Bladder preservation in muscle-invasive bladder cancer (MIBC) may be entering a new era.

For years, the standard of care for appropriate candidates with MIBC has been trimodal therapy (TMT): maximal transurethral resection and chemoradiation, followed by surveillance for clinical complete responders and salvage cystectomy for local recurrence.

About half of the patients are alive and still have their bladder at 5 years, and the results haven’t improved much over time.

Recent developments in MIBC, however, are raising the possibility that outcomes could improve substantially, according to Yale Cancer Center medical oncologist Daniel Petrylak, MD, vice chair of the Southwest Oncology Group (SWOG) Genitourinary Cancer Committee.

Petrylak described new scenarios that might lead to more patients with MIBC safely keeping their bladder in a question-and-answer interview with Medscape Medical News. His comments were edited for clarity.

How is the approach to bladder preservation changing?

We are thinking about how newer systemic therapies change the overall picture. We have more treatments available now and better systemic therapies, and we’re going to see more options for bladder preservation. A broader population of patients than before might qualify.

What are these better therapies?

Enfortumab vedotin plus pembrolizumab (EV/P), in particular. Almost everybody’s getting EV/P in the neoadjuvant setting before cystectomy now. The beauty with EV/P is we’re having high complete response rates.

We’re seeing about a 60% pathologic complete response with neoadjuvant EV/P. Traditionally, it’s been about 30% with chemotherapy. That’s a big change.

Why does that matter for bladder preservation?

Maybe we can harness the high pathologic complete response rates with EV/P for bladder preservation, but it’s uncertain how to do that. We are in a data-free zone with a lot of these things.

The standard of care right now is to remove the bladder if patients have had neoadjuvant therapy, but with such good responses to EV/P, the question has become do you really need to take the bladder out? How do you tell?

As a result, the discussion of what to do when a patient completes neoadjuvant therapy has become very complex. At some point, we’re going to be looking at the response to EV/P very carefully and then deciding about cystectomy.

There is also a trial being designed right now in the bladder preservation setting looking at adding four cycles of EV/P to TMT. The idea is you maximally debulk patients with EV/P prior to TMT. I think that’s where we are going to see improvements.

A SWOG trial is also looking at adding atezolizumab to TMT.

So it’s possible in 5 years that we might have more aggressive systemic therapy for bladder preservation for the appropriate patient. Maybe we can design treatments that are going to increase that complete response rate from 60% to 90% or even 100%.

Are there risks?

Yes. You take a risk with bladder preservation. It’s a concern that sticks in everybody’s mind.

The trouble is that you don’t really know what’s in the bladder until it’s out, and there can be disease outside the bladder that’s hard to detect.

So even if you think a bladder preservation patient has had a clinical complete response, the risk for metastases is 4%-5% in some studies. It’s not the local disease that kills you; it’s the micrometastatic disease that’s outside the bladder.

We want to cut that risk, so we know that all the tumor is gone when patients opt to keep their bladder. But right now, with EV/P in the neoadjuvant setting, even if you had a clinical complete response, you still don’t know if that’s a signal for bladder preservation. There’s no long-term data.

The real question is going to be identifying patients who are clear of residual disease for bladder preservation. We’re developing better ways to determine that.

What are the proposed methods for better identifying patients who are clear of residual disease?

We’re starting to look at circulating tumor DNA (ctDNA), molecular markers, and better imaging techniques. Those are the big ones.

Overall, the field is heading toward better molecular characterization of invasive bladder cancer to understand from a molecular standpoint who’s the person who may be able to keep their bladder vs the person with aggressive disease who needs their bladder out. You need to know who is likely to progress and who is not.

ctDNA could also be used after trimodal TMT to look for relapse, but we don’t have any data yet about giving adjuvant therapy after TMT. The standard practice is cystectomy after recurrence.

EV/P might eventually reduce the number of cystectomies, but we need to know who’s going to be the patient who has a complete and durable response.

M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net.