Research Highlights in Kidney and Prostate Cancer from the European Society for Medical Oncology 2018 Congress, with Brian I. Rini, MD and Jorge A. Garcia, MD, FACP

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In this podcast, Cancer.Net Editorial Board members Dr. Brian Rini and Dr. Jorge Garcia discuss new research in kidney and prostate cancer presented at the European Society for Medical Oncology 2018 Congress, held October nineteenth through twenty-third in Munich, Germany. Dr. Rini is a Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Dr. Garcia is an Assistant Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. They are both also staff members of the Department of Solid Tumor Oncology at Cleveland Clinic Taussig Cancer Institute. ASCO would like to thank Dr. Rini and Dr. Garcia for discussing this research. Dr. Rini: Hello. This is Brian Rini from the Cleveland Clinic Taussig Cancer Center. I'm a professor of medicine and lead the GU program here at Cleveland Clinic, and I'm joined by my friend and colleague Dr. Jorge Garcia. Dr. Garcia: Thank you, Brian. I'm Jorge Garcia. I'm a GU medical oncologist at the Cleveland Clinic as well. Dr. Rini: And we're going to talk to you today about highlights in genitourinary or GU cancers from the European Society of Medical Oncology Meeting, which took place a couple of months ago in Munich, Germany. It's one of the major cancer meetings, with a lot of big data starting to be presented at that meeting in addition to the main ASCO meeting and other meetings. And I'm going to start off by talking about a couple of the highlights in renal cancer, and then Dr. Garcia will describe a couple of the highlights in prostate cancer. In kidney cancer, generally speaking, it's been a pretty exciting time. So about 10 or 15 years ago we went through a wave where VEGF-targeted therapy or therapy targeted against blood vessel sort of became the standard of care. And this was exciting because, frankly, at the time there wasn't much else that was available for patients with metastatic kidney cancer. And that's really been the foundation of how we've treated this disease over the last decade or so. More recently, we've started to use immune stimulating agents, commonly called immunotherapy or IO therapy, as is being used across many, many malignancies, but especially in kidney cancer. And so now we have 2 ways that we treat metastatic kidney cancer. We still use therapy targeted against blood vessels, also called VEGF-targeted therapy, and now we're increasingly using immune therapies. And the most recent efforts at this have actually combined these different modalities. And so probably the largest data that was presented was something called the JAVELIN 101 trial. So this was a randomized phase III trial that compared patients with metastatic kidney cancer who had not gotten any prior treatment to receive either sunitinib, which is a VEGF-targeted agent that's been our standard of care, again, for the last 10 or 15 years, or a combination of axitinib, which is another VEGF-targeted therapy, plus avelumab. And avelumab is 1 of a class of drugs that I mentioned that are immunotherapeutics. We also call them checkpoint inhibitors because of the mechanism by which they work. And there are many of these combination studies that are starting to be reported. A couple have been reported, this is the third, and there will be more to come over the next 6 to 12 months. It's really transforming the way that kidney cancer patients are treated when they walk in the door. So as mentioned, this was a large phase III trial. And the rationale is really that it's 2 different ways to attack the cancer, both attacking blood vessels and trying to stimulate the immune system. About 900 patients were treated on this trial, so about 450 patients treated with either sunitinib or this combination therapy. And what was shown was that, the—what we call—progression-free survival, which I usually describe to patients as how long we can control tumors, was significantly greater with the combination therapy. It was almost 14 months, which is, I believe one of the highest ever reported in this disease, compared to only 7 months with sunitinib. So there was a significant advantage in terms of disease control, which was the primary end point of this trial. What was also looked at is response rate. So when we talk about response, it's really patients who have a significant amount of tumor shrinking on a scan. And what was seen in the overall population who received the combination therapy was that just over half the patients, 51%, had an objective response. And most people had some degree of tumors getting smaller. If tumors get just a little bit smaller we don't necessarily call that a response. If they get at least 30% smaller, that's our threshold for a response. So over half the patients reached that threshold, which is again a very high number compared to usually about 30 or 40 percent with the single-agent anti-blood vessel drugs. And importantly, 3% of patients had a complete response. One of the great things that immunotherapy has done in kidney cancer is change our mindset a little bit from really just trying to control disease to now recognizing that there's a subset of patients who can be cured with this disease. And that really hasn't been true on any large scale ever really, certainly in the time that I've been doing it. And so these new regimens are not only controlling disease longer, but leading to more potential cures of disease. The cure part, obviously, we need more time to pass. We need to follow patients, etc., but I think certainly the possibility is there. They reported on overall survival results, although, the data was what we call relatively immature, meaning—which is a good thing—that most patients were still alive who had received either regimen. So we can't quite yet say for this regimen that it makes patients live longer, on average, but certainly has benefits in terms of tumor shrinkage and disease control. And with more time, other data will come. Interestingly, there was also a very similar study involving a combination with axitinib and pembrolizumab. That data was not presented at the meeting, but there was a press release that happened to come out on the first day of the meeting showing that it also had effects in terms of tumor shrinkage and disease control, and interestingly, also showed a survival benefit. So one of the things we'll sort out over the next year or so is the relative merits of each of these regimens. They're certainly not identical. They'll have different side effect profiles, different ways that they help patients, different patients in whom they might help, etc. So the good news is that there are a number of these regimens that are likely to get approved over the next 6 to 12 months, and then comes the next wave of work of trying to figure out how best to apply them to patients, but this is certainly very exciting data. It was the first combination regimen that included a drug like axitinib, that included a pill that inhibits blood vessels. The other main piece of data that I wanted to go over, I had the privilege of presenting there, which was from a different trial than I just presented, but a similar one. So it was a trial called IMmotion151. And what that trial did was take patients with kidney cancer that had not yet been treated. It randomized them to either sunitinib, as I mentioned, a standard therapy, or to another combination of an immune agent in an anti-blood vessel agent. The names of these drugs were atezolizumab and bevacizumab. It's a regimen that's shown effects in lung cancer and some other cancers. And the clinical data from this study had been presented at the GU Symposium early in 2018. And what we presented at ESMO was some of the correlates from the study. Some of the secondary scientific analyses that often happen in these large clinical trials. And the details of how these analyses are done are a bit complicated but suffice it to say that if we look at patient's tumors, we can look at the expression of genes from these tumors. And different tumors have different biology. They express different genes. And one of the stories that's emerged from analysis of the samples from this trial and also a small prior trial was that some patients have tumors that are very rich in blood vessels and that are very reliant on angiogenesis, and other patients have tumors that are very reliant on T cells and on the immune system effects, and obviously some patients have both of those types of tumor cells in an individual tumor. And so the data are really starting to show this trend that there's different biologic subtypes of kidney cancer. And anybody who treats patients knows this. We give a group of patients the same drug, and some people respond wonderfully, and unfortunately, others don't, and everywhere in between. And it just means the underlying tumors are different. And these large data sets and large analyses are now starting to sort that out and say, "We now have a genetic basis for those clinical differences that we observe in patients." I think it's important because it's a first step, hopefully, towards individualizing therapy and not just treating everybody with the same combination. Treating certain patients with one drug, certain patients with another drug, other patients with a combination. And as I mentioned before, there are many of these combinations coming out, so it would be nice to have a test that would allow us to choose the best combination for the best patient. We're not there yet. We're, I would say unfortunately, a little ways from that point. But these data were presented at ESMO, I think, started to take that step by characterizing tumors. And then the last thing I'll mention is something called sarcomatoid tumors. So the word sarcomatoid is applied in kidney cancer to a subset of about 10 or 15, maybe 20% of tumors that are generally more aggressive. The cells under the microscope are spindle shape. That's what the word sarcomatoid means. And they've always been very difficult to treat. It looks like, however, with these immune therapies that that patient population is particularly susceptible, so they actually do better with immune therapies. And when these genetic signatures were applied to specifically those tumors, not surprisingly, they had a very—what we'd say—an immune rich environment. They were characterized by expression of genes that are relevant to the immune system. So again, it provides a biologic basis for some of the clinical observations that we've made for years, and hopefully, makes us smarter. And I think the immune therapies are certainly going to be of benefit to patients with sarcomatoid kidney cancer, I think that much is clear, and some of the clinical data has pointed towards that. And the ESMO data really provides, again, a biologic basis. Just to summarize kidney cancer from ESMO 2018, one phase III trial presented the JAVELIN 101 with axitinib plus avelumab showing advantages over sunitinib, and then some interesting biologic data. And certainly, more to come with these combos moving forward. I'll ask Dr. Garcia now if he has any comments on the kidney cancer data that I mentioned and then I'll have him describe the prostate update. Dr. Garcia: Thank you, Brian. I think that's an excellent overview of that exciting data. Perhaps my only comment is that the lack of biomarkers can indeed put a lot of pressure on how we select patients and select therapy for those patients with metastatic renal cell carcinoma. And I think that with the JAVELIN trial and 2 or 3 trials also coming very soon into the space, I think that we clinicians are going to be faced with the challenge of deciding between dual immune-oncology approaches or doing it in a sequential manner. And, for that matter, also perhaps looking at the combination of vascular disrupting agents plus immunotherapy. Clearly, we need to actually look at clinical features of patient disease to make those treatment decisions because we haven't been able to pin down biomarkers that can help us guide which is the best approach for those patients up front. Dr. Rini: Yeah, I agree. It's a good problem to have that we have so many active drugs, and we're trying to decide which ones to give which patients, but it's going to be a big challenge moving forward. Dr. Garcia: Great. So let me move now and briefly review what I think is probably the 2 or 3 most exciting reports out of ESMO, in Munich, in prostate cancer. So similar to what Brian mentioned, obviously, there has been a lot of movement into how we manage patients with advanced prostate cancer. I think that the last 3 years have changed how we practice and how we manage patients who are walking in the office with metastatic prostate cancer. That is, patients who either have had their primary tumor resected or have had radiation therapy for primary definitive treatment and over time they will go on and progress and develop systemic disease, or patients who never had their chance to have their prostate treated with either surgery or radiation therapy. The latter group is uncommon because of PSA screening, at least in North America. And we see about 20, perhaps, 30 percent of patients walking in the office with metastatic disease. So just as a way of background, the standard of care for men with advanced disease for the last 3 or 4 decades has been suppression of testosterone, so-called castration, which is removal of testosterone either medically and/or by surgical orchiectomy. Most of us in the United States just do medical suppression with what we call hormonal therapy, which is basically injections received at various intervals to suppress the function between the pituitary access and the testicles so patients are suppressed with their testosterone. Therefore, the disease gets controlled. Traditionally, all patients, the longer they live suppressed from testosterone, the more likely for them to develop resistance to that approach. And traditionally what we have done when that happens is you talk about chemotherapy. You talk about some of the novel oral agents that are able to inhibit signals within prostate cancer cells that allow growth or signals or hormones in our body that we make specifically in the renal glands. With agents such as abiraterone acetate, there are agents capable of suppressing testosterone and production of hormones, then can also activate the signaling within prostate cancer growth. So we now divide patients into 2 main groups when they walk in the office with metastatic disease, what we'll call high volume and low volume. And that definition has been actually processed through the American data called charter data. Patients with high volume disease, specifically speaking, visceral metastases, which is uncommon in prostate cancer—that means lung disease or liver disease—or men with more than 4 metastases in bone, one of which has to be outside the spine and/or the pelvic region, receive hormones and chemotherapy. And clearly, adding docetaxel-based chemotherapy to these men drastically improves their outcome. The French last year in 2017 presented the data of a trial called LATITUDE, which is a trial that looked at the utilization of oral therapy up front in combination with testosterone suppression. In this case, they used abiraterone acetate. And that trial also specifically was aimed for patients with metastatic disease with high volume features. Although, their definition for high volume disease was a bit different than the American definition, that didn't include visceral disease and the presence of bone metastases, but they did include a Gleason score of 8, 9, and 10, which reflects the biology of the tumors of these patients. And in that trial also it was demonstrated that patients who received the combination of abiraterone acetate and suppression of testosterone have a drastic improvement in outcome. We often times tell our patients that with ADT or hormonal suppression and abiraterone we can decrease their risk of dying from prostate cancer by almost 40%. With the LATITUDE and the charter data from America, we now have a standard of care of either using chemotherapy and/or abiraterone for this patient population, but we didn't have a good sense as to what to do for patients with low volume disease. Throughout this time, the British also helped us a little bit with supporting the role of chemotherapy in our patients. The British did a trial called STAMPEDE. It's a very complex trial statistically speaking, but it's a trial that basically takes a significant number of patients with metastatic disease, and basically, you have a backbone of a treatment, in this case, suppression of testosterone or androgen deprivation therapy, and you add newer treatments over time. And it allows you the flexibility of removing treatments that are not performing or adding new treatments that are becoming part of what we use for our patients. This trial actually demonstrated a couple of years ago that the addition of docetaxel-based chemotherapy for patients with metastatic disease made people live longer—specifically, reducing the risk of mortality from their disease—and therefore, solidified the role of docetaxel similar to what we did in the American data. They also included an arm that included abiraterone, and that data also presented last year demonstrated significant survival improvement for those patients with metastatic disease. So now the biggest question was, what do you offer patients with low volume metastases? So their data didn't actually stratify patients by volume of disease, and this is what actually was presented at ESMO this year. And I think the nutshell of this is quite simple. Patients with low-volume disease and/or high volume disease—whether you use the French definition or the American definition—regardless of volume the addition of abiraterone to patients with metastatic disease drastically improves outcome and reduces the relative risk of mortality when you do all therapy. So the standard of care for low volume patients now is suppressing testosterone and adding abiraterone acetate. Perhaps, what is more interesting of this data is they also had an arm within their trial looking at the addition of radiation therapy to a primary tumor for those men with metastatic disease who did not have a primary tumor treated—meaning, with radiation upfront or with surgery—and they walk in the office with metastatic disease. And they randomized those patients to the standard of care at the time, ADT, suppression of testosterone, and docetaxel, or the combination plus radiation therapy to the prostate tumor. And what we saw in that data, there was not a survival improvement when you take all comers. Meaning, the high and low volume patients. However, when you stratify by volume of disease—the low volume disease against high volume disease—it was clear then there is a significant survival improvement for those men with metastatic disease, with low volume disease, who went on to receive ADP, meaning suppression of testosterone, the addition of docetaxel-based chemotherapy, and radiation therapy to the prostate gland. There was almost a 20% difference at 3 years in survival with the hazard ratio, which is the risk reduction of mortality, of what we call 0.68, which is what we tell patients around almost a 30%, 32% risk reduction mortality when we get radiation therapy to a primary tumor. So what that does for our practice is that now if we see someone with low volume metastatic prostate cancer with their primary in place, the standard of care has become suppression of testosterone, the addition of abiraterone acetate, and primary radiation to the prostate tumor. Period. For high volume patients, I would argue the standard of care remains either suppression of testosterone, plus docetaxel-based chemotherapy or suppression of testosterone plus abiraterone. And I think most of us in practice are simply using the combination of oral therapy plus suppression of testosterone. Lastly, I know a very interesting and provocative trial is the trial that is called ERA 233 that looks at the combination of this particular agent, abiraterone acetate, and a radiopharmaceutical agent, also approved in men with advanced castration-resistant prostate cancer. Meaning, men who become resistant to a lack of testosterone and go on to develop progressive disease in the bones. So the rationale behind this combination was that both agents are life-prolonging agents. And since abiraterone can be used in the pre-chemotherapy space in that setting and Radium-223 as a radionuclide can also be used in that particular patient population, we thought that maybe combining a novel oral hormonal approach against a radionuclide-based approach could actually lead to a better improvement in outcome for our castration-resistant prostate cancer patients. So this trial looked at over 800 patients with castration-resistant disease who have never seen chemotherapy and randomized them to receive either the combination of abiraterone plus Radium-223 against abiraterone and a matching placebo. And the primary end point of this trial was, again, looking at survival along with a reduction in skeletal symptomatic events, which is how likely it is for you as a patient to develop symptoms from bony metastases, which is the most common site of metastases in men with prostate cancer. It specifically relates to the need for radiation therapy for pain control. Developing a fracture then requires orthopedic surgery, or developing a tumor in the spine that is pushing the spinal canal, possibly leading to neurologic symptoms. That was the primary end point of the trial. What we learned from this trial is that there was not really a drastic difference in outcome. Meaning, in the ability to delay the progression of disease. There was no difference in the survival between the 2 groups. Meaning, adding Radium-223 didn't improve outcome. What we did learn is that the combination of abiraterone and Radium-223, unfortunately, does increase the risk of this patient population for developing fractures. Specifically, either pathologic, which are fractures in sites where you have bony metastases or complications from areas of bony disease leading to a bone fracture. So that was a big issue because some clinicians are using the combination of abi and Radium-223, and since this trial I think most of now refrain from using this combination. I think it's important for our physicians to understand that this trial did not test the timing of using Radium-223 in castration-resistant disease. It only was aimed to test the combination of both agents. So I think Radium-223 remains a life-prolonging agent that should be offered to our patients with castration-resistant disease, to specifically the patient population for which this agent has been labeled for, but the combination with an oral agent such as abiraterone should actually not be used at this point. This trial and the results of this study changed the label of Radium-223 in the United States and also in the European region, and I think that it’s fair to say that most of us now refrain from using the combination with this oral agent. Whether or not this means that you can now combine Radium-223 with another oral agent, such as an AR inhibitor, remains to be seen. But clearly, with the significant increase in pathological fractures, almost a 16% difference for all patients in the combination arm, I think most of us would be concerned as to seeing patients developing complications from the combination. I don't think we really know the biology behind why this happened, but I think it's fair to say that the data is confident enough for us not to use in clinical practice. So just to summarize, I think the standard of care for prostate cancer now for low volume and high volume disease is using suppression of testosterone and the oral agent abiraterone acetate. For those patients with low volume disease who have their primary tumor in place, radiation therapy to the primary tumor is now the standard of care. The timing remains debatable. So I think most of us will treat patients with systemic therapy, and down the road at some given time we probably will include radiation oncologist to offer radiation therapy. And secondly, the use of the combination of Radium-223 and abiraterone acetate is not now something that one can support with the data from this new trial looking at the combination of those 2 agents. Brian, I don't know if you have any comments or thoughts? Dr. Rini: Sure. Yeah, I mean, as you can tell there's a lot going in prostate cancer as well. I think maybe just to broaden it, 1 of the areas that we're all thinking about is control of the primary tumor in patients whose disease has already spread. And so Dr. Garcia mentioned the data with radiating the primary tumor in a subset of patients, especially in patients with low volume, sometimes called oligometastatic disease. There are studies that are ongoing that are looking at that. Can we treat those patients more aggressively by either radiating or surgically removing their primary, surgically removing lymph nodes, even radiating metastatic site? Hopefully, the window for cure for some prostate cancer patients has expanded to include some of those low volume patients. But I think there's a lot of work to be done because I think there are patients who may not benefit from that, and I think some of these ongoing trials will help to define that. But that's a totally different concept than we had thought about for advanced prostate cancer really. Certainly, in our time that we've been doing this. So I'd like to thank Dr. Garcia for that excellent summary. Thank you for tuning into this podcast. As you can tell, in GU cancers—and we've really just given you a small slice of what went on at one meeting—but there's a lot of important studies going on. A lot of important data that's coming out of large phase III trials that are changing the standard of care and changing it for the better as we continue to move forward in clinical research. Thank you again for your attention. Dr. Garcia: Thank you, Brian. Thanks for the opportunity. ASCO: Thank you, Dr. Rini and Dr. Garcia. Learn more about genitourinary cancers at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. Cancer.Net is supported by ASCO’s Conquer Cancer Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.