Clinical Trials in Genitourinary Cancers: VISION, INTACT, and PROSPER

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 prostate, bladder, and kidney cancer. This podcast will be led by Dr. Sumanta (Monty) Pal, Dr. Neeraj Agarwal, Dr. Petros Grivas, and Dr. Tian Zhang. Dr. Pal is co-director of City of Hope's Kidney Cancer Program and is the head of the kidney and bladder cancer disease team at the institution. He has served in a consulting or advisory role for Novartis, Genentech Roche, and Bristol-Myers Squibb. 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 Novartis and Bristol-Myers Squibb. 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 Genentech Roche and Bristol-Myers Squibb. Dr. Zhang is an assistant 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 Genentech Roche and Bristol-Myers Squibb. View full disclosures for Dr. Pal, Dr. Agarwal, Dr. Grivas, and Dr. Zhang at Cancer.Net. Dr. Pal: Hi, I'm Monty Pal from City of Hope. I'm the Associate Editor for Genitourinary Cancers for Cancer.Net, ASCO's patient education website.  I'm really excited to be here with my colleagues: Dr. Petros Grivas, Dr. Neeraj Agarwal, and Dr. Tian Zhang. We're really excited about this effort. We're hoping it brings some salient details about clinical trials straight to you, our most important audience. Keep in mind that clinical trials are the main way that doctors are able to find better treatments for diseases like cancer. And before any new drug can be approved by the FDA, it must be studied in the context of a clinical trial. Patient participation is vital for clinical trials. By participating in a clinical trial, you can directly help researchers develop better treatments, reduce side effects, or even reduce the risk of cancer altogether. While you may receive new treatments within a clinical trial, the primary purpose of these studies is to move the field of cancer research forward. Keeping participants safe is probably the most important concern in clinical trials, and there may be some risks involved. Because of that, your healthcare team is going to discuss with you in detail these risks before you join on to a clinical study. Now, at this point in time, we're going to discuss 3 studies that are being done in the area of kidney, bladder, and prostate cancer. These studies were chosen by members of the Cancer.Net Editorial Board Genitourinary Cancers panel from the Trials in Progress abstracts that are going to be presented at ASCO's 2020 Genitourinary Cancers Symposium. I'd like to note that none of us have any direct involvement with any of these trials. Each one of us will post our disclosures on the ASCO website if you'd like to see them. We'll certainly have them posted on the Cancer.Net website. I'd like to begin by introducing my very esteemed panel.  First, is Dr. Tian Zhang, who's an expert in kidney, bladder, and prostate cancer from Duke Cancer Research Institute. We have Dr. Neeraj Agarwal, who heads up the Genitourinary Cancers Program at the Huntsman Cancer Institute at the University of Utah. And last, but not least, we have Dr. Petros Grivas from the Fred Hutchinson Cancer Research Institute in Seattle, Washington, an expert in many disease types, including bladder cancer. I'd like to bring on my first guest, Dr. Neeraj Agarwal, to discuss the VISION study. [VISION: An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-positive Metastatic Castration-resistant Prostate Cancer (mCRPC)] Neeraj, this is a study in prostate cancer. What particular patient population within prostate cancer are we focused on here with this study? Dr. Agarwal: So this is a patient population with advanced prostate cancer where prostate cancer has gone beyond prostate to different parts of the body. In technical terms, we call it metastatic prostate cancer. The usual treatment paradigm for these patients is to be treated with hormonal blockade therapies, which can include injections and oral pills, which have different mechanisms to prevent stimulation of testosterone to the prostate cancer cells. However, every patient with metastatic prostate cancer eventually are failed by these treatment options, and the next commonly used treatment option is chemotherapy, which usually controls the disease for a period of many months, up to one year. And after, patient's disease progresses on these 2 different therapeutic options, which include hormonal therapies and chemotherapies. And this is the patient population in which this novel type of radiation therapy or radiation particle treatment is being tested. Dr. Pal: Tell us about what question this study aims to answer. Dr. Agarwal: This study is testing a novel medication, which is a type of a radiation particle, which is supposed to target prostate cancer cells. So whether using this kind of radiation particle in patients with advanced prostate cancer, who have been failed by previous chemotherapy and novel, hormonal therapies. The study is asking whether using this radiation particle as a treatment may improve overall survival. Dr. Pal: Now, this compound is called 177Lutetium-PSMA-617. It's a long name. Tell us about what it actually does. What's the rationale for using this particular drug? Dr. Agarwal: I would like to divide this long name into 2 parts to make it simple. So 1 is the lutetium particle, which is the radiation particle, is a type of radiation known as beta radiation. So lutetium is tagged onto a PSMA-identifying agent known as PSMA-617. So if we just inject PSMA-617, it will go and seek prostate cancer cells, which are expressing PSMA on their surface. If you tag this radiation particle lutetium to the PSMA-617, what essentially happens is that PSMA-617 takes this radiation particle directly to the prostate cancer cells. Dr. Pal: Now, what is this study attempting to demonstrate? Dr. Agarwal: This study is specifically looking at 1 question, which is whether using this radiation particle can improve survival in patients with metastatic prostate cancer who have had disease progression on novel hormonal therapies and chemotherapies. Dr. Pal: And again, it's hard to be comprehensive in a podcast like this, so of course, we refer patients to their physicians for a discussion around safety of these drugs. But could you tell us about any known risks that patients should be aware of in the context of this agent? Dr. Agarwal: Yes. So as you can imagine, this PSMA-617, which is loaded with this radiation particle, is looking for those cells in our body which are expressing PSMA. So of course, the PSMA is expressed highly by prostate cancer cells. But there are also normal cells which express PSMA to a lesser degree. And those cells may also have the potential to be targeted by this radiation particle. So technically, their other cells which may express PSMA, or which are in the vicinity of these cancer cells in the bone, such as bone marrow, these can be targeted to a much lesser degree because of the specificity of this compound. We can see some off-target toxicities, as we call them, but given the highly targeted nature of this compound, those toxicities are usually very well tolerated, except in rare circumstances. Dr. Pal: Excellent, Neeraj. Now, for a little additional commentary on the VISION trial, I'm going to throw it to Dr. Tian Zhang, again, an expert at the Duke Cancer Research Institute Tian, you've had some experience enrolling patients on VISION, correct? Dr. Zhang: That's right, Monty. Thanks so much for having me on. And VISION has actually completed accrual. It was open for a few months here at Duke. We were able to enroll about 10 patients and we're really looking forward to seeing the results of VISION over the next year or 2. And I think it'll be quite applicable to clinical practice. Now, I want to mention that although VISION has completed enrollment, there are other clinical trials that are using PSMA-targeted Lutetium-617 agent as a possibility for other patients to enroll on to other trials in clinical development as we speak, and so there will be other opportunities to receive this agent. Dr. Pal: We're going to shift gears now from prostate cancer and move on to the topic of bladder cancer. And again, I'm thrilled to have Dr. Petros Grivas from the Fred Hutch Cancer Research Institute to discuss a very important trial called INTACT. [Phase III Randomized Trial of Concurrent Chemoradiotherapy With or Without Atezolizumab in Localized Muscle Invasive Bladder Cancer (Study SWOG/NRG 1806)] Petros, the study INTACT really addresses a very important question. Can you tell us a little bit more about it? Dr. Grivas: Thank you, Monty. I think this trial is very important for a number of reasons. Number 1 is trying to address an important clinical question, which is the following: Patients who we consider candidates for bladder-preservation approach, meaning, we try to keep the bladder in place and still kill the cancer, which is not a good option for everybody with bladder cancer. But the proportion of patients after discussions of pros and cons with their providers could be offered this bladder-preservation approach, which is consisted of an optimal resection of the tumor through a procedure called transrectal bladder tumor resection, which means try to remove the bladder tumor through a procedure that is similar to cystoscopy, when you look inside the bladder. And after this tumor is removed, then there is a combination of chemotherapy and radiation, at the same time—we call this concurrent or concomitant—at the same time, chemotherapy and radiation. This approach, which involves the collaboration between the urologic oncologist, medical oncologist, and radiation oncologist, is the standard of care, the standard approach, how we try to preserve the bladder and still kill the cancer in those patients who are considered good candidates for this approach, which, as I've mentioned, is not for everybody. The clinical question is can we improve upon this backbone of chemotherapy and radiation, which is current standard of care, by using a third modality, a third type of treatment, which is immunotherapy? And immunotherapy is known to improve how people live in patients who have metastatic bladder cancer. For example, there's this particular drug called atezolizumab, which is already having FDA approval for patients with metastatic bladder cancer. The question is can we add this drug, the immunotherapy drug, that is activating the immune system, into the backbone of chemotherapy and radiation and use all three approaches, chemotherapy, radiation and immunotherapy together? And if that's the case, is that triplet combination better or not to the current standard of care, which is chemotherapy and radiation? So the INTACT trial is chemotherapy, radiation, plus immunotherapy with this drug called atezolizumab, together, all 3 of them compared to chemotherapy and radiation alone, in order to see whether we can improve upon the results we're getting with chemotherapy and radiation. The primary end point of this particular trial is what we call bladder intact disease-free survival, which means the proportion of patients who have no cancer coming back after treatment. They have what we call a complete response, remission of the cancer, and they still have the bladder intact, in place. And this is what we call a metric of success. This is a huge effort among different investigators across the country. These studies open in multiple cancer centers and sites across the nation. And I think it's a very good example of what can happen in terms of a clinical trial design that is applicable to many patients when different collaborations take place and when people put their minds together. So we're really very enthusiastic about this study, and we'll try to support the accrual and offer this option to the patients who are considered to be good candidates for this attempt for bladder preservation. Dr. Pal: Petros, thanks. That was a great overview of the study. You've really highlighted the rationale and some detail and the metrics for success of this trial. Now, on the subject of this approach, are there any risks that you think patients should be particularly aware of? And again, we leave it to the discretion of treating physicians to have that very thorough discussion of risks and benefits. But off the top of your head what would you counsel patients, in general? Dr. Grivas: I think, Monty, that's a great question, in general, because when a patient is undergoing evaluation for a clinical trial, it's important for them to understand thoroughly the pros and cons of this particular therapy and other procedures and what those mean for the patient's logistical, day-to-day schedules, as well as potential short-term and long-term side effects. In that particular study, I think the important take-home message is we're trying to evaluate the additional role of immunotherapy to the backbone of chemotherapy and radiation. So potential side effects of immunotherapy are something that are very important to be discussed with the patient. Some of the patients may develop fatigue or some degree of occurrence of what we call immune-related adverse events, which means the immune system gets activated, stimulated against the cancer but can, potentially, in a small proportion of patients generate a significant reaction, an immune system activated related reaction against different parts of the body or some parts of the body. So I think it's very important for the patients to discuss carefully with the providers what are those uncommon, but sometimes significant, immune-related adverse events, and have a very good understanding of what symptoms [to] look for in order to be able to communicate or recognize early those potential side effects and have a proper management plan. Because most of those side effects could be managed properly, and with good success, especially if they're caught up early. So I think it's important to have these thorough discussions with the provider. And of course, the side effects of chemotherapy and radiation should be discussed in thorough detail. This is the standard of care, but still is important to delineate what potential side effects can happen. At the end of the day, it's in the balanced discussion about pros and cons. This is a very exciting trial, but I think good education for the patient and their families and their caregivers are very important and critical for the successful detection or diagnosis of any potential side effects. Overall, I think this is a very relevant discussion to have with the provider and a very exciting trial to be involved in. Dr. Pal: Excellent, Petros. Well, great discussion of some of the risks associated with this approach. Neeraj, any thoughts on INTACT? Why should patients be excited about this particular trial? Dr. Agarwal:  I was recently talking to one of my patients about this upcoming trial, who is preparing to go on radiation therapy plus chemotherapy as a treatment option for his muscle-invasive bladder cancer, and cystectomy is not an option. And the way I explained this to the patient is 95% of the work he will have to do will be done by the time he's getting radiation therapy and chemotherapy. And after that, 5% of the work, as far as patient's effort, side effects, toxicities, impact, and quality of life, all are concerns, 95% of that, in my view, is coming from radiation therapy and chemotherapy. And after that, little work from that perspective by the patient has to be done by atezolizumab, as far as getting treatment with atezolizumab is concerned. So as Petros said, this is a highly well-tolerated treatment, which is immunotherapy. And if you look at the potential of this drug to control the recurrence of the disease and allow our patients to maintain their bladder—it’s tremendous. So I think the expected returns are very high, and how much effort patients will have to put on the trials are not as high as you would expect if you are thinking about a trial. Dr. Pal: That was an excellent discussion of toxicities associated with this particular regimen, Neeraj. Petros, before we move on any closing thoughts? Dr. Grivas: No, I agree completely with Neeraj. I think these are important points. I just wanted to add a couple of key take-home message for the patients. Number 1, this trial is available for patients who either are or are not candidates for radical cystectomy, which is the removal of the bladder and again, it has to be a discussion with the providers whether they're good candidates for the attempt for bladder preservation. Half of the patients get the standard of care, which is chemotherapy and radiation at the same time, and the other half get chemotherapy and radiation, plus this immunotherapy called atezolizumab. And again, I think the last point to make is that chemotherapy and radiation have to happen at the cancer center, and some of the patients live far away, so I think it's important to discuss with the patients the pros and cons of the trial because it might entail some back and forth transportation for them if they have to get the radiation and the chemotherapy in the cancer center that is offering the trial. But overall, as Neeraj pointed out, we are very enthusiastic, and I'm personally enthusiastic about the study. Dr. Pal: That's great Petros, appreciate that. Now, in the final portion of our program, we're going to shift gears and talk about the type of cancer that I actually focus on personally in the clinic, and that is kidney cancer. And we have our resident expert in kidney cancer on the Cancer.Net panel, Dr. Tian Zhang from Duke here to discuss the PROSPER study, a very important national effort. [A Phase 3 Randomized Study Comparing Perioperative Nivolumab vs. Observation in Patients With Renal Cell Carcinoma Undergoing Nephrectomy (PROSPER RCC)] Tian, can you tell us about PROSPER? Dr. Zhang: PROSPER is a phase III trial that's open currently for patients who have locally advanced kidney cancer, and we know that in this population of patients who have locally advanced kidney cancer who undergo their surgery, there's still a high rate of recurrence up to about 50% with many dying, unfortunately, from disease recurrence. And so the question that PROSPER aims to answer is can we prevent disease from recurring, and thereby, can we allow patients to live longer from giving up-front systemic therapy in addition to their surgery? And so in kidney cancer, we know that patients will benefit from immune checkpoint inhibitors, and the big question of the study is that with the primary kidney cancer in place, what is the effect of this immunotherapy called nivolumab before and after surgery compared to surgery alone, and how should we use these immunotherapy agents in the perioperative setting to improve overall survival? Dr. Pal: That's very interesting. Of course, in kidney cancer, just as we discussed with prostate cancer, you've got patients who have the disease confined to the kidney. You have patients where the disease has spread. What particular patient population does this study focus on? Dr. Zhang: This study is enrolling patients with locally advanced disease, so either clinical stage II or higher. So that's patients who have primary tumors of greater than seven centimeters, or if they have positive lymph nodes on their scan, so clinical detection of lymph node-positive cancer. Or the study, actually, also allows cancer that has spread to no more than three, so one, two, or three, other sites, which can also be definitively treated at the time of the primary surgery. Patients who have disease spread to the lung, adrenal gland, lymph nodes, pancreas, or soft tissue are allowed. Patients who have spread to the liver or bone are not allowed. And the study is currently ongoing, Monty. It is randomizing up to 805 patients total. As of late January 2020, they're currently at about 390 patients already enrolled. So there's plenty more, about 400 more patients to go on the study. And it is an open and enrolling study. Dr. Pal: That's really interesting. Now, Petros gave us some insights as to the rationale for using immunotherapy in cancer. Is it the same rationale for using this treatment strategy in kidney cancer? Dr. Zhang: Sure. So our standard of care in this setting, as you know, for locally advanced disease is truly just nephrectomy alone to remove the kidney, usually without treatment afterward. And there are multiple adjuvant studies using immunotherapies in this post-operative setting, however, those are all pending. And we're hoping that immunotherapy used earlier in the disease course will allow us to see a benefit overall. Now, nivolumab, the immunotherapy that's studied in the PROSPER trial, is approved for metastatic kidney cancer. And therefore, we know nivolumab is effective at extending overall survival for these patients. And so the question is if we can use this active immunotherapy agent earlier in the disease course if we can to try to prevent disease recurrence. Dr. Pal: That makes a lot of sense. Now, what is this particular study attempting to demonstrate? What are we trying to prove here with this trial? Dr. Zhang: Right. So the primary outcome of PROSPER is the time to disease recurrence or spread to other sites, what we call recurrence free-survival. There are secondary outcomes. So trying to get patients to live longer, overall survival, toxicity of giving nivolumab up front for these patients. As well as, specifically in patients who have clear cell kidney cancer, the time to disease recurrence for those patients, as well. So there are patients who are on the control cohort of surgery alone, and we'll be able to study that tissue in conjunction and compare those with patients who have received immunotherapy or nivolumab prior to their surgeries. So they have a number of biomarkers planned for the tissue that's being collected from the study. Dr. Pal: Very interesting. Well, I can't wait to see the results, ultimately, of this trial. But in the meantime, Petros had outline some of the risks associated with immunotherapy in the context of the study he discussed. Anything to add to that, in terms of the risks that might be entailed in this trial? Dr. Zhang: Right. So it is certainly a randomized trial, as Petros mentioned, so there are patients who are randomized to surgery alone versus patients who are randomized to the immunotherapy up front. So one dose of nivolumab followed by surgery and then maintenance treatment with nivolumab. And I fully agreed with the toxicity profile that Petros outlined very nicely. And when we get patients started on these immunotherapies treatments in clinic, I often talk about, we're activating your immune system, and therefore, toxicities can occur where the immune system is very active. So on the skin it can cause a rash, in the GI tract it can cause diarrhea or colitis, in a very small proportion of patients it can cause inflammation in the lungs or liver, and then, finally, it can affect their endocrine organs: the pituitary, thyroid, adrenal glands, and pancreas. And one more note about treatment with these immune checkpoint inhibitors of nivolumab, and other agents like nivolumab, is that these are really not for patients who have active autoimmune disease. We think that those patients who have active autoimmune disease requiring prednisone or other disease-modifying agents, those patients are probably going to have worsening of their baseline autoimmune disorder. So patients who do have that need to have a very close discussion with their providers before going on any of these trials. Dr. Pal: Well, that's an excellent overview of toxicity, and again, just as I mentioned earlier, I certainly leave it in the hands of the patient and their respective clinicians to go through a very thorough discussion of toxicity, but I think that was a fantastic primer on it, Tian. Thank you for that. Before we close, I wanted to go to Petros for any additional comments on this concept of the PROSPER study. Petros, any additional thoughts? Dr. Grivas: I think that Tian did a wonderful job summarizing all the key points. I think one of the key characteristics of this trial is, again, their rationale. The reasoning behind it, which as Tian mentioned, is we have the immunotherapy up front in the beginning of the treatment while the tumor is still present and the proteins, the antigens of the tumor, are still present, and that might be relevant in the recognition of those elements by the immune system when you give the immunotherapy. And then you have surgery, and then you have continuation of postoperative treatment, as Tian mentioned, and maybe that combination approach may be relevant. We have to see, of course, but I think it's a very, very compelling design that makes sense, at least scientifically speaking. The other point, I think, is as [inaudible] already mentioned, this very [inaudible] teamwork, team effort from multiple investigators across the country. And that speaks volumes of the very nice design, as well as the collaborative in spirit, which I think is important for that patient to know, that people do work together to come up with these clinical trials. We all hope that this trial will keep accruing well and will end up with accrual target in order to answer this important question which is, as Tian mentioned, whether immunotherapy before and after surgery prolongs life and improves the times of cancer remission, which is important and clinically relevant question. And of course, it's a key point to have discussions about sometimes uncommon but significant immune-related reaction and go through the different nuances carefully with the providers when a patient's considering clinical trial. But clinical trials, as you mentioned Monty, is the way to develop new therapies and are very important part of a discussion in the routine patient care. Dr. Pal: Excellent, Petros. Well, on behalf of Dr. Petros Grivas, Dr. Neeraj Agarwal, and Dr. Tian Zhang, I really want to thank you for joining our very first podcast from Cancer.Net. There's so many different clinical trials out there enrolling patients with genitourinary cancers, and we've only had time here to discuss 3 of them. If you have interest in participating in clinical trials, please do get in touch with your healthcare team. And of course, Cancer.Net serves as an excellent resource to communicate with experts in the field and learn more about respective genitourinary types of cancer. Thank you again for joining. ASCO: Thank you, Drs. Pal, Agarwal, Grivas, and Zhang. 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. 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