Recent FDA Approvals in Advanced Urothelial Carcinoma Propel Treatment Forward


Daniel P. Petrylak, MD, discusses advancements in the treatment of patients with bladder cancer.

Daniel P. Petrylak, MD

Daniel P. Petrylak, MD

Ongoing research into the treatment of patients with advanced bladder cancer has ushered in a new era of pivotal trials and FDA approvals within the landscape. This includes treatment with enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer, as well as treatment with nivolumab (Opdivo) plus cisplatin and gemcitabine for patients with unresectable or metastatic urothelial carcinoma.1,2

Furthermore, in January 2024, the regulatory agency granted approval to erdafitinib (Balversa) for the treatment of patients with locally advanced or metastatic urothelial carcinoma harboring susceptible FGFR3 alterations who have progressed on at least 1 prior line of therapy.3 However, one question that remains is the optimal sequence of therapy, according to Daniel P. Petrylak, MD.

“There’s no right or wrong way to sequence [treatment] after a patient has been on first-line therapy with enfortumab vedotin and pembrolizumab,” Petrylak, said in an interview with OncLive®.

In the interview that took place duringthe 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Petrylak discussed advancements in the treatment of patients with bladder cancer, highlighting the impact enfortumab vedotin and pembrolizumab have had on the treatment paradigm and the potential role for nivolumab with chemotherapy in the first-line setting.

Petrylak is a professor of medicine and urology and chief of Genitourinary Oncology at Yale School of Medicine; and medical oncologist at Yale Cancer Center in New Haven, Connecticut. 

OncLive: What would you say has been the biggest advance with antibody-drug conjugates in bladder cancer?

Petrylak: Over the past year, the biggest advance is the phase 3 EV-302/KEYNOTE-A39 trial [NCT04223856] which demonstrated a 31.5-month median overall survival [OS] for the combination of enfortumab vedotin along with pembrolizumab.

[After first-line therapy] we have 3 or 4 different options, one of which is erdafitinib for patients who are FGFR positive; sacituzumab govitecan-hziy [Trodelvy] for all patients; and gemcitabine [plus] cisplatin or carboplatin depending upon platinum eligibility as another option. Overall, there are several different ways to go, including clinical trials.

Prior to the readout of the EV-302 trial, avelumab (Bavencio) maintenance had been the standard of care following platinum-containing chemotherapy. How might the use of that agent be affected by the approval of enfortumab vedotin and pembrolizumab in the first line?

Effectively, what you’re doing with enfortumab vedotin and pembrolizumab is you’re giving a superior cytotoxic agent, which we know works well in [patients with] visceral disease with [a] 40% response rate in the liver, no matter whether you’re in the first line, second line, or third line, plus pembrolizumab which serves as maintenance therapy if you continue it.

Unfortunately for avelumab, there really isn’t a role in a patient being treated with enfortumab vedotin and pembrolizumab because you’re using that combination. The only situations that I could see gemcitabine [plus] cisplatin or carboplatin being used upfront would be in somebody who would not be appropriate for enfortumab vedotin. This could be due to peripheral neuropathy or poorly controlled diabetes.

Also, with the maintenance therapy as well as with enfortumab vedotin and pembrolizumab, [I would not recommend its use in] patients who have pre-existing autoimmune disorders that may be worsened by the checkpoint therapy. There’s still a limited but real role for maintenance therapy after first-line cytotoxic therapy.

Where do you see the use of other ADCs like sacituzumab govitecan coming into play in the treatment of these patients?

Sacituzumab is also an effective agent in urothelial carcinoma and has accelerated approval. The topoisomerase inhibitor recognizes a different antigen–TROP2–it also delivers a different agent called SN-38 to the cancer cell, so it does have activity in platinum-ineligible patients.

It also has activity in patients who have been previously treated and patients who are ineligible to receive cisplatin. It’s never been compared 1:1 with enfortumab vedotin, but there’s good reason to believe that these are non-cross resistant drugs based upon the targets as well as their mechanisms.

How do you see the FDA approval of nivolumab and chemotherapy influencing treatment decisions within the space?

The OS data with nivolumab plus gemcitabine and cisplatin is not at the same level as you see with enfortumab vedotin and pembrolizumab. Certainly, one could give that [combination] to a patient who may not be eligible to receive [the EV-302 regimen]. However, it is important to remember, those are all-comers as opposed to those patients on maintenance therapy who are responders. This [regimen], again, could have a limited but real role in this disease.

What ongoing clinical trials could help clarify lingering questions in the field?

There is a neoadjuvant study looking at enfortumab vedotin and pembrolizumab vs standard of care chemotherapy that I think is going to change things. That will then move that combination upfront and then we’ll need to decide what to do if a patient does relapse. Should they receive enfortumab vedotin and pembrolizumab again? Should they receive gemcitabine plus cisplatin or carboplatin followed by maintenance therapy? We don’t have a good answer to that question.

The real issue is whether we can administer checkpoint [inhibitors] several times over. This is causing a little bit of a dilemma right now. For example, if a patient comes in that has had a radical cystectomy and has high-risk features, we only have disease-free survival data for adjuvant nivolumab, as well as adjuvant pembrolizumab. Do you treat that patient with either checkpoint inhibitor? What do you do if the patient relapses while on single-agent checkpoint therapy or if they relapse after receiving their years worth of adjuvant treatment? Will enfortumab vedotin and pembrolizumab still be as effective in those patients?

Enfortumab vedotin will be as effective, but [it is unknown] if you are losing any potential interaction with those drugs. Do you treat that patient with adjuvant therapy if there’s not going to be any effect on that, or do you wait until a patient relapses? I’ve had patients who have asked me that question already. Can I get enfortumab vedotin with pembrolizumab in the adjuvant setting? Well, we don’t have any end points for that.

How long do you treat that patient? Do you treat them for a year? Are you going to subject patients to neuropathy and skin rash when they may not have necessarily needed it? There are a lot of questions to answer in that respect.

If you are presented with that situation in the absence of definitive data, what would you consider doing?

Well, it’s a shared decision, so I’ll relay all the data to the patients and then it’s up to them to decide. One thing that may be a deciding factor is looking to circulating tumor DNA [ctDNA], but right now I think that has more of an impact on whether to treat or not. Eventually, that patient [with positive ctDNA] may need treatment at some point, but right now, we don’t have any data with enfortumab vedotin in the adjuvant setting. I wouldn’t want to subject that patient to the neuropathy or the adverse effects unless I had absolute proof that they would have a survival benefit from it.


  1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed March 28, 2024.
  2. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed March 28, 2024.
  3. FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. FDA. January 19, 2024. Accessed March 28, 2024.
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