In the EV+pembrolizumab combination, if a patient achieves an excellent response but develops prohibitive EV-related toxicities like neuropathy, a viable strategy is to discontinue EV and maintain the patient on pembrolizumab monotherapy. This can sustain the response while improving quality of life.

When immunotherapy is not an option for metastatic bladder cancer, enfortumab vedotin (EV) monotherapy is an attractive choice over traditional cisplatin chemotherapy, especially if a rapid tumor response is critical or if the patient has baseline neuropathy or renal issues that make chemotherapy tolerance uncertain.

While known for weight loss, GLP-1 agonists are also highly effective for managing hyperglycemia from both steroids and PI3K inhibitors. Using low or "micro" doses can be very helpful in cancer patients, providing glucose control while minimizing GI side effects like nausea.

Advances in drug design mean newer PI3K inhibitors are more targeted, resulting in significantly less off-target toxicity. For example, some investigational agents have a hyperglycemia risk under 15%, a substantial improvement over earlier drugs, making them easier to manage clinically.

For elderly or frail patients with metastatic bladder cancer, treatment choice hinges on goals. Enfortumab vedotin (EV) monotherapy is preferred for a rapid response in symptomatic or bulky disease. In contrast, pembrolizumab monotherapy is better for a lower-intensity approach in patients with low-volume disease where durable benefit and quality of life are prioritized.

On-body glucose monitors give oncologists a richer understanding of a patient's glucose control, including 24-hour trends, time-in-range, and an A1c equivalent (GMI). This real-time data is critical for managing hyperglycemia from targeted therapies, offering more insight than periodic fasting tests.

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.

A key eligibility criterion for the landmark EV-302 trial was glycemic control. Patients with an A1C above 8 were excluded due to hyperglycemia and diabetic ketoacidosis (DKA) risk from the enfortumab vedotin component. This has critical implications for patient selection and monitoring.

While severe (Grade 3+) neuropathy from enfortumab vedotin is rare, oncologists emphasize that Grade 2 toxicity is common and significantly impairs patients' quality of life. This 'moderate' side effect is often painful and interferes with daily activities, warranting an immediate hold on treatment, not just waiting for Grade 3.