A critical but easily missed safety issue with the ADC enfortumab vedotin (EV) is its risk of severe hyperglycemia. The drug is formally contraindicated in patients with a hemoglobin A1c above 8%. Clinicians must screen for this to prevent potentially fatal ketoacidosis.
The potential for urologists to administer PD-1 inhibitors for bladder cancer raises a significant safety issue: surgeons may not be equipped to manage severe, systemic immune-related toxicities like hypophysitis or hepatitis, which traditionally fall under the purview of medical oncologists.
Sequencing antibody-drug conjugates (ADCs) like enfortumab vedotin (EV) and disitamab vedotin is complicated because both use the same MMAE cytotoxic payload. If a tumor develops resistance to the MMAE from EV, it is unlikely to respond to a subsequent ADC using the same payload.
In muscle-invasive bladder cancer, patients whose cell-free DNA remains positive after surgery almost uniformly experience disease relapse. This makes ctDNA a powerful prognostic tool, akin to PSA in prostate cancer, for identifying patients at the highest risk.
New phase 3 trial data shows that the quantitative level of circulating tumor DNA (ctDNA) is directly proportional to recurrence rates in bladder cancer. Patients with the highest ctDNA levels have the worst outcomes, suggesting a gradient of risk that could be used for more precise patient stratification.
Groundbreaking trials demonstrating ctDNA's power in bladder cancer almost exclusively used tumor-informed "bespoke" assays like Signatera. This is a critical distinction, as the results may not translate to more common, non-bespoke ctDNA testing methods used in clinical practice.
The TAR-200, a novel intravesical "pretzel" device, provides sustained delivery of gemcitabine directly into the bladder. This local approach achieves a remarkable 83% complete response rate in NMIBC, offering a highly effective treatment option while avoiding systemic toxicities and frequent catheterizations.
While adding PD-1 inhibitors to standard BCG therapy in high-risk non-muscle-invasive bladder cancer improves event-free survival, it also introduces significant Grade 3 toxicity (around 24%) without mature overall survival data, making its risk-benefit profile questionable.
Remarkable pathologic response rates from just 3-4 cycles of neoadjuvant EV-Pembro are creating divergent research questions. Future trials will explore whether some patients could benefit from more cycles (escalation) while high-responders might be able to skip cystectomy entirely (de-escalation).