How Do Updated NCCN Guidelines and ctDNA Data Reshape MIBC Treatment?

Bladder cancer treatment has shifted substantially with the incorporation of circulating tumor DNA (ctDNA) status into clinical decision-making, alongside the expanding role for antibody-drug conjugates in the muscle-invasive setting.

CancerNetwork® spoke with Kirollos Hanna, PharmD, BCPS, BCOP, the director of Pharmacy at Minnesota Oncology, an assistant professor of pharmacy at the Mayo Clinic Alix School of Medicine, and editorial advisory board member of the journal ONCOLOGY®, about how the updated NCCN guidelines incorporating ctDNA-based molecular residual disease (MRD) testing are reshaping treatment for muscle-invasive bladder cancer (MIBC).¹ He discussed how multidisciplinary teams should approach adjuvant treatment for ctDNA-positive patients following radical cystectomy, the reliability of ctDNA clearance in predicting pathological complete response, challenges in securing payer coverage for serial ctDNA testing, optimal timing of blood draws relative to intravesical therapy and surgery, and what a best-in-class multidisciplinary workflow looks like.

He closed by touching upon the recent expanded approval of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in MIBC, and the unmet need that remains in the metastatic setting.²

CancerNetwork: How might the most recent NCCN guideline update impact standard practice for patients who test positive on multiplex polymerase chain reaction [PCR] ctDNA MRD assays?

Hanna: We have seen a dramatic shift in the guideline updates in bladder cancer over the last several years. This is one of the hallmark shifts we have seen, where they are now utilizing MRD guidance to look at whether patients achieve a pathological complete response, to help guide subsequent treatment decision-making. When you look at the bladder cancer population, a lot of these patients are older, and when they reach the metastatic setting, despite significant updates, the 5-year overall survival [OS] for patients with locally advanced or metastatic urothelial carcinoma is still hovering between 5% and 10%. Our goal in non-muscle invasive bladder cancer [NMIBC] and even MIBC is to try to achieve the best event-free survival [EFS] we can.

Recently, there was an approval of enfortumab vedotin in combination with pembrolizumab that has been extended by the FDA as neoadjuvant treatment prior to surgery. It is exciting that after patients undergo some type of cytoreductive therapy—say, dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or enfortumab vedotin plus pembrolizumab—they go on to radical cystectomy and pelvic lymph node dissection, and we can now assess them down to the cellular level rather than simply being unable to detect disease on imaging. What we have seen, which has driven these NCCN guideline updates, is that patients who do not achieve a negative ctDNA result should be put on some form of immunotherapy, specifically atezolizumab [Tecentriq], because it is the one that is FDA-approved. Patients who go on to immunotherapy after not achieving a negative PCR have much higher EFS, based on findings from the [phase 3 IMvigor011 trial (NCT04660344)].³

With data from the phase 3 IMvigor010 (NCT02450331) and IMvigor011 trials, how should multidisciplinary teams approach the pharmacologic management of patients with MIBC who are radiographically disease-free but persistently ctDNA-positive following radical cystectomy?

Patients who are ctDNA positive after radical cystectomy have an estimated 6- to 20-fold higher likelihood of disease recurrence than those who are ctDNA negative. The ctDNA-negative population generally has improved disease-free survival [DFS] and OS as well. After patients undergo neoadjuvant treatment and surgical removal of the bladder, the ideal candidate for adjuvant treatment is the patient who is ctDNA positive. From what we learned from IMvigor010 and IMvigor011, the utilization of immunotherapy in patients [with ctDNA-positive disease] leads to a significant improvement in DFS—it was almost a doubling of survival in patients who received atezolizumab vs standard of care active surveillance.⁴ That ideal patient is [one who is] ctDNA-positive, where we should be utilizing immunotherapy.

As bladder preservation strategies are explored, how reliable is ctDNA clearance following neoadjuvant chemotherapy or immunotherapy in predicting a true pathologic complete response? From a clinical workflow perspective, can urologic and medical oncologists safely use ctDNA kinetics to de-escalate treatment or omit radical cystectomy in select patients?

This is a hard one. While ctDNA positivity is a poor prognostic indicator, the NCCN explicitly states, and the literature is not yet ample enough to allow us to use ctDNA negativity to de-escalate therapy for MIBC or to consider omitting radical cystectomy—that remains the gold standard of care. Regardless of what is done in the neoadjuvant setting, these patients still have to go to surgery. With more mature data, could that become an option down the line? Radical cystectomy is extremely debilitating, and quality of life is significantly affected over a long period. But we have to be considerate: ctDNA can return false negatives, and the sensitivity of the test remains imperfect, as patients may have tissue scarring or recurrent bladder infections that make sampling difficult. Right now, ctDNA positivity should be used as a high-risk indicator for likelihood of recurrence post-surgery, but I would not recommend, and the guidelines generally do not recommend, using ctDNA negativity to de-escalate treatment.

One area where de-escalation or active surveillance might be considered is when a patient has completed neoadjuvant therapy and surgery but is not interested in adjuvant treatment. For a long time in MIBC, adjuvant treatment was not standard—patients went to neoadjuvant chemotherapy, underwent surgery, and were placed under active surveillance. Depending on what was used in the neoadjuvant setting, if a patient received enfortumab vedotin and pembrolizumab, that combination should be continued in the adjuvant setting. If a patient received dose-dense MVAC, they would not go to adjuvant enfortumab vedotin and pembrolizumab, but options like nivolumab [Opdivo] or atezolizumab exist. Nivolumab is approved as adjuvant treatment regardless of ctDNA positivity or negativity. That could be an area for further exploration, but [there’s] still nothing in terms of de-escalation or assuming these patients are not surgical candidates.

Integrating ctDNA testing effectively requires cross-functional alignment between urology, medical oncology, pathology, and pharmacy. What does a best-in-class workflow look like to ensure that assay selection, tissue-informed vs blood-first approaches, and rapid turnaround times translate into timely, personalized pharmacologic interventions?

This patient population, particularly in [NMIBC] and even more so in [MIBC], now requires a multidisciplinary team approach. Historically, if these patients were not getting chemotherapy, they may have lived solely within urology clinics, but today these patients often become symptomatic early, are referred by primary care to urology, and are found to have [MIBC or NMIBC]. When patients are diagnosed with muscle invasive disease, the gold-standard neoadjuvant treatment is still cytotoxic in nature, whether that is enfortumab vedotin-based therapy or standard cytotoxic chemotherapy, which is where medical oncology comes in. The urologist and medical oncologist need to develop an appropriate treatment plan and maintain good handoff regarding where the patient is in their course.

Pharmacy integration is critical here as well—counseling patients, educating them, and monitoring for symptoms, since neoadjuvant treatments are far from simple to tolerate, with neuropathies, infections, and other toxicities depending on the therapeutic modality. Infusion nurses also play a key role. Post-surgery, an even broader multidisciplinary approach is needed to ensure pathology delivers proper tissue sampling quickly so we can test for ctDNA status, since that result should dictate strategy. Do we use atezolizumab because the patient is ctDNA positive? Could we use nivolumab, regardless of ctDNA status? We also have adjuvant therapy with enfortumab vedotin and pembrolizumab following surgery. One trend I am hearing more about is urology clinics across the country bringing on staff medical oncologists because they may not be comfortable administering cytotoxic chemotherapy—a reflection of how much has changed in bladder cancer and the broader genitourinary space.

What does the recent expanded approval of enfortumab vedotin plus pembrolizumab in MIBC mean for pharmacologic oncology practice, and how should clinical teams balance the reduction in EFS events against the distinct toxicity of this platinum-free regimen when choosing between it and traditional chemotherapy for fit patients?

It is worth stepping back to look at the story of enfortumab vedotin and pembrolizumab in bladder cancer. A few years ago, in locally advanced or metastatic disease, pembrolizumab was a second-line option—the first immunotherapy to show an OS benefit following standard gemcitabine-carboplatin in the second-line setting. Enfortumab vedotin followed, establishing itself as monotherapy in patients who had progressed on chemotherapy and immunotherapy. The [phase 3 EV-301 trial (NCT03474107)] then completely changed the dynamics in locally advanced or metastatic bladder cancer. It became the first combination to displace gemcitabine-carboplatin and remains the only Category 1 NCCN recommendation for frontline locally advanced or metastatic disease. Given how good that data was, it was no surprise that enfortumab vedotin plus pembrolizumab moved into the muscle invasive setting.

The first approval in this setting, a few months ago, was in cisplatin-ineligible patients. What we know about muscle invasive disease is that carboplatin should not be substituted for cisplatin—it is an inferior agent. A few years ago, during a cisplatin shortage, bladder cancer was one of the indications where we made sure to preserve cisplatin supply. The first indication for enfortumab vedotin plus pembrolizumab was in cisplatin-ineligible patients, and the EFS Kaplan-Meier curve was quite profound. Patients receive a few cycles, go on to surgery, then receive a neoadjuvant or adjuvant phase of treatment. Just a few days ago, the FDA approved it regardless of cisplatin eligibility. The data are good. You’re getting very good responses. Pathologic complete response rates are much higher than with standard conventional chemotherapy.

This is not an option for every patient. A patient with uncontrolled severe neuropathy may not be the best candidate, since enfortumab vedotin causes neuropathy related to its MMAE payload; though, dose-dense MVAC also causes neuropathy, just not with the same incidence we would expect with enfortumab vedotin. Similarly, patients with severe skin toxicities or uncontrolled autoimmune conditions may not be ideal candidates, given the toxicity profiles of both pembrolizumab and enfortumab vedotin. For eligible candidates, our go-to is enfortumab vedotin plus pembrolizumab given what the data shows. From a managed care perspective, cost will be higher with 2 branded agents, but given the significant difference in clinical value, it is hard to weigh cost against a regimen that works meaningfully better—this is not a matter of a couple percentage points' difference in response rates. For fit patients without the adverse effects mentioned, most do well, and even those who develop neuropathy or rash tend to see improvement, since this is a finite duration of treatment rather than treatment until progression or toxicity.

Is there anything else you would like to highlight?

Bladder cancer is one of the most highly mutated cancers we know of, and it has been exciting watching the field advance over the past 5 to 10 years. One concern is that as we see this shift of therapies moving into earlier lines of treatment across oncology, we may cure more people and prevent recurrences, but there is still an unmet need. For example, if a patient is treated with enfortumab vedotin and pembrolizumab in the muscle invasive setting, undergoes surgery, completes adjuvant treatment, and progresses within a year, what is the best next option? Do we move to conventional chemotherapy, which we know is not as good? Do we retrial enfortumab vedotin and pembrolizumab, since progression was not the reason treatment was stopped in that setting? And what is the future role of ctDNA in guiding sequencing, de-escalation strategies, or the potential to avoid radical cystectomy altogether?

I am excited about this disease state, but as treatments move into earlier lines, it creates an unmet need in the metastatic setting. We should not hold these therapies back from moving earlier because we want to cure patients, but I am hopeful we will continue to see novel therapeutics in locally advanced and metastatic disease—additional antibody-drug conjugates, FGFR inhibitors, and continued roles for immunotherapy. There is a lot more to come in bladder cancer, and the landscape will have evolved significantly a year from now.

References

1. NCCN recommends ctDNA-MRD testing using Signatera technology in landmark bladder cancer guideline update. News release. Natera Inc. June 23, 2026. Accessed July 14, 2026. https://tinyurl.com/3u8vcr65
2. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. News release. FDA. July 10, 2026. Accessed July 14, 2026. https://tinyurl.com/3nmcpncy
3. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. 2025;393:2395-2408. doi:10.1056/NEJMoa2511885
4. 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