Alicia Morgans: Hi. I'm so excited to be at AUA 2022 where I have the opportunity to speak with Dr. Patrick Hensley, who is talking to us today about BCG-unresponsive bladder cancer, and how we think about the timing of cystectomy. So, excited to talk to you today.

Patrick Hensley: Thank you, Dr. Morgans. Thanks for having me.

Alicia Morgans: Well, thank you, Dr. Hensley. Can you tell me a little bit about how you thought about the particular project that you presented at AUA?

Patrick Hensley: Sure. There's clearly defined criteria for selecting very high-risk patients for early upfront cystectomy before trialing any intravesical therapy. Clearly, patients who progress on intravesical bladder-preserving therapy need a radical cystectomy. So, where do we fall in the middle of that spectrum, with regards to indications and timing of cystectomy? Typically, we're talking about a BCG failure spectrum, and in terms of BCG-unresponsive disease, the timing of cystectomy at the diagnosis of BCG-unresponsive disease.


Alicia Morgans: I think it's such an interesting and important question because, for non-muscle invasive bladder cancer, of course, we try BCG initially, but for a number of patients, they really will have this BCG failure, as you've mentioned. And there are a number of clinical characteristics, disease-related characteristics, that we could consider, as we're trying to think about the timing of cystectomy versus other therapies that we might try in this setting.

Patrick Hensley: Absolutely.

Alicia Morgans: What are you thinking through and what did you include in your assessments?

Patrick Hensley: Well, the indications for upfront radical cystectomy, in the highest-risk patients, and this is probably best fleshed out in the newest updated EAU guidelines where they identify the highest-risk group, and this is multifocal large high-grade T1 patients, those with or without concomitant carcinoma in situ, possibly variant histology, those patients likely benefit from an upfront surgical intervention.

In terms of identifying patients who are on the BCG failure spectrum, prior work at our institution and others have shown that patients who progress on BCG to muscle-invasive disease have worse outcomes compared to even their patients who present with de novo muscle-invasive bladder cancer who get a cystectomy. And by worse outcomes, I mean pathologic upstaging, extravesical disease, lymph node metastases, worse overall, and cancer-specific survival. So, allowing those patients to progress on BCG to clinically muscle-invasive disease is associated with adverse outcomes.



Now, data that we presented recently would suggest that you can still salvage some of that prognosis by administering standard-of-care cisplatin-based neoadjuvant chemotherapy in those patients, and at MD Anderson, we, as an institution, subscribe to a risk-stratified approach to prescribing neoadjuvant chemotherapy, and BCG progression and muscle-invasive bladder cancer is now part of that paradigm, where progressive BCG patients receive neoadjuvant chemotherapy, in addition to lymphovascular invasion, hydronephrosis, variant histology, and palpable tumors signifying clinical T3b or higher disease. So, we've identified those high-risk patients and they all receive standard-of-care neoadjuvant chemotherapy, because we know that's associated with a poor prognosis.


Alicia Morgans: Absolutely. And of course, that's what we would do if they actually had muscle-invasive disease, and so really identifying those that are going to progress in that direction anyway, and doing it earlier, gives us, I think, the benefit of hopefully having more patients with a pathologic complete response. Has that been characterized in your center?

Patrick Hensley: It has. If you look at the complete pathologic response rates for de novo muscle-invasive bladder cancer who receive upfront neoadjuvant chemotherapy versus BCG progressors who receive neoadjuvant chemotherapy, there was statistically no difference in the complete pathologic response rate nor pathologic downstaging rate, which may have a little bit more clinical relevance.

The other thing that we've looked at is if you look at patients who have undergone a salvage cystectomy on trial, so say KEYNOTE-057 pembrolizumab trial for BCG-unresponsive disease, the nadofaragene trial for BCG-unresponsive disease, about anywhere from 40% of the pembrolizumab patients went on to receive a salvage cystectomy after failing pembrolizumab. 26% of the nadofaragene patients went on to receive a cystectomy after failing intravesical nadofaragene. So, if you look at the final pathologic stage of those cystectomy patients, the rates of muscle-invasive disease or higher, pathologic stage T2 or higher, is about 10%, and the rate of occult nodal metastasis is 5 to 10%. So, that's pretty palatable, and I think that those outcomes are well justified to, at least initially, attempt bladder-preserving salvage therapy.



If you look at similarly at, there was a recent multi-institution series published by Dr. Steinberg in General Urology, looking at salvage intravesical gemcitabine docetaxel, and the patients that failed intravesical Gem/Doce and went on to receive cystectomy, similarly, had relatively low rates of muscle-invasive disease and nodal metastasis at the time of cystectomy.


We looked at our institutional data and looked at the timing of cystectomy in BCG failure patients. So, if you diagnose a patient with BCG failure, BCG-unresponsive, non-muscle invasive bladder cancer, and they're still clinically non-muscle invasive at the time, if they undergo a timely cystectomy, again, the rates of muscle-invasive disease and nodal metastasis is very low. If you allow those patients to progress to clinically muscle invasive disease, the rates of extravesical disease is nearly three times higher than those trial patients, and the rate of occult nodal metastasis is five times higher if you allow those patients to progress.


So, all the data, to kind of summarize, would suggest that it's oncologically sound principle to initially try bladder-sparing salvage therapy after BCG failure. But you have to watch these patients very closely. You have to do your best clinical staging modalities that are available, and allowing those patients to progress on salvage therapy to muscle-invasive disease portends a poor prognosis. So, a timely cystectomy before the patient develops muscle-invasive disease is indicated, per the results of our study.

Alicia Morgans: And what do you mean by timely? Can you give us a definition of that?

Patrick Hensley: And that's, it's a spectrum, because there's the upfront cystectomy in the very high-risk patients, there's the obviously indicated cystectomy in the muscle-invasive patients. Timely, if I had to define it in broad strokes, would just be prior to developing muscle-invasive disease. Now, that could be at the time of BCG-unresponsive diagnosis, it could be after the first failure of salvage therapy. Some patients may go on to receive multiple salvage intravesical or systemic therapies, and as long as they don't progress to muscle-invasive disease before their cystectomy, that would suggest that you're doing your due diligence, and you're doing a timely cystectomy, in terms of looking at the pathologic outcomes and the overall and cancer-specific survival after cystectomy.

Alicia Morgans: That's just a hard thing to judge-

Patrick Hensley: Absolutely.

Alicia Morgans: Before you get to the other side.

Patrick Hensley: Absolutely.

Alicia Morgans: So, really curious then, too, if timely is more around the outcome than it is around, sort of, a prospective definition, how do you closely follow these patients, if you're not going to go to that immediate cystectomy?

Patrick Hensley: Sure. I think that leads us to identifying some pitfalls and the current knowledge gap or data that we have. So, the first is our inability to accurately clinically stage these patients. We know that up to 50% of high-grade T1 lesions will be upstaged to muscle-invasive disease at cystectomy. We know that our current clinical staging includes radical TUR, imaging. I think that this is improving over time, but certainly, imaging modalities, such as MRI, and the new VI-RADS scale may improve our ability to clinically stage these patients, but there's still going to be those occult invasive tumors that we're still, kind of, treating as a non-muscle invasive patient. And that's very difficult.

So, I think diligent cystoscopic surveillance, thorough TURs, transmural TUR, sampling the muscularis propria is very important, and multidisciplinary input from all parties involved, including the pathologist and the radiologist and the GU medical oncologist.


Alicia Morgans: Wonderful. Well, I so appreciate you walking us through this area that has some data that you've thankfully provided to us, but remains a bit gray.

Patrick Hensley: Absolutely.

Alicia Morgans: And is really so important for patients who want to try to, I would say, thread the needle between ensuring that they're cured of their cancer and ensuring that it doesn't come back, but also maintain as much of their normalcy as they possibly can, and that timing is so critical. Any final thoughts or messages to those who are listening?

Patrick Hensley: Yeah. I think that our ability to triage patients for a timely cystectomy will be improved as we develop predictive biomarkers, and with each individual therapy that comes out for BCG-unresponsive disease, they need an individual biomarker that's fit for purpose, fit for the mechanism of action for that drug, the biologic response that the tumor and the microenvironment has to that drug, and those biomarkers need to be validated and that takes time, but we're excited to see that data emerge. And I think we'll have a better impact on these patients' care and better be able to advise them on when they should pull the trigger on cystectomy or if they can continue with bladder preservation safely.


Alicia Morgans: Well, I really look forward to hearing from you in the future, as continued work helps us to understand what the timing should be, and certainly appreciate your final thoughts on how we can use molecular testing to try to help us understand, and even imaging biomarkers, to help us understand how to get things right in terms of timing. Thank you today for your time and for your expertise.


Patrick Hensley: Thank you very much for having me.