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Frontiers in Metastatic Bladder Cancer
Evolving Frontiers in Locally Advanced and Metastatic Bladder Cancer: Advances, Challenges, and the Path Toward Personalized Care

Released: April 14, 2026

Fed Ghali
Fed Ghali, MD
Petros Grivas
Petros Grivas, MD, PhD, FASCO
Shilpa Gupta
Shilpa Gupta, MD
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Key Takeaways
  • EV + P is now approved across settings, including locally advanced/metastatic UC and perioperative treatment of cisplatin-ineligible MIBC, supporting earlier use in appropriate patients.
  • ctDNA may help risk-stratify patients and guide adjuvant decisions, but should be used cautiously alongside clinical judgment, given limited data and the risk of recurrence even in ctDNA-negative patients.
  • Effective use of EV + P requires proactive toxicity monitoring, especially for peripheral neuropathy and potentially life-threatening hyperglycemia.

Recent advances in muscle-invasive bladder cancer (MIBC) and metastatic urothelial carcinoma (mUC) have rapidly transformed the treatment landscape, with antibody–drug conjugate (ADC) and immunotherapy combinations such as enfortumab vedotin plus pembrolizumab (EV + P), along with emerging biomarkers like circulating tumor DNA (ctDNA), reshaping clinical practice. Despite the major progress, important challenges remain, including optimizing patient selection, avoiding overtreatment, managing toxicities, and determining the most effective sequencing strategies in an increasingly complex care environment, as reflected in the following questions and expert responses from a recent live symposium.

What do you consider to be the most exciting recent advances in bladder cancer, and what key challenges remain as the treatment landscape continues to evolve?

Shilpa Gupta, MD:
Over the last few years, there has been tremendous progress. In my opinion, one of the most exciting advances is the emergence of ADC and immunotherapy combinations, particularly EV + P, which has revolutionized the treatment of mUC. What’s especially notable is that this combination is already moving into earlier disease settings. In addition, the development of robust biomarkers like ctDNA is very promising and could significantly shape how patients are managed moving forward. That said, 1 major challenge is the risk of overtreatment. As more options become available, healthcare professionals (HCPs) need to consider how much treatment each patient truly needs and can tolerate.

Petros Grivas, MD, PhD, FASCO:
I completely agree. The combination of ADCs with immune checkpoint inhibitors (ICIs), particularly EV + P, has been a transformative strategy. It has changed how metastatic disease is approached and is now approved for use in both mUC and perioperative treatment of cisplatin-ineligible MIBC, while also continuing to be explored in broader localized settings, including cisplatin-eligible patients. Important new data in this space further shift the standard of care. At the same time, 1 of the biggest challenges is personalizing treatment. How do HCPs decide when to escalate or de-escalate therapy? For example, in the perioperative setting, should all patients receive adjuvant therapy as per the clinical trial designs, or can decisions be tailored based on individual factors like toxicity, pathologic stage, and ctDNA? Moving from a one-size-fits-all approach to truly individualized care remains a key unmet need.

Fed Ghali, MD:
One additional challenge is optimal treatment sequencing. Many clinical trials evaluate therapies in a specific disease state, such as the neoadjuvant and/or adjuvant setting, but by the time the results are available, the standard of care before and after that setting may have already evolved. This makes it difficult to fully contextualize the findings in real-world practice. Incorporating biomarkers like ctDNA into clinical decision-making is also complex, especially when many existing trials were not designed with these biomarkers and tools in mind. Integrating these advances into evolving treatment paradigms will be an important focus moving forward.

What are the main challenges in adjuvant therapy decision-making for MIBC, and how should emerging evidence inform clinical practice?

Petros Grivas, MD, PhD, FASCO:
The answer depends also on the neoadjuvant therapy used, considering the evolving therapy landscape. Patient selection for adjuvant therapy requires a careful balance between clinical trial designs and individual patient factors, also considering risks of overtreatment and undertreatment. As more effective therapies move earlier in the disease course, decisions should ideally be individualized based on disease risk, treatment intent, and likelihood of benefit vs risk rather than applying a “one-size-fits-all” approach.

Fed Ghali, MD:
One of the key challenges is that most patients considered for adjuvant therapy have no evidence of systemic disease and have recently undergone a major surgery, yet high-risk features raise concern for recurrence, forcing a difficult clinical decision between more therapy vs observation. In general, there are 3 approaches: 1) observation with treatment at recurrence, 2) adjuvant therapy despite no evidence of visible disease, or 3) a more selective strategy that can be aided via a biomarker like ctDNA. There are pros and cons to each approach. Observation risks missing the opportunity to treat micrometastatic disease early with the aim of cure, whereas adjuvant therapy risks overtreatment of perhaps 43% to 50% of patients who may be cured with surgery. Biomarker-driven approaches are very promising but still evolving, and we don’t yet have all the answers. With highly active regimens like EV + P, the key question is not only who to treat but when to treat. Ongoing data will help clarify the optimal timing of treatment in the perioperative setting.

Shilpa Gupta, MD:
Determining which patient receives adjuvant therapy is also influenced by referral patterns. Multidisciplinary collaboration between urology and medical oncology is essential to ensure appropriate patient selection and timing of therapy.

How can ctDNA be used to guide adjuvant treatment decisions in MIBC, and what are its current limitations?

Fed Ghali, MD:
ctDNA is emerging as a powerful tool to detect molecular residual disease after surgery. Data from the phase III IMvigor011 trial showed that patients with high recurrence risk who are ctDNA positive despite having no radiographic evidence of disease derive meaningful benefit from adjuvant atezolizumab, including improvements in both disease-free survival (median disease-free survival = 9.9 months with atezolizumab vs 4.8 months with placebo) and overall survival (median overall survival = 32.8 months with atezolizumab vs 21.1 months with placebo). This supports ctDNA as an effective way to identify ICI-naive patients most likely to benefit from adjuvant ICI therapy. In more general clinical practice, ctDNA may help inform decisions, particularly in cases where the benefit of adjuvant therapy is uncertain, like in patients who achieve pathologic complete response after neoadjuvant treatment. However, we are often operating in a data-limited space. Although ctDNA appears to reflect underlying disease biology, it is not regimen specific, and ctDNA-guided data for every therapeutic approach are not yet available. Of importance, ctDNA is not a perfect biomarker. Even ctDNA-negative patients can experience recurrence, so a negative result should not lead to complacency. These patients still require close imaging and surveillance, and decisions to omit therapy should be made cautiously.

Shilpa Gupta, MD:
What is particularly compelling is that ctDNA may allow HCPs to move beyond traditional imaging and better risk-stratify patients. Rather than treating all high-risk patients the same, ctDNA may help identify those with true residual disease who are most likely to benefit from adjuvant therapy. For example, in a patient with a pathologic complete response and negative ctDNA, historical data might support observation, but newer perioperative trial designs complicate that decision. In these situations, I consider serial ctDNA testing rather than relying on a single time point and incorporate additional factors such as prior treatment tolerance and patient preferences.

Which patients with mUC are appropriate candidates for first-line EV + P, and which patients may be less suitable for this regimen?

Petros Grivas, MD, PhD, FASCO:
The vast majority of patients with mUC are candidates for EV + P. It has become the preferred first-line standard of care, given its impressive efficacy. Trials, such as EV-302 (in the frontline metastatic setting), EV-303 and EV-304 (both in localized MIBC; stages T2-T4aN0M0 or T1-T4aN1M0) have demonstrated robust and consistent benefit, supporting the use of EV + P across a broad patient population and therapy settings.

The group of patients who may not be suitable for this combination is quite small and typically includes those who are very frail, because of poor functional status and/or significant medical comorbidities. For example, patients with severe autoimmune conditions may not be able to receive pembrolizumab, whereas those with high-grade baseline neuropathy or severe liver impairment may not be able to tolerate EV. Such patients may be better served with less intensive approaches. However, a careful, balanced risk–benefit discussion at the individual patient level is needed for proper informed shared decision-making.

Shilpa Gupta, MD:
I agree. Most patients are eligible for EV + P. In my practice, only a small percentage, perhaps around 5%, of patients are not candidates, typically due to frailty or comorbid conditions that limit tolerance. The phase III EV-303 study in localized MIBC was particularly reassuring, with a median event-free survival of not reached with EV + P vs 15.7 months with radical cystectomy alone, because the data demonstrate meaningful benefit even in a frail, high-risk population, including many patients who are cisplatin ineligible. These outcomes strongly suggest that EV + P can be used broadly, including in patients who previously had limited therapeutic options. Regarding comorbidities, such as autoimmune disease, the treatment approach has evolved. Historically, HCPs were cautious about using immunotherapy in all these patients, but are now more comfortable treating many of them with a more individualized, nuanced approach. Close monitoring and multidisciplinary collaboration with specialists are key, and decisions should be individualized.

Fed Ghali, MD:
One question is how to approach patients with autoimmune conditions, such as Crohn’s disease or ulcerative colitis. In some cases, HCPs may consider alternative strategies or proceed cautiously, especially if the autoimmune condition is severe or poorly controlled. At the same time, the threshold for using immunotherapy has shifted over time. Many patients who would have been excluded from treatment in the past are now being treated with appropriate close monitoring, reflecting growing clinical experience and comfort with managing these risks on a case-by-case basis.

The EV-303 trial also highlights an important point about patient selection, as it enrolled a particularly high-risk population with limited treatment options and still demonstrated strong efficacy, reinforcing the idea that this regimen is active even in highly vulnerable patients, although careful clinical judgment is still required.

Given that EV + P is now the preferred first-line standard of care for mUC, how should HCPs manage key adverse events (AEs) associated with this regimen, and what considerations guide treatment sequencing after progression?

Petros Grivas, MD, PhD, FASCO:
With EV + P now widely used in the first-line setting, it is critical for HCPs, especially those in the community setting, to become more familiar with its toxicity profile. The most common dose-limiting AE is peripheral sensory neuropathy, which occurs in more than half of patients. Careful history and detailed physical exam are essential to assess severity, including impact on daily activities, such as buttoning clothes, tying shoelaces, gait stability, dexterity in fine motor tasks, etc. Other common toxicities include skin rash, pruritus, fatigue, diarrhea, nausea, dysgeusia, anorexia, and weight loss. Another particularly important toxicity to monitor for is hyperglycemia, which occurs in approximately 10% of patients and can be life threatening. This requires very close monitoring in both diabetic and nondiabetic patients. Ultimately, proactive recognition and proper management of all potential AEs are key to maintaining patients on the evolving optimal therapy dose/schedule and optimizing benefit–risk ratio and clinical outcomes.

I also want to emphasize the importance of a structured toxicity assessment, particularly for neuropathy. Although most cases are sensory, a subset of patients may develop motor neuropathy, so HCPs should carefully assess strength and function. Early identification allows for dose modifications and the prevention of more severe complications. Other toxicities, such as ocular symptoms (eg, dry eyes), can usually be managed with best supportive care, like eye lubricants or artificial tears, but expert consultation may be needed in several cases. Overall, high familiarity with these AEs and early intervention is essential.

Shilpa Gupta, MD:
In terms of therapy sequencing, after progression on EV + P, options include platinum-based chemotherapy or targeted therapy, such as erdafitinib for patients with an FGFR3-susceptible alteration or trastuzumab deruxtecan in those with HER2 3+ immunohistochemistry (IHC) in tumor tissue. Clinical trials are also important.

Petros Grivas, MD, PhD, FASCO:
Sequencing after first-line EV + P remains an area of uncertainty. There is no clearly defined standard of care, and decisions should be individualized based on prior therapies given, toxicity profiles, efficacy data, medical comorbidities, functional status, patient preferences/goals/wishes, and molecular profile (tumor next-generation sequencing and HER2 IHC), among other factors. The goal is to tailor therapy and maximize benefit across the disease continuum using the best possible therapy upfront and considering the notable attrition over time. Systemic therapy options include platinum-based chemotherapy or targeted therapy, such as erdafitinib for patients with an FGFR3-susceptible alteration or trastuzumab deruxtecan in those with HER2 3+ IHC in tumor tissue. Clinical trials are very important.

Fed Ghali, MD:
This question highlights the “art of medicine.” As of yet, there are no prospective data defining the optimal order of therapies after EV + P. Instead, HCPs rely on clinical judgment and consider factors such as the route of administration (oral vs IV), toxicity profiles, patient preferences, and access to best supportive care. It is important to consider multiple active options. The focus should be on using the most effective therapies earlier while ensuring patients have access to subsequent lines of treatment as needed.

What role does multidisciplinary collaboration play in optimizing patient selection and treatment sequencing?

Fed Ghali, MD:
Multidisciplinary collaboration is truly critical because MIBC is inherently a complex, multidisciplinary disease. Data from a multidisciplinary clinic study showed that when patients are reviewed in a multidisciplinary manner (ie, by experts in medical oncology, radiation oncology, urology, radiology, and pathology), there are meaningful changes in both staging and treatment plans. This directly impacts patient management and helps ensure more appropriate, individualized care.

Petros Grivas, MD, PhD, FASCO:
Bringing together expertise from the various specialties mentioned above allows for more accurate clinical staging, recognition of potential subtype/variant histology, and more informed treatment planning, which can directly impact patient outcomes. At the same time, HCPs should think about how to implement this approach in real-world settings. Ideally, these discussions occur in multidisciplinary clinics at expert centers, where all specialists can review cases together at the same time. However, access to this particular level of care can be challenging, particularly in rural, underserved, or community settings with fewer resources. This question highlights the importance of building strong communication and collaboration between academic centers and community HCPs so that patient care, regardless of location, can benefit from expert multidisciplinary input.

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In the evolving treatment landscape, what are your questions on how to best manage patients with bladder cancer? Tell us about your recent experiences managing this population of patients.

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Have you incorporated perioperative EV + P into your practice for patients with cisplatin-ineligible MIBC?

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