Just Diagnosed with Metastatic Bladder Cancer--Now What? with Charles Ryan, MD, and Thomas Powles, MBBS, MRCP, MD

June 4, 2015
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This podcast is part of a series for patients who have just been diagnosed with a specific genitourinary, or GU cancer. In this series, Dr. Charles Ryan, a medical oncologist and professor who specializes in the genitourinary tract at the UCSF Helen Diller Family Comprehensive Cancer Center, speaks with experts on specific GU cancers to shed light on what happens after an initial diagnosis.

Today’s guest is Dr. Thomas Powles, clinical professor of genitourinary oncology at Barts Cancer Institute in London. In this podcast, Dr. Ryan and Dr. Powles discuss what happens after a diagnosis of metastatic bladder cancer, including new advances in immunotherapy for bladder cancer.



ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology known as ASCO the world's leading professional organization for doctors that care for people with cancer. This podcast is part of a series for patients who have just been diagnosed with a specific genitourinary or GU cancer.

In this series, Doctor Charles Ryan, a medical oncologist and professor who specializes in this genitourinary tract at the UCSF Helen Diller Family Comprehensive Cancer Center, speaks with experts on specific GU cancers to shed on light on what happens after initial diagnosis.

Today's guest is Doctor Thomas Powles, clinical professor of genitourinary oncology at Barts Cancer Institute in London. In this podcast, Doctor Ryan and Doctor Powles discuss what happens after a diagnosis of metastatic bladder cancer, including new advances in immunotherapy for bladder cancer. ASCO would like to thank Doctor Ryan and Doctor Powles for discussing this topic.

Dr. Ryan: Welcome to the podcast. This is Chuck Ryan from the University of California San Francisco. I'm delighted to be joined today by Thomas Powles a medical oncologist at Saint Barts Hospital in London who is emerging as one of the world's leaders in the medical management of bladder cancer, in particular in the new area of immunotherapy for bladder cancer and I'm delighted to be able to have the opportunity to talk to Doctor Powles about his approach to this disease. Welcome, Tom.

Dr. Powles: Thank you, Chuck. Thank you for that very kind introduction.

Dr. Ryan: So imagine that you're sitting down with a patient and his or her family who have just been diagnosed with bladder cancer, and they've come to see you for a consultation. What are the things that you want to go through? What are the pieces of information that you are looking for as you analyze this case in terms of making treatment decisions for this patient?

Dr. Powles: So, the first thing that we talk about really is advanced bladder cancer, advanced metastatic bladder cancer, and the second part that's complicated is about what the cancer actually looks like under the microscope and what histology looks like. The first part is, effectively, if the cancer is locally invading an organ has spread to the lymph nodes or spread to the visceral metastasis, that group of patients - their treatment tends to be focused around chemotherapy rather than curative-type treatments.

And the second part to this is about what the cancer looks like under the microscope and we talk about transitional cell cancers instead of bladder cancer, because actually there's a watertight lining of the kidneys, the ureter, and the bladder, those all made up of a group of cells called transitional cells, and actually the classic bladder cancer can actually occur anywhere along that track. And the terminology is complicated and it mixes from paper to paper, but we tend to call it transitional cell cancer or bladder cancer of transitional cell origin.

So, those are the first two things I look at. I look at where have these gone to, I make sure that we're talking about the right type of bladder cancer because there are other types. There's squamous and there's adenocarcinomas. And so it's very important that we kick off in the right place. We see a lot of patients with these sorts of metastatic or advanced-type bladder cancer, and one of the things that's really apparent to me at the moment is that we actually have a relatively limited number of treatment options for them.

The first thing that we talk about is chemotherapy and the standard chemotherapies that we're giving are based around very old drugs from thirty years ago, cisplatin or carboplatin as a base backbone and then we add in a second drug. That drug tends to be gemcitabine. There are some people around the world who are giving more intensive chemotherapy regimens. The one that's talked about the most is MVAC, which is a combination of four different drugs with growth-factor support.

Actually, in the grand scale of things, when you compare the two, either directly or indirectly, it looks like the outcome is about the same. The one thing that's really apparent to me is this group of patients tend to be in their 70s, they tend to have comorbidities, smoking is the most common etiological factor and so there tend to be comorbidities. About half the patients I see are not actually fit enough to have cisplatin containing regimens. And under those circumstances we go for an alternative called carboplatin, which is milder, but actually results are less good. When you look from a distance at the proportion of patients who are alive at 5 years, it's actually very low, and actually the median level of survival even in those patients in those patients receiving cisplatin was only 15 months, dropping to about 12 months with carboplatin.

Once you've had the first line of chemotherapy, we tend to take six cycles. I don't think there's any advantage of giving any more than that. Once you've had that first bout of chemotherapy the majority of patients respond to that, but actually the median time of treatment is only in the region of about five months. So, effectively you got a chemo-sensitive disease but you develop chemo-resistance very quickly. And once you develop chemo-resistance, second-line and third-line chemotherapy probably only works in the majority of patients. And in fact, in unselected studies, second-line chemotherapy is no better than best supportive care.

So the picture at the moment, I think, is one of getting that diagnosis right, making sure that you've quantified where the disease has spread to, what type histology looks like because that's very important for prognosis, getting on with the first-line chemotherapy in the knowledge the cancer is likely to come back quickly. And when it does come back it's fatal.

Dr. Ryan: Thank you. That's very comprehensive and I want to unpack some of those comments a little bit. First, let's go back. Let's talk about a patient who's newly diagnosed, has been sent to you by a urologist and has been told that he or she needs to have their bladder removed because they have maybe a high-grade tumor and maybe there are evidence of muscle invasion. You have a role as a medical oncologist and chemotherapy may have a role in this setting even before surgery. Explain your thinking on when you incorporate chemotherapy prior to surgery.

Dr. Powles: Chuck, this is a very controversial area and the data that's available to us at the moment suggest a period of cisplatin-based chemotherapy prior to surgical removal of the bladder. Prior to cystectomy improves the five-year outcome somewhere between 10 and 20%. The data to support this was based around a big meta-analysis. There's no single big positive randomized phase three trial. Unlike in breast cancer and colorectal cancer where we have thousands of patient studies supporting this approach, in bladder cancer, it's a mismatch of different studies being pulled together in a positive meta-analysis but with no single positive trial. The reason these trials weren't positive is they were underpowered and a couple of hundred patients here and it was very unlikely that any of these trials were to be positive because they weren't powered correctly. But actually when you pull them together and you look at it from a distance, you can see all of them are trending towards a survival advantage and then when you pull it together, the meta-analysis shows a significant advantage.

So, therefore, when you look at this, you say these patients, their five year survival is only about 50% and if we could improve that to 65, that must be worthwhile with just 3 cycles of chemotherapy. But when you go around the world to France, Germany, the UK, the United States and Canada, actually the uptake of neoadjuvant chemotherapy is probably only in the region of about 20 or 30%. Yes, it's increasing a bit, but the global community hasn't really bought into this. We've been talking about it for ten years now. So the question is what do we have to do to convince the global community that this is the right thing to do? I think that probably there's an education piece there because it's very unlikely that we're going to set out on a new trial in this setting.

The second part to this is I'm often seeing patients who have had their cystectomy, so I would offer neoadjuvant chemotherapy to patients who have operable disease and who are eligible for cisplatin-based chemotherapy. The second part to this particular problem is, what happens to that patient who I see who's has a cystectomy, who says, "Surely I should have had neoadjuvant chemotherapy, what options do I have now?" And Cora Sternberg's data that was presented at ESMO this year was an adjuvant trial, which was effectively adjuvant cisplatin-based chemotherapy versus observation. She showed a significant reduction in the progression-free survival, and again in an underpowered trial unfortunately, a trend towards a survival advantage.

And there's a meta-analysis being performed including caller's data, and I'm convinced that this meta-analysis in the adjuvant setting is going to be as positive as the neoadjuvant setting. So in my opinion, perioperative chemotherapy has an important role to play, giving a modest reduction in the mortality associated with operable bladder cancer. I think the bladder cancer community probably has got some work to do in terms of getting that educational piece across to more patients and increasing the uptake from what's only about 20%. I think if this was breast cancer and there was a 13% improvement in 5 year survival, I think it would be much more frequently given.

Dr. Ryan: I think that you're absolutely right and you're in the UK and I'm in the US and I will say that we quote the rate of neoadjuvant chemotherapy use in the US to be around 15%, however my center and many other academic centers that have multidisciplinary tumor boards and the like, often aim for upwards of 75 to 80% of patients who undergo cystectomy having received chemotherapy and that currently is the rate that we have at our center. And our neurology department, our tumor board in a way, is held to that metric of achieving a high rate of neoadjuvant chemotherapy use for bladder cancer. So it's a very important point, and it is important to note that it does differ between different types of hospitals and different countries around the world. And I'm glad you brought up that point. Sticking on this point of neoadjuvant chemotherapy, why do you think there is an advantage? Is it because we are with the chemotherapy treating micro-metastatic disease, or is it because we are enabling for a better surgical resection? If you could, just briefly discuss the biological rationale for giving chemotherapy before surgery versus after.

Dr. Powles: So my feeling on this is that if there was a trial comparing pre-operative neoadjuvant chemotherapy with post-operative adjuvant chemotherapy, I'm not convinced we would see a major difference. However, I do feel particularly from a logistical perspective, many of my patients can't get a cystectomy the next day or the next week. The waiting list in our institution is more than four weeks to have a cystectomy. And under those circumstances, we don't have a waiting list for chemotherapy. So actually when you see the patients you can start treatment within a week, and getting control of the disease. I genuinely believe there is a treatment of early micrometastatic disease that's important, and that's why we're achieving these survival advantages. I can't see another way in which we can get these survival advantages unless we assume there is at least some prevention of metastatis or treatment of early metastatic disease with the neoadjuvent approach.

So I think overall, early treatment with neoadjuvent chemotherapy, you don't have to wait for the cystectomy. You can start in the chemotherapy, give three cycles of drugs, plan the cystectomy. Then, there is sort of a seamless type approach to this multidisciplinary treatment. So, that's my feeling on the best way of treating this operable setting in bladder cancer. However, I know the German doctors are very keen on giving upfront cystectomy and then selecting patients for adjuvent therapy based around the positive status, or a T3 disease, or high-risk disease for example. I don't have a real problem with that approach either. The one thing I'm struggling with a bit is with this quite compelling data, those organizations and institutions that said there's no role for neoadjuvent or adjuvent therapy.

So, I'm supportive of both approaches. I don't think we've got enough evidence at the moment to say you have to give neoadjuvent and give adjuvent therapy, but I do think we've got enough data suggesting you should be giving one or the other.

Dr. Ryan: So, if I had to say for the newly diagnosed patient listening to us, they should be asking their doctor the question of whether or not chemotherapy before surgery—if that's in the plan—is appropriate for them, or whether they should wait?

Dr. Powles: Yes, so if I was an individual who was in that position, I'd be saying, "Yes, I want the surgery and I want it soon." I think that's important. I don't think we should be waiting months and months to have surgery obviously. And I would also be saying that I would like to have a discussion about neoadjuvant chemotherapy. And I would like there to be a good reason why it's not for me. And perhaps, the best reason why it's not for an individual would be that if you are not eligible for cisplatin-based chemotherapy, so if your renal function's not great, then the evidence for non-cisplatin neoadjuvant chemotherapy is actually pretty weak. I would say it's lacking altogether. So, it's either cisplatin-based chemotherapy or nothing for me.

Dr. Ryan: Correct. And I think that one of the other important points in this regard is the fact that there is a high operative complication rate to bladder cancer surgery to cystectomy and many patients may take a month or two or even longer to experience a full recovery from that surgery. In many cases, the administration of the chemotherapy before the surgery may have advantages to waiting until after the surgery, because it takes three months to recover from the surgery, there is the possibility that, that window of opportunity for the chemotherapy benefit may close.

Dr. Powles: That's a really good point, you know, and I think that's really important because one of the things that's apparent to me in medicine is that opportunities and windows can close with time, and if you have someone in front of you and you're saying that the moment that they're fit for both cystectomy and chemotherapy, I think you need to start off on that standard pathway. Because assuming that everything after an operation is going to be fine is difficult. Now some of my surgeons come back and say, "Well, actually, assuming everything after chemotherapy is going to be fine is difficult, too." So I can see both sides of that particular argument.

The one argument I do not buy into—it's the one I hear quite a lot—is, "Well, what happens if the cancer grows during the chemotherapy and the patient becomes inoperable?" Because we have to remember that those patients were also included in the randomized trials and in the meta-analysis as well. They're vanishingly rare and the overall benefits, the unselected population, is still significant. So those patients are included that analysis. And remember, the pathological CR8, if you give neoadjuvant chemotherapy, the chances of the cancer totally disappearing at the time of cystectomy in some series goes up to about 30%. So the chemotherapy is having a big effect on early, local disease and it is the only area really where chemotherapy and bladder cancer is resulting in long-term remissions and that's why I think it's important.

Dr. Ryan: So what do you tell a patient who gets chemotherapy and is planning on having surgery? And then they have an evaluation done after the chemotherapy, and they're in that 30% where there is no tumor found, the bladder is examined and there is no tumor, do they request to not have surgery and how do you counsel for those patients?

Dr. Powles: So that's a really difficult discussion. We did a study in the UK in this exact population where we compared radical surgery to radical radiation therapy, so cystectomy to radical radiation therapy. And we ended up not being able to randomize patients because when patients were given patient information sheets and said there's equipoise between the two, they were all opting for the radiotherapy option. So what I say to patients is straightforward. I think that chemotherapy is the icing on the cake. I think that if you didn't remove your bladder, all of the patients would die. I think the meta-analysis is just in the chemotherapy, shifting those goal posts by 10% one way or another. And so it's improving things by 10%, but I say 90% of the work is being done by cystectomy and importantly, I spend a depressingly large amount of my time looking after patients with metastatic disease. And those patients have a poor outcome. And if we want to get 5, 10, 20 years survival from here, we're only to achieve that by pursuing optimal pathways. Remember, even the best-case scenario, we're still looking at a large proportion of those patient's cancer coming back and dying, even with a cystectomy. So, this is not early prostate cancer. This is a much more lethal disease.

Dr. Ryan: Absolutely. I wanted to bring out that point because there have been problems with–and I think it's fair to call it a problem—patients who refuse to have their bladder removed because the chemotherapy has worked so well, only to experience a relapse of their disease later. And that's something we want to avoid. We want the chemotherapy to support the surgical treatment of this disease and hopefully the surgical and chemotherapeutic cure of this disease in certain cases. So you brought up a couple of times now the issue of metastatic disease and the fact that it had the poor prognosis. A metastatic transitional-cell carcinoma remains one of the very challenging diseases that we treat. What in your view are the top developments that are happening in this regard in the management of advanced bladder cancer that you think are hopeful for the future?

Dr. Powles: So it's surprising that there are so few new therapies in bladder cancer. Bladder cancer has a high mutational rate, and next-generation sequencing analysis that was published in [?] recently shows that there is a plethora of different mutations occurring. The issue is many of these mutations are occurring concurrently, so it looks like unlike some other cancers, such as HER2-positive breast cancer, that bladder cancer doesn't seem to be addicted to one particular growth factor or one particular receptor, so results for studies like lapatinib and herceptin and sunitinib and pazopanib, the classic drugs that have been used in other tumor types, VEGF, HER1, HER2, have all been negative. And in fact, when you look almost every drug every tyrosine kinase inhibitor or monoclonal antibody has been tested in bladder cancer, and the results have always been disappointing.

There haven't been that many spectacular developments in this area in fact until probably the last 12 months. And as with everything in life, two or three things have come along at the same time. I think the first thing that has really stood out is the work looking at immune checkpoint inhibitors. These are the PD, PD-L1 inhibitors. MPDL3280A is a PD-L1 inhibitor. PD-L1 inhibitors work by removing—cancers have mutations that they should be identifiable by the immune system. They manage to evade that by producing a camouflage. The cancer coats itself in camouflage, which allows it to evade the immune system, and that camouflage is made up of PD, PD-L1. PD-L1 inhibitors remove that camouflage, make the cancer visible, those mutations that should have been identified previously are now identified by the immune system, and the cancer is recognized, and then hopefully attacked and destroyed

Early results with MPDL3280A, in 70 patients, suggested if your cancer overexpresses this particularly biomarker, you've got about a 50% chance of long-term remission. That long-term remission at the moment is looking like 12, 15 months. The data out there—remember this is a group of patients who have no other treatment options, whose life expectancy is somewhere between six and eight months. It looks like these new drugs are putting a real dent into the cancer in this particular subgroup of patients. There are ongoing trials—one particular trial which we hope will be out this year - looking at MPDL3280A in a large cohort of patients single arm trial. There's second drug of PD-1 inhibitor called pembrolizumab which you may have heard of which is also a PD-1 inhibitor, slightly different mechanism action. Very similar results, response rate slightly lower but actually the biomarker looks less specific. And so it's becoming a very complicated area, but I think the take home message is a series of drugs are being developed in this setting.

I suspect that these drugs will be approved in subsets of patients within the next year or so, and then importantly there are a large randomized phase three studies testing these new drugs against standard therapy, against second-line chemotherapy to demonstrate an overall survival advantage. I'm relatively confident that because to some extent due to the surprising activity of these agents, and at the same time the lack of efficacy in chemotherapy second-line testing that these big randomized phase three studies are actually going to show a significant survival advantage.

Dr. Ryan: So what proportion of the patients are we talking about here? Who these drugs will apply to because they have the marker? Because they have the PD-L1 expression?

Dr. Powles: That's a really good question and there is no right answer because unfortunately we haven't managed to unify the best way of measuring PD-L1. So PD-L1 is the biomarker that we use, and each drug has a companion diagnostic, so each drug will have its own way of measuring PD-L1, and with MPDL3280A, the proportion of patients who are positive with that assay, they're looking at the expression of PD-L1 in the immune component, not in the tumor cells, but on the lymphocytes and the stroma around the tumor cells. I think that's quite a neat concept because it's much more likely that that is the component which is driving the immune evasion rather than the tumor cells themselves. Actually, only about 25% or 30% of patients are positive for PD-L1 in that group.

However, other assays that are being used are looking at PD-L1 expression on the tumor cells. So pembrolizumab is looking for that on the tumor cells, and they actually have a higher proportion of patients who are PD-L1 positive, but their response rates are lower; which is suggesting to me that that biomarker assay, at the moment, may be less specific. We may be bringing in a series of non-respondent into that group.

The final bit of this jigsaw which is intriguing is that in years gone by, with drugs like Cipulus LT, which you know a huge amount about, we never expected to see responses at all in immune therapy. We were happy with no responses, but just showing a survival advantage. We always thought that it would take ages and ages for immune therapy to take into effect, to the fact that these drugs are resulting in rapid and deep responses really suggesting to us that yes, I'm sure those patients are getting benefits. But it's likely there's a huge cohort of other patients who are going to benefit as well who actually just have stable disease.

So it's not until we look at the results of the randomized trial, and it's not until we actually look at the different biomarkers in comparison, the companion diagnostics, we'll be able to answer that question accurately. I think what we can say at the moment is these drugs are resulting in some surprisingly good results in subsets of patients, but it's also likely that other subsets are benefiting as well. And we need to move these drugs earlier in the disease process, because clearly, what we'd really like to do is treat patients with relatively minimal disease where I think immune therapy will work best. And in fact, it's very likely that there will be a series of adjuvant studies after surgery, to see if we can actually stop the cancer coming back in a large proportion of patients.

Dr. Ryan: I think it's important to point out for the patients listening that the randomized trial that you're describing have a structure in which a certain group of the patients will receive the immunotherapy and then another group will receive standard chemotherapy. And so I think it's important to address the issue of what would be the efficacy of standard chemotherapy in that setting, and why such a trial is ongoing and how such a trial is a fair trial. Let's put it that way.

Dr. Powles: Okay, so that's a difficult question; I'm going to do my best to answer it, because I know I've been asked it on a number of occasions. So to quantify the benefit of the drug, in Europe particularly, the regulators and particularly the individual reimbursement agencies want to be able to quantify that accurately with the number of months survival advantage it has over other treatments and quantify that with the quality of life during that period of time. And in Europe particularly, there is a nervousness about treatments being introduced into a setting that haven't been proven to be active in unselected patients. Now, it's possible, and we don't know this yet, remember we're only talking about data on probably 100 patients in the public domain at the moment, it's possible that come December-time, we will have results of a 3 or 400 patient trial, which will show there are a subgroup of patients in which the drug is fantastic. And I think there is a chance that even then, Europe will say, "Yes, we will approve," and some European, not all, some European countries will reimburse as well.

But the issue is that the regulators have, is they're saying things like, "Well, what about, if this PD-L1 is prognostic, not just predictive, so if you overexpress the biomarker, you do well anyway." And we don't actually know that at the moment. So it might be that we're just selecting the winners; we're giving them the drug, and they're doing extremely well. But they may be the people who do well with chemotherapy, too. And in fact, they may be doing well with the best supportive care. And so question number one is, what's the prognostic value of PD-L1, and are we just selecting the winners, and a randomized trial will tease that out. Point number two, then what is the survival advantage? Can we go back to taxpayers and say, "This is money that's better spent than on orthopedic surgery, or on aseptin, or on other drugs that are available in an environment of a limited resource, having the results of a randomized trial is important. But for the individual patient who's taking part in the trial, that's of no consolation to them because clearly the one to one randomization and we know that the standard of care is relatively ineffective, and therefore, the majority of patients who I see who want to participate in these randomized trials are clearly hoping to get the immune-based therapy. There isn't access to cross over which is understandable because you will lose your survival signal if everyone ends up getting the therapy, so this is the very difficult nature of drug development when very promising agents come along.

Dr. Ryan: I agree. That's a very good answer to a very complex question, and I think that for the patients listening, one of the key take home messages was what you call point number one, which is, it may be that the expression of PD-L1 is associated with a better prognosis, and that could be a situation where the drug doesn't quite have the same effect as we might imagine that it might. You answered it better than I just paraphrased it, but [chuckles] that's a very good comment. So a couple of things, so what about the situation where immunotherapy isn't effective or imagine a situation where it's not available. There has been some progress made in some of the sequencing work and you touched on the complicated nature of this. Are there any targeted therapies that are underway? And for the patients listening out there, should they be getting their tumors sequenced through some sort of a genomic facility or company, or should they be asking if their doctors do that?

Dr. Powles: One of drugs I'd like to talk about really quickly, there's a drug called ramucirumab, which is an agent, it targets VEGFR2 receptor. Data was presented at GU ASCO this year. And in an unselected population who previously failed chemotherapy, those individuals who had this drug in combination with a taxane did better than taxane alone in terms their overall survival.

When you look at that survival curve, you look at that and think, "There's something there with that drug." And we haven't seen that with pazopanib or sunitinib or the other VEGF-targeted therapies. And there was some suggestion about whether or not we will see the bevacizumab. And I look at that particular study - and that's going out into a randomized phase three trial - the results are there was a significant difference between the two. And I think that, for me, that is a very exciting targeted agent that we can seem to treat in unselected patients, although it is targeting VEGFR2, the receptor, it's not targeting the antigen like bevacizumab.

So that is another exciting area. But the question you've asked, which is slightly different, is actually should patients be saying, "I want to have my tumors sequenced and then I want to pursue a personalized approach." And at the moment there is some anecdotal data, a couple of case reports here, a few cases there, looking particularly at FGFR3, and patients with FGFR3 mutations in a very small number of patients that we've seen look like what they respond to therapy. And there are some trials that are ongoing looking at FGFR3, and that's probably the most promising target. The secondary, which I'm interested in, is there are some suggestions that individuals with alterations to the PI 3-kinase pathway may be doing better with PI 3-kinase type inhibitors, and that's a second area for me of interest.

So I think that, as I said at the beginning, my concern about this is the majority of tumors have a number of mutations, and it's likely that they'll have more than one driver, and actually having more mutations may make it more responsive to immune-type therapy, but less likely that a single target is going to result in long-term benefit.

Dr. Ryan: So in summary then you've told us a lot about some very interesting new concepts and new treatments that are very exciting. If you could just summarize what you think would be some of the priority aspects of treatment that patients should arm themselves with when they go to see an oncologist with this disease. What are the key things they should be asking?

Dr. Powles: So the key to this disease is actually it's relatively simple. If you're in a position where you have potentially operable disease, you want aggressive treatment early to achieve long-term survival because if you have node-positive disease or metastatic disease or even locally advanced disease, unfortunately, the survival remains poor. We need to be identifying patients early. If you have hematuria or you're in this position where you have a diagnosis of invasive-type bladder cancer, you need to be taking that very seriously. I wouldn't be waiting for new treatments to arrive. I would be treating that aggressively.

In the metastatic setting I would say, at the moment, first-line chemotherapy is effective in the majority of patients who receive it, but unfortunately, when it fails, there are very few other treatment options. I would be encouraging people to take part in clinical trials under those circumstances because my feeling is that there are two or three trials out there at the moment, which probably are going to end up resulting in clinical benefit, particularly for those patients who are on the intervention type arm.

Dr. Ryan: Do you want to specifically name those clinical trials?

Dr. Powles: I can name those trials. The first one and the one we're very involved with is the randomized phase III Roche MPDL3280A versus chemotherapy second-line trial. There is also Merck pembrolizumab versus chemotherapy second-line trial. There are also studies looking at pembro in patients who are untreated who are not fit enough for cisplatin-based chemotherapy. I think that's a nice trial for patients who previously haven't had chemotherapy and are not fit for cisplatin. And there are some specialist centers there are new combinations of immune therapies that are being tested in bladder cancer, so the new CHL4 and PD-L1 combinations are being tested.

Dr. Powles: So there are a number of very exciting trials in this field. As I've said before, we're going to see some adjuvant studies, and I even think there are going to be studies in the non-muscle invasive setting, so for those individuals who have local disease who are not needing cystectomy yet, but are getting recurrent disease or failure of local treatments, we're using these drugs in that setting as well. So, actually, if you go on ClinicalTrials.gov and have a look and look up these drugs, you'll see that there's a trial for almost every setting at the moment. Now, they may not be available in every area, but this is a rapidly expanding field.

Dr. Ryan: Thank you. That's a great summary. It is I think a very important time in the development of research for bladder cancer. It's a very hopeful time for new agents, new therapies being introduced into the clinic, but of course, the key to all of that is getting patients access to the new medications and working out exactly when and whom they should be used, and the only way that we can do that is through clinical trial enrollment. You mentioned ClinicalTrial.gov as a resource. Cancer.Net will also have resources on that available through ASCO.

So I want to thank you for your time and your graciousness with your information and your incredible depth of knowledge on this topic. I'm sure it'll be very useful to the patients and their families who are listening, and I think it would also be very useful to patients and their families, as well as to practicing physicians out there who wish to learn more about the treatment of this disease. Thank you very much.

Dr. Powles: Thank you very much for inviting me, Chuck. It was a real pleasure to chat.

ASCO: Thank you, Dr. Ryan and Dr. Powles. A comprehensive guide to bladder cancer can be found at www.cancer.net/bladder. And for more expert interviews and stories from people living with cancer visit the Cancer.Net Blog at www.cancer.net/blog.

Cancer.Net is supported by the Conquer Cancer Foundation, which is working to create a world free from the fear of cancer by funding breakthrough research, sharing knowledge with physicians and patients worldwide, and supporting initiatives to ensure that all people have access to high-quality cancer care. Thank you for listening to this Cancer.Net podcast.