Treatment Options for Cisplatin-Ineligible Patients With Advanced Urothelial Carcinoma

Cisplatin-based chemotherapy is typically considered the standard of care for bladder cancer, but researchers estimate that approximately 50% of patients are ineligible for cisplatin treatment due to their age or comorbidities.

Shilpa Gupta, MD, director of Genitourinary Medical Oncology at the Cleveland Clinic Taussig Cancer Institute and co-leader of the Cleveland Clinic Genitourinary Oncology Program, discussed treatment options for cisplatin-ineligible patients with advanced bladder cancer.

GU Oncology Now: What are some of the major challenges in treating cisplatin-ineligible patients who have advanced bladder cancer?

Shilpa Gupta, MD: That’s a great question. More than 50% of our patients have comorbidities like chronic kidney disease, heart disease, peripheral neuropathy, hearing loss, or just poor performance status in general, which makes them unfit to receive cisplatin, which can have renal toxicity, ototoxicity, and neuropathy as the key side effects. Obviously, patients with significant heart failure cannot get cisplatin because of the crude overload issues. These comorbidities make it challenging to treat these patients, so we need agents that will not affect these comorbidities. The challenge is to find treatments that are well tolerated by patients who have all these comorbidities.

GU Oncology Now: How have treatment advances, such as US Food and Drug Administration (FDA) approval of enfortumab vedotin for patients who are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy, changed the care and prognosis for these patients?

Shilpa Gupta, MD: That’s a great question. Frontline therapy, for example, for patients who are cisplatin ineligible, has really evolved over the last few years. In the past, gemcitabine and carboplatin used to be the only thing we had for these patients. Median survival rates were really dismal, 6 to 7 months, up to 9 months maximum. Then, when we had single-agent immunotherapy—like pembrolizumab and atezolizumab—approved based on single-arm trials, that became the preferred option back in 2017. Then in 2018, there was a label restriction for use of single-agent immunotherapy, because the preliminary data from phase 3 trials—comparing immunotherapy versus carboplatin-based chemo in cisplatin-ineligible patients—showed that patients receiving immunotherapy were doing worse. Finally, in 2020, we had the JAVELIN Bladder 100 study come out, which showed that cisplatin-ineligible patients who received gemcitabine and carboplatin, followed by avelumab maintenance, had really improved overall survival. More recently, based on the negative phase 3 trials, KEYNOTE-361 and IMvigor130, our preferred option for these patients is carboplatin-containing chemotherapy followed by avelumab maintenance.

The FDA further restricted the label for pembrolizumab to only those patients who are ineligible to receive even carboplatin. Now having said that, if patients are given immunotherapy in the frontline setting, then enfortumab vedotin has shown activity in the EV-201 trial, in 1 of the cohorts. But I will say that the general standard of care currently is to use carboplatin-based regimen when possible. If patients are getting single-agent immunotherapy only, which is not a majority of patients, that drug is an option.