Clinical Trials in Genitourinary Cancers: KEYLYNK-010, KEYNOTE-866, PDIGREE

May 5, 2020
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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.



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. Brian Shuch, Dr. Neeraj Agarwal, Dr. Petros Grivas, and Dr. Sumanta (Monty) Pal.

Dr. Shuch is the director of the Kidney Cancer Program at UCLA Health and the Alvin & Carrie Meinhardt Endowed Chair in Kidney Cancer Research at the institution. He has served in a consulting or advisory role for 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 AstraZeneca, Bristol-Myers Squibb, Exelixis, and Merck.

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 AstraZeneca, Bristol-Myers Squibb, Exelixis, and Merck.

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 Bristol-Myers Squibb and Exelixis.

View full disclosures for Dr. Shuch, Dr. Agarwal, Dr. Grivas, and Dr. Pal at Cancer.Net.

Dr. Shuch: Hi, I'm Dr. Brian Shuch from UCLA's Institute of Urologic Oncology. And I'm really thrilled to moderate today's Cancer.Net podcast on GU clinical trials. I'm joined today by Dr. Neeraj Agarwal from Utah's Huntsman Cancer Center, Dr. Petros Grivas from the University of Washington's Fred Hutch Cancer Center, and Dr. Sumanta Pal from the City of Hope Cancer Center. Thanks for being here today, and we'll jump in to discuss 3 clinical trials in the urologic cancer space, one for prostate, one for bladder, and one for kidney cancer. Let's discuss some of the goals of clinical research first, okay? Neeraj, can you let us know what is the purpose of a clinical trial, and the ultimate goal?

Dr. Agarwal: All these clinical trials aim to identify better treatments with the hope that the treatment will be safe and effective. An ultimate goal for all the clinical trials is to get approval [from the FDA for the routine use of the new treatments being tested.] I'd like to add, that the way I explain this to my patient, a clinical trial is the only way I can get cutting-edge therapy for my patients in my clinic without having to wait for many years for FDA approval of those drugs.

Dr. Shuch: Petros, it seems that patient engagement is really essential to this type of clinical research. What is the patient's role here, and what can they expect by participation in a clinical study?

Dr. Grivas: They can directly help [the research team] define better treatments and also improve existing therapies. And they can do that by either participating in clinical trials directly, and can also help us find the clinical questions. And the patient advocate groups are helping us do that by giving us input how to design clinical trials. And, of course, a number of trials that we're conducting are focusing on disease prevention or treatment of the cancer. And I think the patient's role overall is critical in every patient who's asked their provider about clinical trials.

Dr. Shuch: So Monty, for your patients, how do you ensure patients are safe when they participate on these types of trials?

Dr. Pal: Safety is our primary concern when conducting a research study. The patients are taking risks by participating, and these risks should be very clearly delineated in the context of a consent form. It's really critical that we, as investigators, perform very close monitoring in association with our patients. But we also have very intensive oversight of our clinical trials by independent monitoring committees, by the drug companies, and even the FDA. Now, trials can actually be closed early if there are safety concerns that emerge, or if drugs don't appear to be effective. Keep that in mind.

Dr. Shuch: Got it. It's reassuring that for these types of trials, there's very close monitoring. So Petros, with the potential risk that we discussed, why would a patient participate? What are the benefits here?

Dr. Grivas: Brian, this is a critical question. And I think the purpose of cancer research and clinical trials is to try to benefit the patient individually, but also to try to move the field forward, in terms of more knowledge about cancer research, also benefit the community and the society, in general.

Dr. Shuch: How does a patient identify if a clinical trial's right for them? And how can they potentially participate?

Dr. Agarwal: I think the most important role is of the physician who is seeing the patient. And the physician may alert you to a specific clinical trial that is focused on your current condition. So maybe 10 or 15 or 20 clinical trials you saw on the Huntsman Cancer Institute website, but maybe 1 or 2 are specifically needed for a patient's given situation. Also, not every center has a clinical trial for every condition.

Dr. Shuch: We’ll jump in to discuss 3 clinical trials that were chosen by members of Cancer.Net editorial board for genitourinary cancers. And they were basically chosen from the Trials in Progress abstracts that were submitted and presented at the ASCO GU 2020 Symposium. So because these are ongoing clinical trials, we may not have final results for these trials at this time. But I'd like to note that none of the members of this discussion have any direct involvement for these trials. For reference, all relevant disclosures can be found on the notes for this episode of Cancer.Net. So let's jump in. Neeraj, let's discuss the KEYLYNK-010 study. [Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339-010/KEYLYNK-010) (KEYLYNK-010)] Can you briefly summarize this study for us?

Dr. Agarwal: So this study is for patients who have progressive metastatic castrate-resistant prostate cancer, meaning the metastatic prostate cancer or advanced prostate cancer, which has already progressed on multiple previous lines of therapy, including chemotherapy and 1 of the novel hormonal therapies, which include enzalutamide and abiraterone. These are all standard therapies which are approved currently by FDA for treatment of our patients. Before I talk about this clinical trial, which includes multiple drugs, which is basically testing a combination of immunotherapy, pembrolizumab, with olaparib, which is a PARP inhibitor—and I'm going to explain those drugs in a moment—and comparing these drugs with other drugs, which are already approved by FDA and include enzalutamide and abiraterone. These drugs are manufactured by Merck, AstraZeneca, Pfizer, and Janssen. And I have consulted on a scientific advisory boards to all these companies and received honoraria for consulting to these companies. 

So with that in the backdrop, I'd like to go ahead and briefly summarize this study. The patients who are progressing on the standard treatment option for metastatic castrate-resistant prostate cancer, including prior chemotherapy, and 1 of these novel hormonal therapies, which include abiraterone or enzalutamide, but not both, these patients are randomized on a 1-on-1 fashion to the novel combination of pembrolizumab with olaparib versus other hormonal therapy, which the patient has not received in the past. The patient's disease has progressed on abiraterone or enzalutamide. Then they are randomized to the novel combination pembrolizumab with olaparib versus abiraterone or enzalutamide.

Dr. Shuch: So Neeraj, what's the current standard of treatment for these patients at this time?

Dr. Agarwal: The current options are very limited. I would say the only chemotherapy, which may be used again, is docetaxel. Sometimes, we re-treat patients with 1 of these drugs on which they have already progressed. Cabazitaxel is another drug which can be used. But please note that by the time patients have already had disease progression on these previous therapies, the expected benefit by trying these currently available options are very limited. Most of the time, patients experience disease progression within 3 to 4 months on these currently-approved medications.

Dr. Shuch: So what is the exact problem that you're trying to solve or show with this study?

Dr. Agarwal: So pembrolizumab is an immunotherapy, and it’s already approved for patients with multiple types of cancer. Olaparib is an oral pill which is already approved for patients with advanced breast cancer and ovarian cancer. Olaparib works by incapacitating the cancer cells from repairing their DNA, which in turns lead to cancer cell death.

Taking a step back, if when we treat patients with olaparib, these cells also get unusually sensitive to action by concomitant treatment with immunotherapy. And this is based on the laboratory data, pretty strong laboratory data. And hence, there is a rationale for combining pembrolizumab with olaparib. And what olaparib is doing is, it is killing the cancer cells by incapacitating them from repairing their DNA, and simultaneously making them very sensitive to action by immunotherapy. And then we are using pembrolizumab at the same time, which is immunotherapy, and hence we expect these 2 drugs to synergize, and lead to an exponential increase in cancer cell death.

Dr. Shuch: So Neeraj, so it sounds like there's pretty strong scientific rationale. But what question does this study aim to answer? Patients want to live longer? They want to be more stable on therapy?

Dr. Agarwal: The study has 2 major primary endpoints, which basically means 2 major questions the study is asking. Number 1 is, are patients going to live longer when they receive this novel combination versus standard therapy? And secondly, are they going to respond for [a] longer time, meaning they will have a longer duration of disease control defined as the radiographic progression-free survival. That is another primary endpoint of the study. So the study is asking whether patients are living longer, with better control of their disease with this novel combination.

Dr. Shuch: So Neeraj, with this new approach, are there any specific risks that patients would want to know about for this type of study?

Dr. Agarwal: Pembrolizumab is already FDA-approved for more than 10 different kinds of cancers at least. This is an immunotherapy, which basically up-regulates our immune system in a rather non-specific way. Most of the patients, the vast majority of patients take pembrolizumab very well with minimal side effects. But then a small minority of patients, I would say somewhere around 4 to 5 percent, patients have hyper activation of the immune system, which can attack our own organs. So the most common side effects with any immune checkpoint inhibitor like pembrolizumab include diarrhea, liver toxicity, skin toxicity, and less frequently lung toxicity, or attack of immune system on the endocrine glands. These are only some of the toxicities which we usually see on our clinic, but it doesn't mean other rare toxicities may not happen. So these drugs require close monitoring. They're given every 3 weeks. So pembrolizumab, especially, is given every 3 weeks. And it is very important that patients are seen regularly by their oncology providers, so that if there are any of these toxicities are happening, they can be controlled at a much earlier stage, rather than becoming very severe and being picked up at a more severe stage.

So I just want to add the toxicities of olaparib, which is already approved for patients with breast cancer and ovarian cancer. So we are not talking about any experimental drugs here for human beings. Both of these drugs are approved for various cancers already, with very well-defined toxicity profile. The combination is unique. Combination is being tested for the first time. So olaparib can cause bone marrow suppression, which basically means it can lead to anemia, low platelet counts, and low neutrophils, which are the defense cells fighting for us against infection. Most of these toxicities are easily manageable by modifying the dose of olaparib. 

Dr. Shuch: Neeraj, it sounds like this could be a really important study, and we'll keep an eye out for future updates. Please keep us posted. So let's move on to some of the exciting kind of work in bladder cancer. Petros, can you discuss this ongoing study that was presented at ASCO GU, the KEYNOTE-866 protocol? [Perioperative Pembrolizumab (MK-3475) Plus Neoadjuvant Chemotherapy Versus Perioperative Placebo Plus Neoadjuvant Chemotherapy for Cisplatin-eligible Muscle-invasive Bladder Cancer (MIBC) (MK-3475-866/KEYNOTE-866) (KEYNOTE-866)

Dr. Grivas: Sure. Before I start, I want to say that I have done consulting with this trial sponsor, which happens to be Merck, for unrelated reasons and not for this trial.  And this trial is open in our institution, but I'm not involved directly into that study. This particular clinical trial is trying to evaluate the following question. Right now, the standard of care for patients who are aiming to go for removal of the bladder—we call this radical cystectomy—is to get chemotherapy with the regimen consisting of gemcitabine and cisplatin combination chemotherapy before cystectomy. We call this pre-operative, before the operation, or neoadjuvant cisplatin-based chemotherapy. And that's a standard of care in patients who are fit enough to tolerate this study, because this study can cause side effects. So the question is, can you now use immunotherapy, in particularly this drug called pembrolizumab, which is activating the immune system, in combination with chemotherapy. So chemotherapy plus, pembrolizumab, as compared to chemotherapy plus placebo before patients get cystectomy, removal of the bladder.

Dr. Shuch: So these are patients who are going to go for surgery?

Dr. Grivas: That is correct. This patient population are those patients who have made a decision to go for removal of the bladder, and we call this, as I mentioned, radical cystectomy. And I mention this because there are some other treatment approaches.

Dr. Shuch: The current standard of care is chemotherapy and then surgery. So what is the problem that the researchers are trying to solve?

Dr. Grivas: The main question is, does the addition of this immunotherapy to chemotherapy increases chance and [the likelihood of] not finding any residual cancer when the bladder is removed, and whether it actually increased the time of being cancer-free and alive down the road. So does the addition of immunotherapy to chemotherapy improves how these patients do over time, in terms of less of cancer recurrence, meaning cancer coming back, and longer life?

Dr. Shuch: Okay. So you want to see the tumors disappear, and then you want to prevent patients from having recurrences with this study.

Dr. Grivas: That is correct, and ideally, live longer, if possible.

Dr. Shuch: And how was it specifically designed? What was the rationale with this type of approach?

Dr. Grivas: Brian, this is an important question because we have to use previous information to inform the design of those trials. And I would mention that there are some observations about chemotherapy and immunotherapy combinations might work well in other cancer types. And particularly, in patients with bladder cancer, there were a few previews, smaller-sized clinical trials that showed promising results, meaning higher chance of making the cancer disappear when they take the bladder out. And because those trials were very promising and also showed that the combination of chemotherapy and immunotherapy was feasible, then the bigger trials now being launched to confirm the results and compare this combination with the standard of care right now. So strong previous data supports this larger trial to evaluate whether this addition makes sense.

Dr. Shuch: So, Petros, patients generally are going to go to surgery. You're giving them a different medication, immune medication. What would be additional risk that patients would have with this approach?

Dr. Grivas: So every time you add a new therapy, there is a chance of side effects as Dr. Agarwal mentioned before. And particularly, when you add immunotherapy, there is a small but real chance of having immunotherapy-related adverse events. And that's what we call side effects from a very activated active immune system. And I think it's important to have this discussion with the patient about benefits or risks before the trial starts. And before the patient makes a decision. Overall, these immunotherapy-related adverse events usually, as I mentioned, are not very common, especially when we compare the immunotherapy with the chemotherapy. However, we have to be very careful, especially with a combination. And these patients are monitored very closely for any side effect that might happen. And I think education is important for both the patient and the medical provider team, how to monitor and do a close observation for those side effects. The side effects of chemotherapy are standard. And that is something that's also a part of the discussion with the patient.

Dr. Shuch: Got it. And is this still open? And when do you think we'll see results for this work?

Dr. Grivas: Yes. The trial is still open. There is a way to go. It started accrual fairly recently, and I think their efforts for accruing patients in multiple cancer centers. So I would definitely consider this clinical trial for patients who are thinking about getting removal of the bladder and who [are well enough to] get chemotherapy, and they can discuss that option with a medical provider because the trial's going to be open at their cancer center or another cancer center. So definitely, it’s open and accruing patients.

Dr. Shuch: I see. It seems very exciting that they're moving this type of therapy to a new space. Petros, keep us posted as this trial progresses.

Dr. Grivas: Thank you. Will do.

Dr. Shuch: So moving on to kidney cancer. Monty, let's discuss this PDIGREE trial. [Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study] Besides obviously having a very interesting name, it seems like it's a pretty novel type of approach. Can you briefly summarize the study and design?

Dr. Pal: Yeah. Thanks, Brian. So the intent of this study is to take patients with advanced kidney cancer—these are folks where the cancer has [spread] beyond the borders of the kidney to the lungs, to the liver etc. All patients receive standard immune-based treatment in the upfront setting. And then a couple of months in, they actually look at the response that they've achieved, and based on that, decide on different lines of treatment beyond that.

Dr. Shuch: So who is the ideal patient for this study? Who is it intended for?

Dr. Pal: Yes. So this particular study, as I've mentioned, is really for those patients with advanced disease. And beyond that, we in the clinic are using different criteria [to assess] how functional a patient is. It's based on their labs, etc., to define whether or not they have what's termed good risk, intermediate risk, or poor risk. And I think as you're looking at treatment options, as a patient with kidney cancer, it's important to figure out which one of those risk criteria you fit into. This particular trial is intended for patients with intermediate and poor risk.

Dr. Shuch: Got it. So these are patients that are newly diagnosed. Correct?

Dr. Pal: Exactly. Exactly.

Dr. Shuch: So what is the current standard of care for these patients? What would you give them outside of this trial?

Dr. Pal: There's a number of options for kidney cancer. When I started in this business, we only had about 2 to 3 treatments for the disease. And now, it's expanded to more than 12 FDA-approved therapies, which is just mind-boggling. Typically, if you're just diagnosed with advanced or metastatic kidney cancer, you'll start with a combination of immune treatments, 2 immune therapies. And that's really the basis of this particular trial. Or you might get a mix of targeted treatment and immune treatment up front.

Dr. Shuch: So Monty, if we have so many exciting therapies, what is the problem that the clinical trial team is trying to solve here?

Dr. Pal: Great question. I think the big issue is that we know that patients who aren't doing well in therapy need to be switched. We know that patients who are doing exceptionally well on therapy can be continued on their current treatment. For the in-betweens, for patients who might have some stability in their tumors, but maybe not the type of shrinkage that we want to see, we really don't know what the best option is. And that's really where the PDIGREE trial comes into play.

Dr. Shuch: So with that in mind, how is it designed to kind of answer that question?

Dr. Pal: So again, we're taking patients who are receiving immune therapy in the upfront setting. We're taking a look at their response at around the 3-month mark. And typically, if you're a patient with kidney cancer, that's how often I would image you with scans. So at the 3-month mark, we look and see. If you've got a complete response—I think it's pretty intuitive—you're just going to continue on immune treatment. If you're actually having a very poor response, meaning the cancer is continuing to grow, it's migrating to new sites, you'll go on to targeted therapy.

On the other hand, if you're in-between, if tumors are maybe shrinking more modestly, or just staying the same size for the most part, that's when you would be randomized to either continue on immune therapy alone, or go on a mix of targeted therapy with immune therapy.

Dr. Shuch: So what is the overall question that the study is hoping to answer? The patients who are getting that additional targeted therapy, what is the hope for them?

Dr. Pal: I think really what we're hoping to see is that those patients actually have delays in their cancer progression. There will be a longer time until they see their cancer grow. Furthermore, we're hoping, actually, that we might improve the survival of these patients.

Dr. Shuch: Got it. So the patients who are starting this therapy, and they have an additional medication, that targeted drug, what would their specific risk be by participating in this study with that drugs?

Dr. Pal: So we've had some great conversations with Dr. Agarwal around the targeted therapy in prostate cancer. He was talking about PARP inhibitors. In kidney cancer, the general principle of targeted therapies are they tend to cut off the blood supply to tumors. But they don't just do it there. They can do it in other organ systems, as well. By virtue of that, you can have a handful of different side effects, including hand-foot syndrome, which is peeling of the skin on the hands and soles of the feet. You can potentially have high blood pressure as a consequence of that mechanism. You can also have diarrhea. These tend to impact the gut. Those tend to be some of the principal side effects. But, of course, I always refer patients to the consent form for these studies for a more exhaustive review.

Dr. Shuch: Got it. But some patients may not have any of these side effects. True?

Dr. Pal: You're absolutely right. It's just amazing to me that I have more than a handful of patients in my practice who experience little or none of these toxicities. Having said that, it's still so important to disclose the possibilities when you're discussing these trials.

Dr. Shuch: Got it. Is this trial still open to patients? And when do you think the results would be available?

Dr. Pal: So at this particular trial is planning to accrue several hundred patients. And we're really in the trial's infancy. We've just had over about 150 patients accrued to date. So there's still ample opportunity to get the study for your patients in practice. And to the patients who are listening to this, it's certainly a trial that I would like you to inquire about at your respective cancer centers. It's open all over the country.

Dr. Shuch: Well, Monty, that seems really fascinating. The idea that it's an adaptable trial, that patients start on therapy, and you see how they do. We'll definitely keep an eye out for that trial in the next few years.

Dr. Pal: Thanks a lot, Brian.

Dr. Shuch: Great. So thanks to our guests. Thank you for tuning into this podcast. I'd like to thank my guests Dr. Neeraj Agarwal, Dr. Petros Grivas, and Dr. Sumanta Pal. There are many types of clinical trials for urologic cancers that are ongoing, all with the shared goal of improving the way we treat these diseases. If you're wondering about participating in a clinical trial that might be right for you, definitely, talk to your healthcare provider. Please tune in next time for further discussions on additional advances in our urologic cancer field. Thank you so much.

ASCO: Thank you, Drs. Shuch, Agarwal, Grivas, and Pal.

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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