Frontline vs Sequenced Therapies in BCG-Unresponsive Bladder Cancer: What's the Best Approach?

In the fifth segment of this NMIBC roundtable, the panelists discuss the evolving landscape of bladder cancer treatments, focusing on balancing bladder-sparing therapies and timely radical cystectomy. The group explores the sequencing of emerging agents, the impact of treatment lines on efficacy, and practical considerations for patient counseling.

Watch the final segment of this roundtable series: Molecular Biomarkers and Risk Stratification in High-Risk Non-Muscle Invasive Bladder Cancer

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Dr. Li:
So now we have all these agents, and it’s conceivable that after you treat with one agent, you have recurrence of high-grade disease, you treat with another. Are you guys more comfortable now that we have a lot of these data to continue to treat in the bladder sparing way? At what line do you actually talk with the patient about radical cystectomy?

Dr. Margulis:
Every line.

Dr. Rose:
Every line.

Dr. Crispen:
Every line, yeah.

Dr. Margulis:
It’s a guideline recommendation. And I think we can’t forget the fact that this is lethal disease. There’s a window of curability. Every clinical trial out there shows that if you miss the boat and you get to be muscle invasive, your outcomes are not nearly the same.

Dr. Crispen:
Every time they come in and they’ll have their next recurrence, I always go back and talk to them about cystectomy. And for me, I talk to them about not necessarily metastatic progression, but regional progression. I say, “Your disease eventually is going to start spreading up your ureters. It’s going to go out through your urethra.”

And so it may not be a matter of us talking about other systemic therapies, “But when I do take out your bladder, how many other organs am I going to take out? Is that going to impact your urinary diversion options?”

Dr. Rose:
Absolutely.

Dr. Crispen:
And so I have that discussion with them and I remind them about that, especially for the upper tract progression, every time so they do realize what they could be generating by putting off cystectomy.

Dr. Li:
So Mike O’Donnell always raises up this question of, “If you have a cisplatin patient, you continue to treat with bladder sparing agents, they tend to spread up the upper tracts.” And he’s actually an advocate for taking urine cytology selectively from these upper tracts whenever the patients have a recurrence. Is that your practice at all?

Dr. Crispen:
I do not do that routinely when they come back. When they’re in the BCG responsive settings and they have recurrence, I don’t. I do go back and image them to make sure that they do not have an upper tract lesion that I’m missing that’s just continuing the shed into their bladder. But I’m not as aggressive to continuously get the selective cytologies like O’Donnell.

Dr. Rose:
But it’s interesting, if you look at NCCN guidelines in terms of upper tract imaging, it’s not always indicated to re-image those patients. But myself included, if someone has a recurrence, I have no hesitation to repeat upper tract imaging.

Dr. Li:
For sure. So I think a discussion needs to be had with the patient every single time that they come back. But nevertheless, with the abundance of data that are being generated in the first line setting, second line setting, and also in the real world, we know that there are patients who just cannot tolerate a radical cystectomy that are being treated with multiple lines of therapy. So with these data emerging in the real world now, I’ll tell you from my part, I’m a little bit more comfortable treating some of these patients with more therapies instead of just asking them, “Hey, radical cystectomy is the standard of care. Let’s do this.” Has that been your experience as well?

Dr. Margulis:
Well, it’s nice because these things are studied in prospective manner. So you have some solid data. Before it was basically third line, third time BCG, or giving something that you really don’t get a good sense of perspective. You have anecdotal evidence. So from a prospective by actually having some evidence so you know what you’re going to get and having that discussion with the patient is helpful. I think the real question will be, as all of these products are studied in the second line, when you start sequencing them and giving them in third and fourth line, which I see happening very shortly, you don’t really know what the performance of those agents in those lines is. I suspect it’s lower as you go down the lines, biology probably selecting for something more aggressive naturally. And so you’re dealing probably with more aggressive disease. So I have to be careful. If you start sequencing these things, you can’t assume that that treatment will perform as well as it performed in its original study.

Dr. Rose:
Just extrapolating from BCG data, gemcitabine data, we know patients who have failures and then go on to those therapies as salvage therapies do not perform as well. And you’re right, the CR rates that we discussed might not be valid in the second and third line setting, right?

Dr. Li:
So in line with that, the natural question that raises is do you hit the disease with the most effective therapy upfront, or do you actually keep that on the back end when you actually have more aggressive disease?

Dr. Margulis:
Well, I tell you what I think. I think you go in with your front-runner. You go in and that’s a standard oncology practice to go in with the treatment. Now you can make an argument that, listen, maybe I have something that’s not effective, but it’s really tough on you and then let me get that in while patient can tolerate it. But as a general principle, I think you go in with your most effective drug as patient’s going to stay on that longest generally, right?

Dr. Li:
Yeah. And also, I think you have to take into account the vulnerability of the bladder, if you will, over the time course of treatment. I think TAR-200, as we all discussed, is going to be really well-tolerated no matter which line you give, upfront or not. But some of the other intravesical therapy agents, maybe not so much. After the bladder’s been beaten up, after multiple lines of treatment, you’re not going to be able to hold the infusants as much anymore.

Dr. Crispen:
I agree. And that’s a little bit surprising with the nogapendekin alfa inbakicept data, with that being given with BCG, that’s an intense treatment. It’s repeat induction, then with intense maintenance for a year. I personally haven’t had experience with that agent. But with the toxicity data that’s been put out there, I think it looks pretty good that those patients can tolerate that much BCG again. Because in my own personal experience, just BCG-naive patients, I can have difficulty tolerating maintenance. And so then for those patients to get repeat induction and then additional therapies on top of it, it’s good to see though that you can re-induce and get some tolerability at the same time.

Dr. Li:
No, I think it’ll be really interesting to see long-term, kind of, just the long-term toxicity within the bladder of all of these agents. So then, you’ll lead off with one that may not damage the bladder as much, and you also have to obviously take into account all of the TURBTs that we have to do, too.

Dr. Margulis:
See, we’re already assuming, you can use the other drugs in third line and they’re going to do as well. See, that that’s the problem. We don’t know. So you have to be careful about that.

Dr. Rose:
So I think what you were suggesting though is that if you have a patient who has a functional bladder, we know can tolerate intravesical therapy, do you prioritize intravesical therapy that patient would have to hold, shorter dwell time, and keep something like TAR-200 in your back pocket for someone who’s either less functional or a bladder that is less functional. But to echo his point, I tell patients all the time, “If you were my dad, this is what I would do, and I would go after the modality with the highest efficacy rate.”