Upcoming data for the HER2-ADC Disitamab Vedotin will test if its efficacy is enriched in HER2-high patients. This trial spotlights a key field-wide dilemma: is specific enrichment necessary, or does a "bystander effect," as seen in breast cancer, mean even low HER2 expression is enough, complicating patient selection and the drug's positioning.

Data from trials like Niagara suggests a powerful new paradigm for assessing treatment success. Combining urine tumor DNA (uTDNA) for local disease and circulating tumor DNA (ctDNA) for systemic relapse offers a more dynamic view than traditional pathology and is poised to become the superior surrogate endpoint in bladder cancer trials.

Upcoming trials like RETAIN and IMVigor011 are using circulating tumor DNA (ctDNA) to guide complex treatment choices in muscle-invasive bladder cancer. This biomarker-driven approach aims to personalize therapy, potentially enabling bladder preservation for some patients and identifying others who need additional adjuvant treatment.

In the SURE-01 trial, nearly a third of patients declined radical cystectomy after strong responses to sacituzumab govitecan. This patient-driven decision highlights a significant, growing interest in bladder preservation, pushing the field to validate less invasive approaches for select patients.

With highly active agents yielding 30% complete response rates, the immediate goal should be to cure more patients by exploring potent combinations upfront. While sequencing minimizes toxicity, an ambitious combination strategy, such as ADC doublets, offers the best chance to eradicate disease and should be prioritized in clinical trials.

Despite the perception that cisplatin-ineligible patients have worse disease biology, the pathologic complete response rates to neoadjuvant EV Pembro were nearly identical (56-57%) in both cis-ineligible (KEYNOTE-905) and cis-eligible (KEYNOTE-B15) trials. This suggests the regimen's high efficacy may overcome underlying biological differences.

Current bladder cancer trials often fail to differentiate between patients with primary resistance (never responded) versus acquired resistance (responded, then progressed). Adopting this distinction, common in lung cancer research, could help identify patient subgroups more likely to benefit from immunotherapy re-challenge and refine trial eligibility criteria.

Experts question if HER2 status truly predicts ADC efficacy in urothelial cancer. The benefit seen across low-expression levels suggests HER2's main role may be simply to target the chemo payload to cancer cells, rather than indicating a specific biological dependency.

The control arm relapse rate in the SUNRISE 2 trial was only ~20%, while in the EV-303/KEYNOTE-905 trial it was ~60%. This huge discrepancy highlights that current clinical staging and selection criteria are poor at identifying patient risk, signaling an urgent need for better stratification tools like ctDNA for more effective clinical trials.