In recent years, the perioperative management of muscle-invasive bladder cancer (MIBC) has undergone rapid transformation. The emergence of immunotherapy, antibody-drug conjugates (ADCs), and precision biomarker-driven treatment has fundamentally reshaped the therapeutic landscape.At the recent China Clinical Oncology Annual Advances Symposium (BOC) and Best of CSCO 2026 China, leading oncology experts gathered to discuss the latest international advances and their translation into clinical practice. During the meeting, UroStream interviewed Prof. Wasilijiang-Wahafu from the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences to discuss advances in neoadjuvant therapy for MIBC, the clinical value of biomarkers such as ctDNA and HER2, and strategies for balancing efficacy and safety during perioperative treatment.
UroStream:
Several important studies evaluating neoadjuvant treatment for MIBC—including immunotherapy, targeted therapy, and combination regimens—have recently reported results. How do you view the impact of these new strategies on the perioperative treatment landscape for MIBC?
Prof. Wasilijiang-Wahafu:
This question goes directly to one of the most important topics in genitourinary oncology today. To understand where perioperative treatment for MIBC is heading, it is helpful to review the evolution of neoadjuvant therapy over time.
The first era was the chemotherapy era.
The landmark SWOG 8710 trial established cisplatin-based neoadjuvant chemotherapy as the standard of care. Subsequently, the VESPER study demonstrated that dose-dense ddMVAC could further improve outcomes, increasing the pathologic complete response (pCR) rate to approximately 40%, which essentially represented the upper limit of efficacy achievable with conventional cytotoxic chemotherapy.
However, chemotherapy has inherent limitations. Nearly half of patients with MIBC are ineligible for cisplatin because of advanced age, impaired renal function, or other comorbidities. Historically, these patients had no effective preoperative systemic treatment options and proceeded directly to surgery.
Beginning around 2018, immunotherapy ushered in a new era of neoadjuvant treatment.
Seminal studies such as PURE-01 and ABACUS demonstrated that neoadjuvant immunotherapy alone could achieve pCR rates of 30%–40%, providing an effective preoperative option for cisplatin-ineligible patients and filling an important unmet clinical need.
Subsequently, investigators explored combinations of immunotherapy and chemotherapy. Although modest improvements were observed, these regimens did not produce transformative gains. For example, in the NIAGARA trial, durvalumab plus chemotherapy achieved a pCR rate of approximately 37%, indicating that considerable room for improvement remained.
The third era began with the advent of antibody-drug conjugates (ADCs).
ADCs have fundamentally broken through the efficacy ceiling of previous therapies and have become the major breakthrough in neoadjuvant treatment for MIBC, particularly when combined with immunotherapy.
Among cisplatin-ineligible patients, the EV-303 study evaluated a Nectin-4-targeted ADC plus pembrolizumab, achieving a pCR rate of 57%, compared with only 8.6% in the surgery-alone group—a remarkable improvement.
Among cisplatin-eligible patients, the EV-304 trial directly compared the ADC-based regimen with standard chemotherapy and likewise demonstrated a pCR rate of approximately 56%.
Equally noteworthy are the important contributions from China.
The domestic Phase II RC48-C017 study evaluating disitamab vedotin plus toripalimab in HER2-positive disease reported a remarkable pCR rate of 64% after six cycles of neoadjuvant treatment, substantially exceeding the results historically achieved with chemotherapy.
The evolution from 30%–40% pCR rates during the chemotherapy era to greater than 60% with ADC–immunotherapy combinations clearly demonstrates the clinical superiority of these new treatment strategies, which have now become the preferred approach for neoadjuvant therapy in MIBC.
At the same time, advances in drug therapy have also transformed our treatment philosophy.
Historically, neoadjuvant therapy was intended primarily to shrink tumors before surgery. Today, pivotal Phase III studies consistently employ a comprehensive perioperative strategy combining neoadjuvant systemic therapy with postoperative maintenance immunotherapy.
The landmark NIAGARA trial, for example, demonstrated significant improvements in both event-free survival (EFS) and overall survival (OS) using neoadjuvant durvalumab plus chemotherapy followed by postoperative maintenance immunotherapy.
Similarly, the EV series of studies has adopted this comprehensive treatment paradigm.
This means that surgery is no longer viewed as the endpoint of treatment. Instead, maximal tumor reduction before surgery, followed by postoperative eradication of microscopic residual disease through immunotherapy, creates a complete continuum of potentially curative treatment.
Overall, perioperative management of MIBC has undergone two fundamental transformations.
First, patient stratification has evolved. Previously, treatment decisions depended largely on whether patients were eligible for cisplatin. ADC–immunotherapy combinations have overcome this limitation, providing highly effective individualized treatment options regardless of cisplatin eligibility.
Second, treatment goals have fundamentally changed. Traditional neoadjuvant therapy focused primarily on facilitating surgery and achieving an R0 resection. Today, the objective is the eradication of microscopic metastatic disease and sustained improvement in overall survival.
Neoadjuvant treatment for MIBC has therefore entered the era of precision-guided perioperative management.
UroStream:
Studies such as IMvigor011 and RC48-C017 have demonstrated that biomarkers including ctDNA-based molecular residual disease and HER2 expression can accurately identify patients most likely to benefit from treatment. Could you discuss the clinical value and future potential of biomarkers such as ctDNA and HER2 in MIBC?
Prof. Wasilijiang-Wahafu:
The development of biomarkers—including circulating tumor DNA (ctDNA), molecular residual disease (MRD), and HER2—represents one of the most important advances in precision perioperative treatment for MIBC.
Their greatest value lies in enabling risk stratification, individualized treatment, and precision medicine, replacing the traditional “one-size-fits-all” approach.
Let me first discuss ctDNA and MRD.
Historically, postoperative adjuvant therapy was recommended largely according to pathological risk factors, resulting in substantial overtreatment. Many low-risk patients were unnecessarily exposed to drug toxicity, while clinicians lacked reliable tools to identify those truly requiring intensified treatment.
Studies such as IMvigor011 have fundamentally changed this paradigm.
These trials demonstrated two key findings.
First, serial ctDNA monitoring can accurately identify high-risk patients who should receive postoperative immunotherapy.
Second, it can spare low-risk patients from unnecessary treatment and associated toxicity.
Patients who remained ctDNA-negative and underwent surveillance alone achieved outstanding outcomes, with 1-year OS of 100%, 18-month OS of 98%, 12-month DFS of 92%, and 18-month DFS of 88%, indicating that additional adjuvant therapy was unnecessary.
In contrast, ctDNA-positive patients harbored molecular residual disease and had substantially poorer outcomes. Patients managed with observation alone experienced a median DFS of only 4.8 months and a median OS of 21.1 months. Early initiation of systemic therapy, including immunotherapy, improved DFS to 9.9 months and OS to 32.8 months, representing a significant survival benefit.
These findings clearly demonstrate that ctDNA is much more than a prognostic marker—it is becoming a critical tool for determining whether postoperative treatment should be administered and when it should begin.
At the same time, we must recognize current practical limitations.
The ctDNA platform used in IMvigor011 employed highly individualized testing requiring whole-exome sequencing of the surgical specimen, identification of trunk mutations, development of patient-specific probes, and serial monitoring every six weeks.
Although this personalized approach provides exceptional sensitivity and specificity, it is also technically demanding, time-consuming, costly, and associated with substantial health-economic challenges. Consequently, it cannot yet be directly translated into routine commercial testing platforms.
Therefore, while ctDNA undoubtedly represents the future of precision oncology, broader implementation will require standardized testing methodologies, bioinformatic pipelines, and consensus regarding testing frequency.
Turning to HER2, its value is equally important.
Because urothelial carcinoma exhibits substantial biological heterogeneity, HER2 expression provides an actionable therapeutic target for precision treatment.
The Chinese RC48-C017 study, built around the HER2-targeted ADC disitamab vedotin, successfully demonstrated that HER2-directed therapy may enable de-escalation of cisplatin use—or even chemotherapy altogether—in neoadjuvant treatment, opening an entirely new era of precision therapy.
The results were particularly impressive.
Among patients with HER2-positive MIBC, six cycles of disitamab vedotin plus toripalimab achieved an overall pCR rate of 64% and a pathologic downstaging rate of 75%.
Patients with HER2 IHC 3+ disease derived even greater benefit, achieving a remarkable pCR rate of 84.6%, a level of efficacy that would have been unimaginable during the chemotherapy era.
Long-term follow-up further demonstrated an outstanding 24-month overall survival rate of 91%.
Overall, HER2 testing serves three major purposes.
First, it accurately identifies patients most likely to benefit from ADC-based therapy, allowing targeted immunotherapy combinations to replace conventional chemotherapy while avoiding chemotherapy-associated toxicity.
Second, it facilitates exceptionally high rates of local tumor eradication, thereby improving surgical outcomes.
Third, it establishes an important molecular foundation for future precision bladder-preservation strategies.
UroStream:
With the rapid introduction of new therapies for MIBC, clinicians must manage the distinct toxicities associated with immunotherapy, chemotherapy, and ADCs while also optimizing surgical timing and perioperative care. How can physicians best balance treatment efficacy and safety?
Prof. Wasilijiang-Wahafu:
Achieving the optimal balance between efficacy and safety has become one of the most important challenges in contemporary perioperative management of MIBC.
Previously, clinicians mainly managed chemotherapy-related toxicities such as myelosuppression and hepatic or renal dysfunction.
Today, however, the spectrum of adverse events has become considerably more complex. ADCs may cause peripheral neuropathy and characteristic cutaneous toxicities, while immunotherapy introduces the risk of immune-related inflammatory events involving multiple organs.
Successfully balancing efficacy and safety requires three key strategies.
The first is establishing a mature multidisciplinary team (MDT) approach.
The traditional model centered solely on urologic surgery is no longer sufficient.
Surgeons must serve as the coordinators of perioperative care, working closely with medical oncologists, endocrinologists, and other specialists throughout treatment.
This multidisciplinary collaboration maximizes the likelihood of achieving high pCR rates while ensuring prompt management of severe treatment-related toxicities, thereby preventing patients from missing their optimal surgical window because of systemic adverse events.
The second strategy is maintaining flexibility in surgical decision-making.
Operative planning should be continuously adjusted according to each patient’s treatment tolerance.
If severe ADC-related toxicity or immune-related adverse events occur during neoadjuvant therapy, systemic treatment should be interrupted promptly, and definitive surgery should be prioritized to avoid continued toxicity.
Likewise, if patients develop complications such as impaired bowel function before surgery, surgeons may elect to perform a simpler urinary diversion rather than a more complex urinary reconstruction, thereby reducing perioperative risk.
Dynamic adjustment of surgical strategy according to treatment-related toxicity is essential for balancing efficacy and safety.
The third strategy is returning to the principles of precision medicine.
One of the major causes of treatment-related toxicity is the indiscriminate application of highly intensive therapy.
Future management should rely on precision tools such as serial ctDNA monitoring, HER2 molecular classification, and tumor microenvironment assessment to repeatedly reassess patient risk and individualize treatment.
For patients who achieve a pathological complete response and complete molecular clearance, therapy should be appropriately de-escalated rather than unnecessarily prolonged, thereby avoiding avoidable toxicity associated with overly intensive treatment.
In summary, the emergence of new therapies is not intended to indiscriminately intensify treatment.
Rather, these advances provide clinicians with far greater flexibility and precision in designing individualized perioperative treatment strategies.
Moving forward, multidisciplinary collaboration, surgical safety, and molecular biomarker-guided decision-making will form the three pillars of modern perioperative management, allowing us to maximize survival while preserving patients’ postoperative quality of life.
Prof. Wasilijiang-Wahafu:
