15th Shanghai Urologic Oncology Academic Conference
Editor’s Note: The combination of antibody–drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs) is rapidly transforming the clinical management of urothelial carcinoma. Meanwhile, circulating tumor DNA (ctDNA) is emerging as a highly promising biomarker, offering critical support for precision medicine and bladder-preserving treatment strategies.At the 15th Shanghai Urologic Oncology Academic Conference, Oncology Frontier – Urology Frontier invited Professor Thomas Powles to share in-depth insights on optimizing perioperative treatment, biomarker-driven patient selection, and the evolving “de-escalation of surgery” paradigm in bladder cancer.
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Oncology Frontier – Urology Frontier
In the perioperative setting for MIBC, ADCs such as Enfortumab Vedotin (EV) are enabling “platinum-free” neoadjuvant strategies. How mature are the current data on ADC monotherapy or ADC–immunotherapy combinations? Could ADCs replace cisplatin-based regimens as the standard of care within the next 3–5 years?
Professor Thomas Powles: This is currently one of the most high-profile and challenging questions in urothelial cancer. In fact, we have already witnessed a fundamental paradigm shift in the metastatic setting.
Advances in Metastatic Disease
ADC–ICI combinations—most notably Enfortumab Vedotin (EV) plus Pembrolizumab—have demonstrated superior efficacy compared with traditional chemotherapy. Clinical evidence suggests these regimens nearly double overall survival (OS) relative to conventional chemotherapy.
Breakthroughs in Perioperative MIBC
In the neoadjuvant setting for muscle-invasive bladder cancer (MIBC), EV plus Pembrolizumab has achieved a pathologic complete response (pCR) rate of approximately 55%, indicating efficacy that may exceed surgery alone.
Additionally, the NIAGARA trial, which evaluated Durvalumab combined with neoadjuvant Cisplatin + Gemcitabine, demonstrated a 25% reduction in the risk of death, reinforcing the importance of early immune intervention in improving long-term outcomes.
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Oncology Frontier – Urology Frontier
Immunotherapy has moved from second-line metastatic use into neoadjuvant and adjuvant settings, yet long-term OS benefits remain limited in studies such as CheckMate 274 and IMvigor. With emerging biomarkers like ctDNA, which patients truly need perioperative immunotherapy, and how can future trials avoid overtreatment?
Professor Thomas Powles: As our treatment arsenal expands, we must ask critical questions: Do all patients need intensive systemic therapy? Are there subgroups who can safely avoid overtreatment?
At present, we still lack an ideal predictive biomarker. Traditional markers—including PD-L1 expression, tumor mutational burden (TMB), and T-cell effector signatures—have not reliably predicted immunotherapy benefit. Similarly, Nectin-4 expression has not shown a clear correlation with ICI outcomes in ADC-treated populations.
The Promise of ctDNA
Despite these limitations, ctDNA represents one of the most promising emerging biomarkers. It enables precise identification of patients at high risk of recurrence, directly informing prognosis and treatment intensity.
We are entering an era of biomarker-guided individualized therapy, integrating ctDNA and urinary tumor DNA (utDNA).
- Patients who clear ctDNA may benefit from shortened treatment duration
- Patients who remain persistently ctDNA-negative may avoid radical cystectomy altogether
This biomarker-driven “subtraction strategy” will be critical for precision oncology and minimizing unnecessary treatment.
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Oncology Frontier – Urology Frontier
Prospective studies such as POUT, ABACUS, and IMvigor011 have shown that postoperative ctDNA positivity predicts recurrence and can guide adjuvant immunotherapy escalation. However, testing timing, mutation panels, and thresholds remain inconsistent. When might ctDNA-guided risk stratification enter clinical guidelines, and what evidence is still needed?
Professor Thomas Powles: ctDNA is fundamentally reshaping the treatment logic of MIBC, shifting practice away from a “one-size-fits-all” model toward true personalization.
Evidence from IMvigor011
This trial enrolled postoperative ctDNA-positive MIBC patients, randomizing them to Atezolizumab or placebo, while ctDNA-negative patients underwent observation only.
Findings showed that ctDNA-negative patients had an excellent prognosis, with a two-year bladder cancer–specific mortality of only ~3%, suggesting limited benefit from adjuvant therapy in this group. In contrast, ctDNA-positive patients derived meaningful benefit from immunotherapy.
Neoadjuvant Predictive Value
ctDNA also has strong predictive utility in the neoadjuvant setting.
- Gemcitabine + Cisplatin + Durvalumab achieved ctDNA clearance in ~70% of patients
- EV + Pembrolizumab is expected to yield even higher clearance rates
Toward “Surgery De-escalation” in Bladder Cancer
If a patient demonstrates:
- No residual disease on MRI, and
- ctDNA negativity following neoadjuvant therapy,
this strongly suggests a clinical complete response (cCR) and a very low risk of local recurrence.
Radical cystectomy imposes a substantial quality-of-life burden, particularly for older patients (70–80 years old). Looking ahead, by integrating MRI, ctDNA, utDNA, and highly effective regimens such as Disitamab Vedotin (RC48) + Toripalimab or EV + Pembrolizumab, we may enable more than 50% of patients to achieve durable remission without surgery.
This represents a major step toward functional cure, organ preservation, and truly patient-centered bladder cancer care.
Professor Thomas Powles
