Clinical Trials in Genitourinary Cancers: TALAPRO-2, KEYNOTE-905, COSMIC-313

July 9, 2020
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In today’s podcast, Dr. Timothy Gilligan, Dr. Sumanta (Monty) Pal, Dr. Petros Grivas, and Dr. Tian Zhang discuss 3 clinical trials that are exploring new treatment options across prostate, bladder, and kidney 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 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. Timothy Gilligan, Dr. Sumanta (Monty) Pal, Dr. Petros Grivas, and Dr. Tian Zhang.

Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig Cancer Center. He has no relevant relationships to disclose.

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 Astellas Pharma, Exelixis, and Pfizer.

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 Exelixis, Merck, and Pfizer.

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 Exelixis, Merck, and Pfizer.

View full disclosures for Dr. Gilligan, Dr. Pal, Dr. Grivas, and Dr. Zhang at Cancer.Net.

Dr. Gilligan: Hi. I'm Dr. Timothy Gilligan from the Cleveland Clinic. I'm joined today by Dr. Monty Pal from the City of Hope Cancer Center, Dr. Petros Grivas from the Fred Hutchinson Cancer Research Center and University of Washington, and Dr. Tian Zhang from Duke Cancer Institute. Today, we're going to discuss three ongoing clinical trials in prostate, bladder, and kidney cancer. As you may know, clinical trials are the main way the doctors are able to find better treatment for cancer and other diseases. Patient participation is vital for clinical trials. By participating in a clinical trial, you can directly help researchers develop better treatment, reduce side effects, or even reduce the risk of cancer all together. The three trials we'll discuss today were chosen by members of the Cancer.Net Editorial Board Genitourinary Cancers Panel from the trials and progress abstracts that were presented at ASCO's 2020 Genitourinary Cancers Symposium. 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 visit the show notes for this episode on Cancer.Net.

So to get started, the first study we'll discuss is the TALAPRO-2 trial for prostate cancer, [Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC (TALAPRO-2)] and Dr. Pal is going to discuss this. So if we could get started, just to begin with, who is the study designed for?

Dr. Pal: Thanks a lot, Dr. Gilligan. Well, this study addresses a unique disease population. It's patients with prostate cancer that's metastatic, and that implies that the cancer has migrated out of the prostate to other organs. But beyond that, it also implies that these patients have also developed some resistance to first line hormone treatment. So patients in this study [have] so-called hormone resistant or castration resistant [prostate cancer].

Dr. Gilligan: So if a patient was in this situation, and they weren't going on this trial, what would be the standard treatment for them at this time?

Dr. Pal: There are several options for these patients. Hormone therapies like abiraterone and enzalutamide could be considered. Chemotherapy is also a consideration.

Dr. Gilligan: And can you say a little bit more about what the patients would receive if they went on it? The subjects of the study, what they'll get?

Dr. Pal: Some patients with prostate cancer may have [a deficiency in their cancer’s ability to repair damage to DNA]. This is something that we've seen in other tumor types, breast cancer perhaps being the most notable example. Pancreatic cancer being another one. In this particular trial, [the researchers] try to exploit that by using a class of drugs called PARP inhibitors. In this case, a drug called talazoparib. So patients in this study receive a standard hormone therapy called enzalutamide. And they receive that with or without this drug, talazoparib.

Dr. Gilligan: So they will get either-- what you described before is the standard of care—hormonal therapy, or that combined with this new drug.

Dr. Pal: That's exactly right, Dr. Gilligan.

Dr. Gilligan: I wanted to make that clear because this is a trial that has placebo, and sometimes research [participants] have concern about, "Do I want to be on a trial that has a placebo?" Do you want to say anything about that?

Dr. Pal: It's very important to bear in mind that every patient that enrolls in this study is going to get the standard treatment in this setting. As I've mentioned before, enzalutamide represents one of those options. And, of course, in this trial above and beyond that, they have the possibility of getting talazoparib or a placebo. So certainly patients won't be receiving placebo alone in this trial.

Dr. Gilligan: Do you want to say anything more about what's kind of interesting about this new approach to treating prostate cancer?

Dr. Pal: What I think is quite inventive about this study is that talazoparib, the PARP inhibitor, is being combined with hormone therapy. And I think that's the real difference in what this protocol offers versus the treatment strategies that now represent a standard option for patients.

Dr. Gilligan: Right. And my understanding is that the hope is that by using this combination, we'll be able to make treatment more effective.

Dr. Pal: Absolutely. When we talk about PARP inhibitors and prostate cancer currently, we're typically restricting it to patients who have these so-called DNA damage repair mutations. And that's certainly a finite group of individuals. In this particular trial, we're actually going to look not just at those patients, but all patients within this disease state. So we go beyond the 25 to 30 percent of patients who are estimated to have alterations in DNA damage repair.

Dr. Gilligan: Right. I think that's an important point: to get on this trial, patients don't have to have a particular genetic profile. So how will success be evaluated? How will we know if it's working?

Dr. Pal: In this case, we're going to be looking at the delay in cancer growth as the primary outcome measure. We're certainly hoping that the combination of enzalutamide with talazoparib is going to slow growth relative to enzalutamide plus placebo. The innovative endpoint that's explored in this study is also diving deeper and looking at those patients who have these DNA damage repair mutations that's going to also reflect one of the primary outcome measures in this study. And that's something quite important to bear in mind.

Dr. Gilligan: So we have some experience with PARP inhibitors. Can you say something about what we know about the side effects?

Dr. Pal: Fatigue is a relatively common side effect. Decreases in blood counts is another potential side effect. And in particular in my clinical experience, I've seen drops in the white blood cell counts. That of course makes patients more susceptible to infection. Diarrhea may also be one of the consequences within this class of drugs. And certainly, I would refer patients to a more comprehensive discussion of these side effects with their clinicians before entering into the study.

Dr. Gilligan: Is the trial still accruing patients? And do we know when we might expect results?

Dr. Pal: I think that there are many trials within this particular space. This one is ambitious in that it hopes to accrue over a thousand patients. I don't have a good finger on the pulse of when results will report. But I'm sure that'll be the subject of future podcasts for us. 

Dr. Gilligan: Well, thank you very much Dr. Pal. It's a very exciting study and exciting new area of research in prostate cancer.

Dr. Pal: Definitely.

Dr. Gilligan: We're going to move on now to the second study we want to talk about, which is the KEYNOTE-905 study. [Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Cisplatin-ineligible Participants With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303)] And Dr. Grivas is going to talk to us about that. Can you orient us, Dr. Grivas, to what this study is, for which group of patients, and what it's looking at?

Dr. Grivas: This clinical trial is applicable to patients with localized, meaning not spread, bladder cancer. And when the bladder cancer has invaded the muscle layer of the bladder, we call this muscle invasive bladder cancer. And these patients usually go for cystectomy, the removal of the bladder. And ideally, they get chemotherapy before, but some patients may not be fit enough for chemotherapy. So those patients go straight to cystectomy, the removal of the bladder. So this clinical trial is trying to evaluate whether immunotherapy with this drug, called pembrolizumab, helps these patients before they get the cystectomy.

Dr. Gilligan: Can you tell us a little bit more about pembrolizumab and what we know about it? Where it's used currently in bladder cancer?

Dr. Grivas: Pembrolizumab has three different indications for patients with bladder cancer. The first one is in an earlier stage, what we call non-muscle invasive bladder cancer, which is a very superficial cancer, when the cancer is not invading through the muscle layer. And there's a specific indication for those patients who get therapy with BCG, which is a form of immunotherapy given inside the bladder. And if the cancer is not responding well to this BCG, usually, they go for removal of the bladder. But some of them may not be able to do that or do not want that. And pembrolizumab has a track record in those specific scenarios of BCG-unresponsive tumors as we call them for those patients who cannot get cystectomy or don't want to have it.

The other two indications are for patients who have metastatic, [meaning bladder cancer that has spread to other organs.] And there are two specific indications of pembrolizumab immunotherapy in that particular setting. So this trial is trying to expand upon the role of pembrolizumab in bladder cancer.

Dr. Gilligan: So it's been shown to be a benefit when the disease is more advanced and now we want to see if it's helpful earlier on in the period of time around surgery.

Dr. Grivas: Right. And it's interesting in a particular setting we're looking at this trial, because we have indications literally before and after in an earlier states, the non-muscle invasive disease setting. And also as you mentioned, Dr. Gilligan, in the more advanced setting. So we're trying now to see whether this middle setting of muscle invasive bladder cancer, whether there's a role of pembrolizumab by itself before removing the bladder.

Dr. Gilligan: Are patients who are eligible to get chemotherapy prior to cystectomy able to go on this trial or is it only for patients who are not [well enough] to get chemotherapy?

Dr. Grivas: This is for patients who are not in good condition to undergo chemotherapy. So if someone is in good condition to undergo chemotherapy, then the trial does not apply to them. This is only in those who cannot safely receive chemotherapy before the cystectomy.

Dr. Gilligan: Thank you for clarifying that. What data do we have that makes us think that it may be a good idea to give immunotherapy prior to cystectomy? Because this has been looked at a little bit already, and I think it's why this trial is being done. Can you say a little bit about that?

Dr. Grivas: Sure. I would like to underline that as you alluded before, the standard of care therapy for patients who undergo cystectomy, the removal of the bladder, is to undergo chemotherapy with a drug called cisplatin before cystectomy. But as we discussed before, this is the standard of care with a high evidence. However, many patients, maybe 50, maybe 55 percent of patients may not have enough condition to undergo this chemotherapy safely. And that is the population we would try to capture. And to answer your question, there have been so far, four clinical trials looking at immunotherapy before cystectomy. And all of those four clinical trials look very promising in that regard.

So based on this promising information, this new trial the KEYNOTE-905 is a phase III trial trying to confirm the promising data from the previous phase II trials and help us make a final decision whether this should be the standard of care or not in patients who cannot undergo safely chemotherapy in that setting.

Dr. Gilligan: What are the known side effects and risks of immunotherapy?

Dr. Grivas: Immunotherapy overall is much better tolerated than chemotherapy. However, it can still cause significant side effects, especially in a small proportion of patients. So the main thing we need to keep an eye on is if the immune system gets too overstimulated, it can cause what we call immunotherapy-related adverse events or side effects. And any organ of the body could in theory be attacked by an overstimulated, overactive, immune system. So they are different forms of “-itis.” For example, if you have inflammation in the lungs, it's pneumonitis. In the liver, hepatitis. So we have to be careful and educate our patients, educate our medical providers and the teams, follow the patients and then report any new symptoms for changes in order to be able to recognize early and manage properly these side effects.

As I mentioned, it's not common to have a severe reaction, but it can happen. So education helps, and I recommend to the patients to discuss with a medical provider the potential of those immunotherapy-related adverse events that usually, if they occur, can be managed with proper treatment to try to suppress, “cool down,” the immune system. So education is important.

Dr. Gilligan: So just to summarize then, this is a trial for patients who would normally be treated with surgery alone, and we're looking at whether adding immunotherapy before and after surgery can improve those outcomes.

Dr. Grivas: That's exactly right. Especially for those patients who cannot safely undergo chemotherapy before the surgery.

Dr. Gilligan: And how are we going to measure whether it's successful? Whether that immunotherapy has improved outcomes or not?

Dr. Grivas: The two measures that we're are looking at in this particular trial are the following. Number one, we tried to see how many patients--what is the proportion of patients from everybody who gets in the trial—who has no residual cancer cells at the time of the removal of the bladder, at the cystectomy. When the pathologist looks at the cystectomy sample in the lab after the bladder is removed from the body, what is the proportion of patients with no cancer inside the bladder after the immunotherapy compared to no immunotherapy at all? So we're going to compare these. We call this “complete response,” meaning no cancer is found in the bladder after its been removed, after the immunotherapy. And we're going to compare this complete response in the two groups.

The other metric we use is to see how many patients have no recurrence regardless, meaning the cancer came back after the treatment. After the cystectomy, how many of those patients either had the cancer come back later or died from another cause. So we use these metrics and we compare the two metrics in the two populations in the trial with and without immunotherapy before the surgery.

Dr. Gilligan: And currently, the relapse rate's roughly 50 percent, so we're hoping for a lower number than that.

Dr. Grivas: Correct. We try to look for a lower number, and we try to see to compare these two populations with and without immunotherapy and see if immunotherapy adds value in that particular setting.

Dr. Gilligan: Is this trial still open and do you know when we might see results from it?

Dr. Grivas: The trial is open. It started recently, so I will strongly encourage the patients to discuss with their providers and look at particular locations where this trial is open. So definitely, there is room to go. And I think the trial will take a few years to complete and then report the results. So definitely an ongoing trial options for the patients.

Dr. Gilligan: Great. Well, thank you very much. So an exciting trial for patients with localized bladder cancer going through surgery to see if we can improve outcomes, increase the cure rate, by adding this interesting new immunotherapy. Thank you, Dr. Grivas.

Dr. Grivas: Thank you so much.

Dr. Gilligan: So now we're going to move on and talk about the COSMIC-313 trial with Dr. Zhang from the Duke Cancer Institute. [Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (COSMIC-313)] Can you tell us who this trial is designed for, or which group of patients?

Dr. Zhang: Absolutely. We know that for patients with kidney cancer with a clear cell component and intermediate or poor risk by IMDC criteria, that both immunotherapy combinations with ipilimumab and nivolumab as well as the targeted therapy blocking blood vessel formation, called cabozantinib, have both demonstrated significant benefit for these patients. And these are approved treatments. So this particular trial is attempting to combine these starting as a triplet of ipilimumab, nivolumab, cabozantinib for four cycles and then maintenance nivolumab with cabozantinib. And this triplet treatment is compared to a placebo-controlled regimen of the same immunotherapies without the targeted therapy.

Dr. Gilligan: So if a patient weren't going to go on this trial, what's the current standard of care?

Dr. Zhang: Both the immunotherapy combination as well as having the cabozantinib by itself, are our standard of care therapies for these patients in these categories.

Dr. Gilligan: Is this restricted to any particular group of kidney cancer patients?

Dr. Zhang: These patients must have at least one of the IMDC criterion. So these are markers of inflammation, like high neutrophil count, low hemoglobin, or high platelet levels, high calcium levels, as well as poor performance status in less than one year from diagnosis to needing these type of treatments. Patients have to have kidney cancer that spread to other sites of their body or locally advanced disease which is not surgically resectable. And as a note, other treatments that are approved in patients who have intermediate poor risk disease include combinations of immunotherapies with targeted therapies like pembrolizumab with axitinib or avelumab with axitinib.

Dr. Gilligan: So then just to be clear, these are drugs that are already being used, have already been shown to work, and we're trying to see if we combine them do we get a better result than using them by themselves.

Dr. Zhang: That's right. And I think that's a main point. If two agents work on their own, can they be combined to work better? It is important to note that we must follow these patients for their side effects to make sure that the benefit of the triplet therapy would be worth the potential added toxicity of this combination.

Dr. Gilligan: So as you mentioned, there's already a standard treatment that includes targeted therapies, immunotherapies, axitinib and pembrolizumab. What do you think is the interesting or different about the approach in this study?

Dr. Zhang: The main difference of this triplet combination is the addition of ipilimumab which is a CTLA 4 inhibitor. This is even a bit of a stronger immunotherapy, which targets the dendritic cell interaction with cells to activate the immune cells even more. And so we know that ipilimumab in kidney cancer does drive increase the ability for us to achieve a complete response, meaning that this combination is a really active immunotherapy combination for metastatic kidney cancer. So if we can add the ipilimumab effect with a very strong targeted effect of the cabozantinib the thought is that this triplet might be even more effective than the current standard of care, pembrolizumab-axitinib or avelumab-axitinib combinations.

Dr. Gilligan: Thank you for clarifying that. Just to make sure our listeners are clear on this. They're two doublets that are already approved—two kinds of immunotherapy or immunotherapy combined with targeted therapy. This will be the first triplet, if I understand correctly, that if this is shown to be more effective, it would be the first triplet therapy where we're using three different agents, our strongest immunotherapy combined with targeted therapy. Is that a fair summary?

Dr. Zhang: Absolutely. I think that's a great summary.

Dr. Gilligan: So how will success be evaluated? What are the endpoints for this?

Dr. Zhang: Success for this particular study will be evaluated by improving time until tumor growth and the safety of the triplet combination so the primary outcome of this particular study is improving progression free survival. But one of the key secondary endpoints, of course, is to make sure that the benefit of this triplet is worth the potential combined side effects. And then also to follow patients and see if it also improves survival to make patients live longer.

Dr. Gilligan: Do we have any sense of how long it'll be before we see outcomes from this? Or results?

Dr. Zhang: This is an ongoing international trial enrolling in the US but also spanning Europe, Asia, South America, Australia, and New Zealand sites. It will enroll up to 676 patients, and it's open currently. And patients should discuss it with their oncologist and see if it's open in a site close to them.

Dr. Gilligan: Dr. Grivas earlier told us about some of the side effects or risks with immunotherapy. This is combining immunotherapy with targeted therapy. Can you say a little bit about what we're gonna be watching for in terms of side effects or what we might expect?

Dr. Zhang: Sure. I think all of the immunotherapy side effects that Dr. Grivas told us about pertain to this study as well. The rashes, the diarrhea, inflammation of the lungs or liver, and affected endocrine dysfunction. But the targeted therapies can also have high blood pressure, rashes on the hand and feet, so called hand foot syndrome, also diarrhea, and elevation of liver enzymes, as well as the loss of protein in the urine. I think the one overlapping toxicity of cabozantinib with a combination of ipilimumab and nivolumab, the immunotherapy combination, is the diarrhea. So patients who start on this trial should be careful to report any diarrhea early on so that their oncologist and their investigators on the study can get an early handle and manage their diarrhea well.

Dr. Gilligan: Thank you. That's very helpful. One last question, I want to get back to that issue of eligibility. Sometimes when cancer patients want to go on a trial and they find that they are told they're not eligible to go on, this trial looking at intermediate risk patients specifically so a good risk patient might want to go on it and couldn't. Can you say a little bit about how those decisions are made and what the rationale for selecting groups of patients for trials is?

Dr. Zhang: Sure. We know that the IMDC criteria were really made in the setting of targeted therapies, and they were a set of prognostic markers and markers of inflammation, for example, and of time from initial diagnosis to treatment. But now they've been used often as stratification markers in our treatment trials and as selection now for eligibility. In particular for this patient population, ipilimumab, nivolumab seem to have more benefit in this intermediate and poor risk population. And so that's why, for this particular study, they're selecting specifically those patients with intermediate poor-risk disease.

Dr. Gilligan: So we want to focus on the patients who are most likely to benefit, it sounds like you're saying.

Dr. Zhang: That's right. So the favorable risk patient population do have a better prognosis in general, but those patients may not have as much benefit from the immunotherapy doublet.

Dr. Gilligan: All right. Thank you. Well, that brings us to the end of this podcast. Thanks for listening. 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. This is Timothy Gilligan. Thank you very much.

ASCO: Thank you, Drs. Gilligan, Pal, Grivas, and Zhang.

Visit 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.

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