Alicia Morgans: Hi, I am so excited to have here with me today Dr. Arjun Balar, who's an Associate Professor of Medicine at NYU Langone Perlmutter Cancer Center. Thank you so much for being here.

Arjun Balar: Thanks for having me.

Alicia Morgans: Wonderful. So we have talked about so many things related to bladder cancer and I always appreciate your expertise. Today I want to talk about bladder sparing, bladder preservation protocols. What is it, first of all, and then what's new? Where are we going? How do we make bladder sparing, bladder preservation even better in the future for our patients with muscle-invasive urothelial cancer?

Arjun Balar: I think this is, in my opinion, one of the most important advances that I hope we will continue to build upon in the treatment of bladder cancer, and something that I'm really passionate about, which is this concept of bladder preservation therapy in muscle-invasive bladder cancer. So a little bit of context is always important, we have historically thought of radical cystectomy as the standard of care. Sometimes we throw around words like the "gold standard" and that's a little bit problematic because we've never compared the concept of organ preservation therapy directly against surgical therapy in practically any disease, right? So we had never done that. So it's hard to say anything is the gold standard.

But in general, we've had this notion that radical cystectomy is considered the best curative treatment for muscle-invasive disease. Also, we recognize still despite the surgery, about 50% of patients will still relapse and develop metastasis.

Bladder preservation therapy is just that, which is it incorporates ideally three modalities of treatment. One is a maximal transurethral resection of the bladder tumor. The concept of that is to maximally reduce the amount of tumor within the bladder, and then after a few weeks of recuperation and healing of the bladder after such a procedure, concurrent chemoradiation is administered. So those are your three modalities. The radiation therapy is usually about six weeks long and sometimes there's a bladder boost and there's some changes or modifications that you can make to the radiation plan, and that's a little bit controversial.

And then also along with the concurrent chemoradiotherapy. That chemotherapy includes standards such as weekly cisplatinum, 5FU mitomycin, and something that we've been doing recently which is twice weekly gemcitabine. If it's done in the appropriate way, the outcomes in terms of cure rates appear to be very similar to those in the surgical series. The problem is that it's not widely uptaken, not many people believe in it, and I'm not sure that many patients are counseled about that as an option. And so if we look at just the United States in general, the vast majority of patients who are cystectomy candidates undergo a cystectomy, are never really even counseled about tri-modality bladder preservation, and I'm not sure that that necessarily needs to be the case.

Alicia Morgans: I completely agree. And we use bladder preservation strategies and bladder sparing protocols in my institution, I know you do too. I also am a very strong advocate for it. And I think I'd really like to talk about the ideal patient for bladder preservation because I think that a lot of the controversy comes from people who are in the habit of using bladder preservation in a palliative setting, which is not actually bladder preservation for cure, which is what we're talking about, where we're really looking for these similar survival benefits as we see with neoadjuvant chemotherapy and cystectomy. So who is the ideal bladder sparing candidate? Because it is a very specific population.

Arjun Balar: I have some strong opinions about that, and one of those has to be this concept of well who is an ideal candidate? Well, I think what that means is that are you identifying good prognosis patients? So the issue is here is that if you say that classically the ideal bladder preservation candidate has been described as a small tumor, generally two to three cm in size, no bigger than that, located at the dome of the bladder, minimally muscle-invasive, no carcinoma in situ, no hydronephrosis. They're located at the dome, so the radiation therapy plan is much safer. So those patients are deemed to be ideal candidates for bladder preservation therapy, but one would probably think that those are actually just good prognosis patients, right? They would probably do equally as well with cystectomy.

And the fact is that poor prognosis patients who undergo cystectomy also do poorly. I think what we've done, and I think some of my colleagues who have been in the radiation oncology field who have been doing this for years, would even admit that this definition of an ideal bladder preservation candidate has actually pushed them a little bit into a corner to say, "Well, these are the only patients who are candidates for bladder preservation therapy, because we wanted to make our data look good."

When that happens though, that switches the argument over that everyone otherwise should get cystectomy. I would argue that those characteristics that we've defined are simply good prognosis patients, and they're going to do well. And so I think we need to start challenging some of those notions about how we identify so-called ideal candidates.

Now there are some patients who are in the extreme, which is they have large multifocal, bulky tumors, bilateral hydronephrosis. I completely agree that those patients should not be counseled about bladder preservation. Those patients are ideal candidates for cystectomy and that's what they should be getting. But there are patients in between that may have multifocal tumors, that might have hydronephrosis on one side, that might have some CIS and some mixture of those characteristics, but may still be good candidates for bladder preservation therapy.

Alicia Morgans: And may have a tumor that's at a location other than the dome.

Arjun Balar: Exactly.

Alicia Morgans: And I think that most of us in practice usually think that way. I actually think of it as here's a patient with muscle-invasive bladder cancer. Is there any reason this patient cannot spare his or her bladder? That's how I think about it because that's how I would want my clinician to think about me.

Arjun Balar: Exactly. And I think we need to start having that conversation.

Alicia Morgans: Absolutely. So when you are treating patients and using this bladder sparing approach, what are you doing? I mean you talked about the chemotherapy options. What are you doing though for the future? So what are the trials that are really trying to advance the already, actually quite good, intact bladder survival rates for this population?

Arjun Balar: So I think everyone's familiar with immunotherapy and it has had such a tremendous impact in the treatment of patients with advanced bladder cancer. Checkpoint inhibitors are completely changing how we think about this disease, and I think that now that we have these new tools to treat patients, we can now revisit some of our inherent biases about how we treat patients and start using them in early-stage disease.

Just to summarize, there are ongoing studies of checkpoint blockade as neoadjuvant treatment, we have an FDA approval for pembrolizumab in BCG unresponsive NMIBC. So there are so many areas of evidence that show the checkpoint blockade is active in this disease and now we can perhaps include it in bladder preservation regimens, and we're starting to do that now. We've launched at NYU a relatively small investigator-initiated study of roughly 54 patients looking at pembrolizumab added to hypofractionated radiation therapy, so four weeks. There is some data to suggest that hypofractionation may be more immune synergistic. I think we need to tease that out a bit more. Along with gemcitabine twice weekly.

We've enrolled 47 out of 54 patients and patients have actually done remarkably well on this treatment, data I hope to be able to share in 2021 when the data's finally mature. And then on that study which we launched in 2015 or so has cultivated and actually sparked interest in launching Phase III trials. SWOG-1806, a very important study a colleague of mine, Dr. Parminder Singh is the lead PI of that trial is randomizing patients to chemoradiation with or without atezolizumab, which is a PD-L1 antibody, that study is ongoing and is enrolling quite well. And KEYNOTE-992 which just became publicly shown out there is just activated on clinicaltrials.gov is looking at pembrolizumab in combination with chemoradiation. That study is global and so will be enrolling around the world.

I think the data from these two trials will be contemporary, they will enroll patients with mixed baseline characteristics and I think is going to start challenging this notion that cystectomy is the gold standard for everyone.

Alicia Morgans: I agree. And just so that everyone knows, in the SWOG study at least, which is actually open across all of the cooperative groups, is going to be open at hundreds of centers throughout the country, and you can please comment on KEYNOTE as well, but in the SWOG study, there is atezolizumab given in combination essentially with chemotherapy during the radiation. So it's chemoradiation with the checkpoint, and then there's actually a tail of about six months of atezolizumab administration every three weeks. And the pembrolizumab in the KEYNOTE study?

Arjun Balar: Almost identical in that regard there. I mean there's some subtle differences in terms of stratification factors, the power, the number of patients enrolled. We have hypofractionation included in the KEYNOTE-992. Maximal TURBT is actually mandated as part of KEYNOTE-992. But I'm sure that most participating sites on the SWOG study will probably do that as well. There's also a tail, which means that patients will receive pembrolizumab.

What's also good about this study is that it may... There's dosing of 400 milligrams every six weeks for pembrolizumab in this trial, which I hope will improve enrollment and compliance, because every three weeks treatments, sometimes every six weeks, might be better for patients.

Alicia Morgans: Sure.

Arjun Balar: The primary endpoints are very similar. Bladder intact, disease-free survival and these two studies are really exciting.

Alicia Morgans: Absolutely. And you know, as I think about it, one of the benefits, even if we don't find that adding a checkpoint in this setting actually adds benefit, we don't know. That's why we're doing the trial. But even if we find that this trial is negative, I am really excited that the trial is bringing chemoradiation and bladder sparing approaches to all of these institutions across the country to the forefront of all of our minds. Because I do think that this is where we need to go in the future. We need to do better with maintaining people's lives, and part of that, if we can do it, is keeping their bladder in place.

Arjun Balar: Absolutely.

Alicia Morgans: Absolutely. So I would love to hear your take-home message. What is your overarching theme for bladder sparing?

Arjun Balar: In reflecting on the last four or five years, if we look back at the 30 prior years in bladder cancer, we have kind of two main pillars. We have cisplatinum and then we have cystectomy. And cisplatinum has been shown to improve survival and cure patients, but those two treatments, cisplatin, and radical cystectomy are our best treatments and yet half of our patients can't get it because of safety concerns and there's all this other stuff. And so immunotherapy has provided an option that is an alternative potentially to these. And I'm really excited that we have these new tools that are now available to challenge some of these preconceived notions.

Alicia Morgans: Wonderful. And there's definitely hope and opportunity for patients to get involved in clinical trials. We always encourage that they do, and for clinicians to look for opportunities for their patients, or maybe open one of these studies at their own institution so that they can gain experience and have that comfort with this type of approach. Thank you so much for sharing your expertise and your time today.

Arjun Balar: Absolutely. Thank you.