Yale Launches Innovative Clinical Trial for Metastatic Bladder Cancer

Fed Ghali, MD: Until a few years ago, patients with bladder cancer fell into two very distinct camps. Those with localized disease had a high chance of cure and control through surgery. But those whose cancer had metastasized (spread to other organs) largely faced a different outcome. Only about 10% were still living five years later. It was a grim prognosis.

Treatment was also quite siloed. Surgeons worked on localized disease. Medical oncologists treated metastatic patients with systemic therapy. There wasn't much crossover between these approaches, especially as the disease advanced.

Ghali: Thanks to tremendous strides from many, including our colleague Daniel Petrylak, MD, and his work with enfortumab vedotin, we've seen increased signs of hope in the last few years. Enfortumab vedotin is a type of targeted therapy called an antibody drug conjugate, and when coupled with immune therapy has been transformative.

Someone with metastatic bladder cancer can now be stabilized. We're seeing a survival rate closer to 45%, which is more than double the historical rate. These drugs are too new to have a five-year lookback yet, but we're hopeful that 30 to 45% will survive at five years and beyond. That would be a major advancement.

It was rare with chemotherapy alone for this subset of patients to survive a long time. Now that this cancer can often be controlled with systemic therapy much more often, we want to see how they do when we combine these agents with surgery.

Ghali: This is a Phase II, single-arm clinical trial investigating whether we can improve outcomes for patients with locally advanced or oligo-metastatic urothelial carcinoma (five or fewer distinct metastatic lesions) who respond well to enfortumab vedotin-based therapy.

Here's how it works: Patients receive enfortumab vedotin-based first-line therapy for at least three months. If their disease is stable or responding well, they become candidates for what we call consolidative surgery—removal of the bladder with standard lymph node dissection, and if applicable, resection of metastatic lesions that haven't been irradiated. Essentially, after the drug therapy has done its work controlling the cancer, we go in surgically to remove what remains.

Through this trial, we want to learn: Do they live longer? Are their responses more durable (more resistant to the cancer)? Do they have a better quality of life?

Ghali: The very fact that we can ask these questions and do trials like this shows how far bladder cancer research has come. The hope is that something like this may present a cure to those with metastatic bladder cancer. No one would have considered that possible just a few years ago.

It's also innovative in how we're approaching patient care. I believe the future is more specialized treatment for smaller, more precisely defined patient groups rather than broad categories. This trial reflects that philosophy.

Ghali: We shouldn't oversell this. This is a single-arm trial, and research can move slowly. We're trying to nudge the needle on this work and understanding.

But there is reason for optimism. This trial has the potential to provide meaningful evidence not only for patient care but also for future lab-based research and correlative studies of novel biomarkers. We think it could be a key resource for future studies.

Ghali: The real strength here at Yale is the ability to do multidisciplinary research. For instance, we have surgical oncology, radiation oncology, medical oncology, and urologic surgery all collaborating on this trial.

Petrylak; Joseph Kim, MD; Kiran Tiraga, MD, MPH; and Yi An, MD, have all been pivotal partners.

We're also working with Ping Mu, PhD, and Curt Perry MD, PhD, whose translational research on the samples will contribute to the correlative studies.

Not many institutions have the infrastructure and culture to pull all these disciplines together.

Ghali: We're looking for patients 18 and older with confirmed locally advanced or oligo-metastatic urothelial carcinoma (five or fewer metastatic lesions). They must be surgical candidates and have adequate organ function.

Importantly, they must have begun enfortumab vedotin-based first-line therapy at least three months prior to surgery. Their most recent scan must show stable disease, partial response, or complete response.

There are exclusion criteria as well, including cancer that has spread to the brain or spinal cord, and certain medical conditions that would make surgery too risky.

Ghali: Of course, we’re eager to see the results and go where the science points us. If it is as promising as we hope, the next step would likely be a larger trial. Randomizing patients could be challenging. Many patients don't want to be randomized between systemic therapy and surgery. But that's looking ahead, and there are other approaches that can be used. Right now, we're focused on answering fundamental questions about whether this combined approach offers meaningful benefit.

Ghali: There's a clear need for better options for patients with metastatic bladder cancer. This trial represents hope—evidence-based, carefully studied hope. It shows how far we've come and points toward a future where metastatic bladder cancer might be treatable in ways we couldn't have imagined just a few years ago.