Clinical Trials in Genitourinary Cancers: CheckMate 914, KEYNOTE-992, KEYNOTE-991

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 who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so clinical trials described here may no longer be enrolling patients, and final results are not yet available.  Before any new cancer treatment can be approved for general use, it must be studied in a clinical trial in order to prove it is safe and effective. In today’s podcast, members of the Cancer.Net Editorial Board discuss 3 clinical trials that are exploring new treatment options across kidney, bladder, and prostate cancer. This podcast will be led by Dr. Timothy Gilligan, Dr. Tian Zhang, Dr. Petros Grivas, and Dr. Neeraj Agarwal. Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig Cancer Institute. He has no relevant relationships to disclose. Dr. Zhang is an associate professor of medicine at Duke University School of Medicine and is a medical oncologist at Duke Cancer Institute. She has served in a consulting or advisory role for Bristol-Myers Squibb and Merck, and has received research funding from Astellas Pharma. Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine. He is also an associate member of the clinical research division at the Fred Hutchinson Cancer Research Center. He has served in a consulting or advisory role for Bristol-Myers Squibb and Merck. Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah. He has served in a consulting or advisory role for Bristol-Myers Squibb, Merck, and Astellas Pharma. View full disclosures for Dr. Gilligan, Dr. Zhang, Dr. Grivas, and Dr. Agarwal at Cancer.Net. Dr. Gilligan: Hi. I'm Dr. Timothy Gilligan from the Cleveland Clinic Taussig Cancer Institute. I'm joined today by Dr. Tian Zhang from the Duke Cancer Institute, Dr. Petros Grivas from the University of Washington and Fred Hutchinson Cancer Research Center, and Dr. Neeraj Agarwal from the Huntsman Cancer Institute and University of Utah. Today, we're going to discuss 3 ongoing clinical trials in kidney, bladder, and prostate cancer. As you may know, clinical trials are the main way that doctors are able to find better treatment for diseases like cancer. Patient participation is vital for clinical trials. By participating in the clinical trial, you can directly help researchers develop better treatment, reduce side effects, or even reduce the risk of cancer altogether. The 3 trials we'll discuss today were chosen by members of the Cancer.Net Editorial Board Genitourinary Cancers panel from the Trials in Progress abstracts that were presented at ASCO's 2020 Annual Meeting. Because these are ongoing clinical trials, final results from these studies are not available yet. I'd like to note that none of us have any direct involvement with any of these trials. To view our full disclosures, please view the show notes for this episode on Cancer.Net. We're going to start with Dr. Zhang discussing the trial CheckMate 914. Why don't we begin with who the study is designed for? CheckMate 914 is a study in the adjuvant setting, so it's a study after patients have had their primary kidney cancers removed, and everybody needs to have a kidney tumor that's either 7 centimeters or larger or have extension beyond the kidney or any nodal involvement. So after their kidney tumors have been removed, this study really is in that timeframe after nephrectomy or after surgery with complete resection of their tumor. Dr. Gilligan: What's the current standard of care for these patients if they're not on a trial like this? Dr. Zhang: We often will compare against that standard which currently in the adjuvant setting we either do observation until disease recurrence or there is 1 oral treatment that's approved called sunitinib. But sunitinib really has some controversial data around it, and so it's not often used. And so currently, many patients are still observed as standard of care in the setting. Dr. Gilligan: And so if a patient goes on this trial, what can they expect?   Dr. Zhang: So patients who are enrolled to CheckMate 914 are randomized to either a combination immunotherapy called ipilimumab with nivolumab, which is approved in the metastatic setting for kidney cancer, or they're placed on placebo for these 2 treatments, or there is a third cohort that receives nivolumab alone with a placebo of ipilimumab. And so these patients are receiving either active immunotherapies or a placebo, which would be our current standard of care, sort of observation until disease recurrence. Dr. Gilligan: So patients will either get the current standard, which is observation, or else they'll have 1 drug or 2 drugs if I'm understanding correctly? Dr. Zhang: That's right. Dr. Gilligan: What is the hope of this study? What is the outcome that we're hoping to see? Dr. Zhang: The primary outcome of this study is disease-free survival, so that means time until disease recurrence for all comers. And we're really trying to prolong time until disease recurrence or time until metastasis for these patients. There are some secondary outcomes that are very important as well, so prolonging overall survival as well as the incidence of adverse events that are seen from these treatments. And then there is an independent radiographic assessment to look for disease-free survival intervals as well. Dr. Gilligan: And the hope is that these treatments will prevent recurrence or at least delay recurrence then? Dr. Zhang: That's absolutely correct, yes. And we have had 2 other adjuvant trials with immunotherapies in this space of atezolizumab and pembrolizumab, but those trials have finished accruing. And so this is the main ongoing and accruing trial that's looking at active immunotherapy options in this space. Dr. Gilligan: What risks should patients be aware of that they might encounter if they go on this treatment? Dr. Zhang: So with all immunotherapies, we talk a lot about the immune mediated adverse events and just the usual rundown of those. And in my clinic, we talk a lot about the common rashes. In the GI tract, it can cause some inflammation or colitis. Very rarely, it can cause some inflammation in the lungs or liver and then very commonly, endocrine dysfunction. So we watch pituitary, thyroid, adrenal, and pancreas function very carefully. But all of these side effects are well described for the ipilimumab, nivolumab combinations as well as nivolumab on its own in the metastatic setting. So most people should know what to monitor for and what we're looking out for and how to manage these toxicities. Dr. Gilligan: Right. So these are drugs that have been in wide use for some years now, so we have significant experience managing the side effects is what I'm hearing you say. Dr. Zhang: That's right. Dr. Gilligan: Is this trial still open to patients? Dr. Zhang: Yes. This trial is still accruing. It's a global study about to enroll up to 1,600 patients. So it's a very large global trial that is still active and still accruing patients. So I would encourage people and also oncologists to refer patients for the trial at a center close to them if possible. Dr. Gilligan: And when might we expect results for a study like this? Dr. Zhang: These adjuvant studies take a while to finish accruing and then it takes a while to finish seeing the data. So I would hazard a guess that we're still years away from seeing the data from this trial. Dr. Gilligan: So once again, this is for people who have had surgery to remove a kidney cancer and looking at ways to reduce the risk of subsequent relapse. Well, thank you for summarizing that so coherently and succinctly. Let's move on now, and we're going to talk about the trial KEYNOTE-992 with Dr. Grivas. Dr. Grivas, who is this study designed for? Dr. Grivas: So this is a clinical trial, a phase III clinical trial that applies to patients who opt to pursue what we call bladder preservation, which is an attempt to keep the bladder intact and still try to treat bladder cancer with concurrent use of chemotherapy and radiation. And this bladder preservation approach applies to a proportion of patients with bladder cancer still in the bladder but not spread. And as I mentioned before, the decision to pursue that strategy depends on particular patient characteristics, how the cancer looks on the CAT scans, and also how it looks under the microscope. Dr. Gilligan: What is the current standard of care for these patients? Dr. Grivas: So patients who are characterized as great candidates for this bladder preservation approach, because this does not apply to everybody with bladder cancer, the standard of care right now is patients undergo what we call a transurethral bladder tumor resection, which means that the urologists go through the urethra and they resect or remove or scrape, remove the visible bladder tumor, and then the patients undergo concurrent, meaning at the same time, chemotherapy and radiation. Dr. Gilligan: How does the study aim to improve or change the standard of care? What would be different as a result of the study if it's successful? Dr. Grivas: So this particular clinical trial, the KEYNOTE-992, is asking the question whether the addition of immunotherapy with 1 of those immune checkpoint inhibitors that activates the immune system, does this addition add value in the combination of chemotherapy and radiation? So the patients are being randomized by a computer system to either getting chemotherapy-radiation, as is the standard of care that we just discussed, or chemotherapy plus radiation which is standard of care, plus the addition of this drug called pembrolizumab, which is an immunotherapy aiming to activate the immune system. Dr. Gilligan: And it's given at the same time as the chemotherapy and radiation on the study? Dr. Grivas: That is correct. It's given at the same time. And then there is also some—what we call continuation of pembrolizumab for some time after the end of chemotherapy and radiation, and pembrolizumab in this study is given every 6 weeks. Dr. Gilligan: And what makes people think that this might be helpful to add this additional treatment? Dr. Grivas: The notion is that the addition of immunotherapy to chemotherapy-radiation therapy has the potential to make the chemotherapy, radiation therapy work better. What happens sometimes when you give chemotherapy-radiation, this can actually result in a killing of some cancer cells and the contents of those cancer cells can be released, and they may be recognized by the immune system and stimulate the immune response. So if you combine that chemotherapy and radiation with immunotherapy with this agent that stimulates the immune system, the assumption is that this may work better compared to chemotherapy and radiation alone. But we have to do this trial to confirm whether this is true or not. Dr. Gilligan: So patients going on the study, basically, either they'll get the standard of care, which is the chemotherapy and radiation, or the standard of care plus the addition of immunotherapy to see if that results in better outcomes. Am I understanding that correctly? Dr. Grivas: That's exactly right. And the outcomes are being measured by how many patients maintain the bladder intact, in place without the need to remove it, without the need for cystectomy. And also, at the same time, we want to see if those patients can maintain a cancer-free status, so whether the treatment results in a cancer-free state and whether we are measuring a recurrence as Dr. Zhang mentioned before, if the cancer comes back. And also, of course, we measure how many patients are alive over time. So the goal is to see if we can improve upon the rate of patients with no cancer coming back, no recurrence, and being able to keep the bladder intact if possible. Dr. Gilligan: So for both of these trials, the question seems to be if we intensify treatment, can we increase the cure rate and keep patients cancer-free longer? Dr. Grivas: That's exactly right, and that's the promise or the assumption of this trial, whether the addition of immunotherapy to chemotherapy and radiation can improve those chances. Dr. Gilligan: What are the known risks that patients should be aware of? Dr. Grivas: As Dr. Zhang mentioned before, every time we have the immunotherapy in clinical trials or in clinical practice, we have to do a good job educating, of course, all the medical providers, team members, and the patients for early recognition and reporting of what we call immunotherapy-related potential side effects. And as we discussed earlier, any organ of the immune system could be a target of an activated immune system. The reality is that if the side effects from immunotherapy happens, usually it's a mild to moderate degree and usually can be managed by holding of the immunotherapy drug and maybe sometimes give some steroids to cool down the immune system. Obviously, we need to be extra vigilant, and I always err on the caution of overeducated patients to avoid underreporting so we make sure we know ahead of time if a side effect happens. Dr. Gilligan: Is there any reason to be worried that immunotherapy could make the side effects of chemotherapy and radiation worse? Dr. Grivas: It's a great question, and we have to look in that during the course of the trial. The notion is so far, based on the available data, that it's safe to combine chemotherapy, radiation, and immunotherapy. There have been some early data suggesting that, and this is reassuring. At the same time, we need, again, to be extra vigilant, again, over-educating our patients to report any changes so we can be able to compare the potential side effects in the 2 groups. But so far, it seems to be a feasible strategy. Dr. Gilligan: Good. And is this trial still open for patients? Dr. Grivas: Yes, it is open and accruing patients actively, and I think it's a great opportunity for patients to discuss with their providers, urological oncologists, medical oncologists, radiation oncologists, whether they could be good candidates for this bladder preservation approach, if that's a good fit for them and the particular cancer at hand, and if so, whether they can be candidates for this trial or another trial called SWOG 1806, which is in the same space and setting. Dr. Gilligan: And when might we expect results from the study? Dr. Grivas: It may take time because this trial is still early in the accrual process. It may take a few years. The current estimate is probably 2026, so 5 years from now. However, the faster these trials accrue, maybe the faster is to have the results. So this might have been overestimation, but it depends with how quickly the study will accrue patients. It's a very exciting study and definitely, I encourage patients to discuss this and the SWOG 1806 with their providers. Dr. Gilligan: Thank you very much. We're going to move on now, and Dr. Agarwal will tell us about the KEYNOTE-991 study. Dr. Agarwal, who is this study designed for? Dr. Agarwal: This is a study which is designed for patients with newly diagnosed metastatic castration-sensitive prostate cancer. In simple words, this is for those patients who have been diagnosed to have a prostate cancer which has gone to different parts of the body. Dr. Gilligan: And what's the current standard of care for these patients if they don't go on the study? Dr. Agarwal: Fortunately, the current standard of care has gone through a paradigm shift in the last 5 to 6 years. It started with chemotherapy with docetaxel being approved for these patients in 2014 with 2 positive clinical trials showing benefit for docetaxel chemotherapy as far as improvement of survival is concerned. After that, 3 more drugs known as novel androgen axis inhibitors, so deeper blockade of androgen pathway, which is a driver behind prostate cancer progression. So these 3 drugs, abiraterone, or also known as Zytiga, enzalutamide, also known as Xtandi, and apalutamide, also known as Erleada. These 3 drugs and chemotherapy are currently approved agents for our patients with newly diagnosed metastatic prostate cancer. Dr. Gilligan: And what is this study looking at to potentially change that or to add another option? Dr. Agarwal: So this study is using the backbone of androgen deprivation therapy, which is standard testosterone suppression therapy, plus enzalutamide or Xtandi. And then patients who are receiving the standard of care therapy with standard testosterone suppression therapy, plus enzalutamide, they will be randomized to pembrolizumab versus placebo. Pembrolizumab is an approved immunotherapy for multiple cancer types and pembrolizumab, also known as Keytruda, works by activating our immune system to fight against cancer cells. In a way, this study is actually testing whether addition of this novel immunotherapy pembrolizumab to existing regimen of androgen deprivation therapy plus enzalutamide is going to improve survival outcomes. Dr. Gilligan: What do we know about immunotherapy and prostate cancer? Dr. Agarwal: So far, immunotherapy, as we call them, immune checkpoint inhibitors, many of them are approved for multiple cancer types. They have not been successful as single agents in the context of advanced prostate cancer. So this is a trial which is testing whether immunotherapy, the pembrolizumab is going to be effective in combination with enzalutamide and testosterone suppression therapy. Dr. Gilligan: So patients will get the standard of care therapy either way. And then the question is, does adding immunotherapy make it even more effective than it is without it? Is that correct? Dr. Agarwal: That's true. The primary end points of the trial are overall survival and radiographic progression-free survival, which basically means the investigators are going to look for improved survival, overall survival, and delaying of disease progression by adding pembrolizumab. Dr. Gilligan: And we've already discussed the risks of immunotherapy on the previous 2 trials, but can you tell us again for patients who are particularly interested in this study what risks should they be aware of? Dr. Agarwal: So pembrolizumab belongs to a class of drugs known as PD-1 or programmed death 1 receptor inhibitor. Usually, this class of drug, as a class, these are highly well-tolerated drugs and only a small number of patients, I would say less than 5% of patients, would develop grade 3 or 4 side effects which will require treatment with corticosteroids like prednisone. And those side effects usually happen when these immune checkpoint inhibitors are able to activate the immune system beyond desired limits. And when the immune system is activated to very high levels, the immune system can attack our own body and can result in diarrhea, skin rashes, liver enzyme abnormalities, and if not controlled in time can lead to hepatitis, which is inflammation of the liver, inflammation of the lungs causing pneumonitis or cough, dry cough mostly. So these are the common grade 3, 4 side effects which happen in up to 5% of patients with pembrolizumab.   Dr. Gilligan: Just for our listeners in case they're not familiar, when you talk about grades 3 and 4 toxicities, what should they understand that to mean? Dr. Agarwal: In simple words, I would say grade 1 and 2 side effects are the ones which do not require any systemic therapy with steroids. Patients can go on with their daily activities without much problems. And mostly, these are controlled with medications which are over-the-counter. Even if we use prescription medicines, they're usually not able to affect the patient's overall lifestyle or quality of life. So these are the side effects which are pretty easily manageable mostly with over-the-counter drugs, symptomatic drugs, and patients lifestyle and quality of life are usually not affected by the side effects. And grade 3 and 4 side effects are those which require intensive therapy, in this context, with prednisone or corticosteroids sometimes requiring hospitalization and requiring multidisciplinary care with other specialists who are specializing in gastroenterology or pulmonology or on many other specialties. So that's how I would like to simplify the definition of grade 1, 2 versus grade 3, 4 side effects. Dr. Gilligan: That's great. Thank you very much. Is the trial still open for accrual? Can patients still go on it? Dr. Agarwal: Yes. Yes. Trial actually just opened for accrual, which is good news for our patients. And I would like to highlight that patients who have been diagnosed with newly diagnosed metastatic prostate cancer and they have started hormonal therapy like androgen suppression therapy, they still have 3 months to enroll in the trial. So if you have been diagnosed with metastatic prostate cancer and if you have started the treatment with testosterone blockade therapy, you can still go on the trial. You have 3 months to go on this clinical trial. And if you have started chemotherapy with docetaxel, which is a standard of care for our patients with this diagnosis, you can still go on the trial after receiving up to 6 cycles of chemotherapy with docetaxel. So this trial allows actually patients to go on the trial for up to 3 to 6 months after being diagnosed with metastatic prostate cancer. Dr. Gilligan: So that's very helpful to know. At the conclusion of chemotherapy, they would then start the enzalutamide and either the pembrolizumab or placebo? Dr. Agarwal: That's correct. Dr. Gilligan: Well, great. And when do we expect to see results from the study? Dr. Agarwal: So as we know this, which is great news for our patients, survival has gone up by almost 2 to 3 fourths over the last 10, 15 years, and in this disease setting, any trial takes up to 5 to 6 years to show results. So I estimate based on the available information on the ClinicalTrials.Gov website, the trial is scheduled to finish in 2026. Dr. Gilligan: I see. Well, great. So thank you very much. Thank you all 3. That's hopefully a helpful summary of these 3 important new trials. Dr. Agarwal: Yes, it's a pleasure to be here, Tim. Dr. Grivas: Thank you so much. Dr. Gilligan: Thank you. Thank you for listening to this podcast. There are many different clinical trials currently enrolling people with genitourinary cancers. If you're wondering whether participating in a clinical trial might be right for you, please talk to your health care team. ASCO: Thank you, Drs. Gilligan, Zhang, Grivas, and Agarwal. Visit www.cancer.net/clinicaltrials to learn more about participating in clinical trials. All treatments have side effects—please talk to your health care team about possible side effects to watch out for. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.