Commentary

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Insights, Innovations, and Challenges Ahead in the Treatment of Urothelial Carcinoma

Author(s):

Daniel P. Petrylak, MD, discusses the importance of molecularly-driven clinical trials and ongoing research with novel therapeutics in urothelial carcinoma.

Daniel P. Petrylak, MD

Daniel P. Petrylak, MD

We sat down with Daniel P. Petrylak, MD, at the 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies to get an inside look at upcoming and ongoing research in urothelial carcinoma.

In the interview, Petrylak detailed the utility of circulating tumor DNA (ctDNA) in this patient population, highlighted planned research with novel therapeutics in the landscape, and emphasized the importance of treatment with enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) following the combination’s FDA approval in December 2023.

He also shared key takeaways for community oncologists regarding the management of neuropathy associated with enfortumab vedotin. Petrylakprovided further insights into the evolving treatment paradigm of this disease in another interview with OncLive. 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: How do you foresee the use of ctDNA being further integrated into the treatment paradigm for patients with urothelial carcinoma?

Petrylak: If it’s sensitive and specific enough you could potentially obviate the need for serial imaging, [which is] a big health care cost. If there is a positive finding, that may precipitate someone being imaged, or if there is a negative finding, you may not need to image the patient at that point; that is one of its biggest uses. That could employ a large savings to the health care system by not having to perform serial imaging.

In terms of treatment, are there any therapeutic targets that have shown early potential?

We’re working with Flare Therapeutics on their PPAR-γ antagonist [to target what is] expressed in approximately 25% of urothelial carcinomas. That’s one interesting therapeutic area.

There are other antibody-drug conjugates that are now being developed for different targets. One that I’m particularly interested in is something called SLITRK6, which we just published [data] on. This was another antibody that was developed alongside enfortumab vedotin, but this recognizes a different epitope on the cancer cell–SLITRK6–which is expressed in about 90% of urothelial carcinomas. Overall, the question is whether there is cross resistance between the drugs. We really don’t know the mechanisms of resistance to enfortumab vedotin, or for that matter pembrolizumab, and who is going to be de novo from the beginning.

Who needs it and who will benefit from it? I think that’s something that needs to be worked out carefully, especially in the adjuvant setting where you may be treating somebody unnecessarily. There’s a lot of work to be done in that area.

The critical issues in the future are going to be around how we sequence these drugs. When possible, get your patients into trials to help us determine the optimal [treatment] sequence.

It’s possible [that we’ll start to see individual trials address multiple lines of sequencing]. What I really would like to see is more molecularly-based studies that are looking at different markers and different targets for these drugs, because right now we’re operating blind for second-line therapy.

What advice would you give to community oncologists who may not see patients with advanced bladder cancer every day?

In terms of dosing enfortumab vedotin, I use the analogy of running a marathon. You don’t want to use all your energy up-front. You have to save some, especially when you get towards the end of the line, towards mile 20.

With enfortumab vedotin, if somebody mentions that they have neuropathy, you’re better off dose reducing or holding [the drug]. This is because once the neuropathy sets in it’s a little more difficult to take care of, and you don’t want to compromise what’s going to win the race for you, which is longer administration of the drug, perhaps more cumulative doses over time.

My advice is to talk to your patients, have a nurse practitioner or yourself see that patient every time they come in. [You must] be very aggressive with asking questions about neuropathy such as: Can you button your shirt? Can you write? Can you tie your shoes? Are you having any numbness in your fingers and toes? Asking those questions and getting an answer that’s positive should send off some warning signs to watch out for neuropathy if it worsens.

It’s appropriate to hold the dose; it’s [also] appropriate to dose reduce if this occurs. In my experience, when we’ve held doses the disease remained fairly stable during that timeframe, so that’s something the practitioner needs to keep in mind.

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