Second-Line Strategies in Metastatic Urothelial Cancer: Balancing Options and Risks


Arlene Siefker-Radtke, MD, delves into the complexities of managing progressive disease in metastatic urothelial cancer, outlining considerations for immune checkpoint inhibitors, antibody drug conjugates, and other targeted therapies.


Arlene O. Siefker-Radtke, MD: So unfortunately, we’re still not curing most patients with metastatic urothelial cancer. Relapse and progressions are expected. And I’m often asked, what do we do once they have progressive disease? I think the first step is typically assessing whether they’ve had that prior immune checkpoint inhibitor. If they have not had an immune checkpoint inhibitor, then most commonly I do utilize agents like pembrolizumab, the immune checkpoint inhibitor associated with a response rate of around 20% and improvement in median overall survival compared to single-agent taxane.

However, I don’t use that in the second line for all patients. There have been prognostic factors associated with adverse outcomes, arguably liver metastases, which can be associated with B symptoms like fevers and chills or night sweats or rapid progression and lack of response to immunotherapy. [That] is 1 setting where I will consider use of additional cytoreductive treatment, such as one of the antibody-drug conjugates or erdafitinib. When we look at options in the second line space, we have enfortumab vedotin, 1 antibody-drug conjugate associated with a 40% response rate. However, it has the toxicity profile of peripheral neuropathy, and patients who are on it a long period of time have a very high rate of developing progressive neuropathy, especially if they have other conditions that contribute to the neuropathy, such as poorly controlled diabetes.

In addition, poorly controlled diabetes can impact a patient’s ability to receive enfortumab vedotin. One potential sign that the treatment is not being cleared as effectively is if a patient has hypoglycemia. And in fact, the Clinical Trials Inc monitoring of hemoglobin A1C at baseline and exclusion for a high hemoglobin A1C after they saw an increased incidence of diabetic ketoacidosis associated with insulin resistance is also associated with patient deaths on treatment. So personally, when giving treatment in the second-line setting with enfortumab vedotin, I consider whether they have preexisting neuropathy or type 2 diabetes with neuropathy. If this patient who again [has] poorly controlled diabetes has neuropathy or has elevated glucose is making monitoring for enfortumab toxicity challenging, then I would be more likely to look at either sacituzumab govitecan or treatment with erdafitinib.

If you don’t have the mutation panel back, I certainly wouldn’t wait to get the mutation results because patients with liver metastases often progress rapidly and that’s why testing for mutations early in the disease becomes important. Fifteen percent to 20% will have an FGFR3 alteration and response rates with erdafitinib in the second-line setting are around 40%, so I would certainly consider erdafitinib if a patient has an FGF alteration present. However, the majority of patients do not have FGFR3 alterations present. And in a patient like this—with poorly controlled diabetes, hypoglycemia making monitoring challenging, and likely neuropathy from their diabetes, their previous cisplatin-based chemotherapy as well—more often, one might consider sacituzumab govitecan.

When we compare sacituzumab govitecan…it’s currently approved in patients who’ve had prior chemotherapy and immunotherapy for their urothelial carcinoma. Response rates on the basis of a phase 2 clinical trial were around 25% with the median overall survival that again appears similar to other agents in the postchemotherapy, postimmunotherapy setting. So I think this option is certainly very reasonable and is associated with cytoreduction in patients with rapidly growing disease. However, sacituzumab govitecan does have its own [adverse] effect profile that one needs to monitor for and to manage.

And that [adverse] effect profile includes neutropenia and neutropenic fevers. This neutropenic fever rate, I believe, is higher in our urothelial cancer patient population. Again, we’re treating elderly patients with comorbid medical conditions who have had prior aggressive chemotherapy, often with cisplatin. So when I treat a patient with sacituzumab govitecan, which is given on day 1 and day 8 of a 3-week schedule, I am personally giving growth factor support due to the high rates of neutropenia to try to prevent any readmissions to hospital for neutropenic fever and improve the toxicity profile. Patients may also have diarrhea such as has been associated with the irinotecan analogs, so diarrhea may be something to monitor for and treat as well and consider appropriate dose reductions.

Transcript is AI-generated and edited for clarity and readability.

Case: A 73-Year-Old Man with Metastatic Urothelial Carcinoma

Initial Clinical Presentation:

  • A 73-year-old man presented to you from their local urologist with dizziness and hematuria
  • PMH: hypertension and diabetes (uncontrolled)
  • SH: former smoker; consumes alcohol 2-3 times per week
  • Chest x-ray and CT revealed a 3.7-cm mass on the right lateral wall of the bladder and liver metastases
  • Cystoscopic biopsy/pathology confirmed stage IV urothelial carcinoma
  • ECOG PS 1
  • CrCl 65 mL/min
  • The patient received gemcitabine + cisplatin (6 cycles)
    • Partial response at completion of chemotherapy
    • No maintenance therapy given, although discussed with patient

Current Clinical Presentation:

  • 7 months later, disease progression was discovered on routine follow up imaging


  • The patient received pembrolizumab and a partial response was achieved at 6 cycles
  • Molecular testing showed no FGFR2 mutation or fusion
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