Future Directions in Urothelial Cancer Treatment: Clinical Trials and Novel Agents


Arlene Siefker-Radtke, MD, highlights the ongoing quest for improved treatment options in metastatic urothelial cancer, emphasizing the role of clinical trials and novel agents in addressing unmet needs.


Arlene O. Siefker-Radtke, MD: Despite the plethora of treatments that we’ve just discussed here today, we are still not curing our urothelial cancer patients with metastatic disease. So finding better treatment options remains an unmet need and finding treatments that they can tolerate in the setting of comorbid medical conditions is [a] high area of interest as well. I would certainly encourage support of clinical trials. We have several novel agents that may have improved toxicity profiles compared to other antibody drug conjugates. Some of these novel agents are like enfortumab vedotin. They target nectin-4 expression, bringing monomethyl auristatin E directly to the tumor, and may have improved clearance via the kidney. The compound by Bicycle Therapeutics does appear intriguing as to whether it may have an improved toxicity profile compared to currently available therapy.

However, treatment with that is still very early. There [are] other agents that target HER2 expression on tumor cells. Some of these target the antibody-drug conjugate that also brings the monomethyl auristatin E. This is the same target or the same a conjugate that’s used for enfortumab vedotin. Unfortunately, that’s also associated with peripheral neuropathy and can be a challenge for our patients with type 2 diabetes and preexisting neuropathy from other comorbid medical conditions. I’ve mentioned earlier that enfortumab vedotin with pembrolizumab was just recently granted accelerated approval in the frontline space for cisplatin-ineligible patients. So again, the ability to treat more patients who are not candidates for cisplatin-based therapy and gain an improved survival and response rate is another unmet need. And I look forward to seeing the results from randomized clinical trials comparing enfortumab vedotin with pembrolizumab with other standard-of-care chemotherapy.

We also see other novel agents targeting different mutation profiles and other checkpoint inhibitor combinations being explored. So for any patient who has interest in clinical trials, please do consider referral to your nearby or local cancer center or even larger cancer centers further away if the patient is willing to travel. I think there’s more hope now today than ever that we’re finding improved strategies. We’re finding sequential treatments that may impact our patients. And arguably, patients are living longer today than when I first started in the field over 20 years ago. So there’s more hope that we are making that impact. We are making a difference not only with chemotherapy but with targeted agents, immune checkpoint inhibitors and, finally, our antibody drug conjugates as we are learning how to sequence them and extend patients’ lives.

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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