .0047). The median OS values in these respective arms were 32.8 months (95% CI, 27.7-NE) and 21.1 months (95% CI, 14.7-NE; HR, 0.59; 95% CI, 0.39-0.90; stratified P = .0131; Table 2).7 Similar efficacy was observed between patients who tested ctDNA positive at baseline vs those who converted to ctDNA-positive status upon repeat testing.

“IMvigor011 makes the landscape [and] the decision-making more interesting,” Sonpavde said. “In the setting where IMvigor011 was done, which is with or without neoadjuvant chemotherapy alone and no chemoimmunotherapy beforehand, it makes sense to use the IMvigor011 approach…. [However], I don't think you can make the case that if [a patient has ctDNA-]positive [disease], we give [this regimen, and if they have ctDNA-]negative [disease], we don't.”

What factors are needed for more widespread implementation of ctDNA testing in clinical practice?

“There are panel-based testing approaches in specific tumor types, such as colorectal cancer, lung cancer, and breast cancer, but that has not happened in urothelial cancer, prostate cancer, kidney cancer, and other tumor types,” Powles said. “Instead of using those panel-based approaches, we're probably better off using a personalized approach, where we're tracking specific mutations that are identified within this particular cancer.”

Powles explained that this approach may lead to more specificity to inform individualized treatments, as well as fewer false positive results. Tan added that future tests should have improved sensitivity to help with treatment decision-making, especially in the perioperative setting, where curative-intent treatment may still be an option for certain patients. However, he cautioned that one main limitation of ctDNA testing in bladder cancer is that it cannot detect cancer in the central nervous system. The role of ctDNA assays in metastatic disease also remains unclear, Grivas added.

“We have opportunities to design trials for escalation and de-escalation, building upon IMvigor011 in the localized setting, but also [to] try to answer questions in the metastatic disease setting,” Grivas said. “As these assays become more readily available, we'll have the opportunity to do that.”

Sonpavde concluded the discussion with insights into the issue of overtreatment, explaining that this may occur in many patients who receive perioperative treatment, as it is possible for certain patients to be cured with cystectomy alone. He emphasized that identifying better biomarkers may help determine which patients would benefit most from adjuvant treatment and pave the way for improved bladder cancer outcomes in the future.

“Patients who are ctDNA negative before neoadjuvant therapy, postneoadjuvant therapy, and then again post cystectomy have good outcomes,” he said. “Now, I've been wondering [whether] we're overtreating [these patients] with even more adjuvant components of the therapy. This all needs to be proven, and more studies need to be done…. Could we use ctDNA to have a bladder-preservation approach in patients who achieve clinical CR or [who are] ctDNA negative? These are all [topics] to explore. [ctDNA testing] could have a role in the bladder-preservation setting post neoadjuvant therapy.”

Thomas Powles, MD, MRCP, MBBS, is a professor of genitourinary oncology, director of the Barts Cancer Centre, and lead for solid tumor research at St Bartholomew’s Hospital in London, United Kingdom.

Joaquim Bellmunt, MD, PhD, is director of the Bladder Cancer Center in the Genitourinary Oncology Program and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

Petros Grivas, MD, PhD, is a professor in the Clinical Research Division, medical director of local/regional outreach, and medical director of the International Program at Fred Hutchinson Cancer Center in Seattle, Washington. He is also a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.

Guru P. Sonpavde, MD, is the medical director of genitourinary oncology, assistant director of the Clinical Research Unit, and the Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute in Orlando, Florida.

Alan Tan, MD, is an associate professor of medicine in the Division of Hematology and Oncology in the Department of Medicine at Vanderbilt University Medical Center, as well as a genitourinary oncology specialist at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

References

1. FDA approves durvalumab for muscle invasive bladder cancer. FDA. March 28, 2025. Accessed November 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
2. US FDA approval of Inlexzo (gemcitabine intravesical system) set to transform how certain bladder cancers are treated. News release. Johnson & Johnson. September 9, 2025. Accessed November 18, 2025. https://www.multivu.com/johnson-and-johnson/9342851-en-johnson-and-johnson-fda-approval-inlexzo-gemcitabine-intravesical-system
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5. Powles T, Assaf ZJ, Degaonkar V, et al. Updated overall survival by circulating tumor DNA status from the phase 3 IMvigor010 trial: adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma. Eur Urol. 2024;85(2):114-122. doi:10.1016/j.eururo.2023.06.007
6. Galsky MD, Gschwend JE, Milowsky MI, et al. Adjuvant nivolumab versus placebo for high-risk muscle-invasive urothelial carcinoma: 5-year efficacy and ctDNA results from CheckMate 274. Ann Oncol. Published online October 17, 2025. doi:10.1016/j.annonc.2025.09.139
7. Powles TB, Kann A, Castellano Gauna DE, et al. IMvigor011: a phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Ann Oncol. 2025;36(suppl 2):S1749. doi:10.1016/j.annonc.2025.09.109