Clinical Trials in Genitourinary Cancers: KEYNOTE-641, P3BEP, PIVOT-09

August 20, 2020
Download MP3 (11.84 MB/17:53)

In today's podcast, Dr. Sumanta (Monty) Pal, Dr. Neeraj Agarwal, Dr. Timothy Gilligan, and Dr. Tian Zhang discuss 3 clinical trials that are exploring new treatment options across prostate, germ cell, 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, germ cell, and kidney cancer.

This podcast will be led by Dr. Sumanta (Monty) Pal, Dr. Neeraj Agarwal, Dr. Timothy Gilligan, 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 Astellas Pharma, 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 Astellas Pharma, Bristol-Myers Squibb, Nektar Therapeutics, and Merck.

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

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 Bristol-Myers Squibb and Merck.

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

Dr. Pal: Hi. I'm Dr. Monty Pal from the City of Hope. I'm joined today by Dr. Neeraj Agarwal from the Huntsman Cancer Institute and University of Utah, Dr. Timothy Gilligan from the Cleveland Clinic Taussig Cancer Institute, and Dr. Tian Zhang from Duke Cancer Institute. Today we're going to discuss 3 ongoing clinical trials in prostate, germ cell, and kidney 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 a clinical trial, you can directly help researchers develop better treatment, reduce side effects, and 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 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 the episode on Cancer.Net.

Now, the first trial we're going to discuss is the KEYNOTE-641 trial for prostate cancer. [Study of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-641/KEYNOTE-641)] Dr. Agarwal, can you tell us who this study is designed for?

Dr. Agarwal: This trial is designed for patients with advanced prostate cancer, or metastatic prostate cancer, who are experiencing disease progression on standard androgen deprivation therapy, a state known as castrate resistant prostate cancer.

Dr. Pal: And if you see these patients in your clinic right now, what is the current standard of care?

Dr. Agarwal: The most commonly utilized [treatments for] these patients include drugs which block androgen signaling inside the prostate cancer cell. And one of the most commonly utilized drugs is enzalutamide followed by abiraterone.

Dr. Pal: Tell us a little bit about how this particular study aims to improve or change the current standard of care.

Dr. Agarwal: Early clinical data showed that adding the immunotherapy agent pembrolizumab to enzalutamide may improve survival outcomes. The response rates in that smaller study were meaningful and were very promising. Based on those earlier data, this trial has been designed and is asking two main questions. Number one, whether adding the immunotherapy agent pembrolizumab to enzalutamide will improve overall survival. And the second question is, whether adding pembrolizumab to enzalutamide will delay disease progression.

Dr. Pal: Are there any risks that patients should be aware of with this regimen?

Dr. Agarwal: Both agents are very commonly utilized for many years now in oncology clinics. Enzalutamide is an oral pill which blocks androgen signaling and is associated with side effects such as fatigue, muscle loss, bone loss, falls, and many others which are relatively easy to manage over time. Pembrolizumab is an intravenous therapy approved for multiple cancer types, and is associated with immune-related side effects. Many of these can be severe in 4 to 5 percent of patients receiving pembrolizumab. These can include diarrhea, abnormal liver function tests, or liver toxicity, a skin rash, lung toxicity, which can include pneumonitis [or lung inflammation]. But most of these side effects can be managed as long as they are promptly detected. So I think education and close monitoring with oncologists is the key for early prevention and management of the side effects.

Dr. Pal: Those are great tenets, not just for this clinical trial but in using these agents in general. Thanks a lot. And final question for you, Dr. Agarwal. Is this trial still open right now? And if so, when do you think we might see some results from it?

Dr. Agarwal: This trial is open across the United States and different parts of the world. And the primary results, early results, will be available, I'm hoping, in 2023, in the middle of 2023.

Dr. Pal: Well thank you for that excellent overview, Dr. Agarwal. I'm going to turn my attention now to Dr. Gilligan to discuss a topic that we don't often have on this podcast. But this is nonetheless a critical disease space for us to discuss. Dr. Gilligan is going to tell us about the P3BEP clinical trial in testicular cancer. [Accelerated v's Standard BEP Chemotherapy for Patients With Intermediate and Poor-risk Metastatic Germ Cell Tumours (P3BEP)] Dr. Gilligan, can you tell us a little bit about who this study is designed for?

Dr. Gilligan: Yes, germ cell tumors are cancers that start in the reproductive cells, most commonly in testicles of adolescent or adult men. But germ cell tumors can also start in children - typically not in the testicles but elsewhere in the body - and they can start in women in the ovaries or elsewhere. In children, we sometimes see [germ cell tumors starting in the brain]. Those are not included in this trial. But basically, everybody else with germ cell tumors are eligible for this - men, women, and children - if they have a poor or intermediate prognosis. And just to clarify one more piece about that, this is for people who have advanced stage disease. Again, men, women, or children with advanced stage metastatic germ cell tumors, as long as it didn't start in the brain. And as long as their prognosis is in the intermediate or poor risk category, not the good risk category.

Dr. Pal: So glad that you pointed that out, Tim. I have to tell you that I gave this incorrect label of a testicular cancer study, but critical for our listenership to know the germ cell tumors can occur both in males and females. Can you tell us a little bit about the current standard of care for the patients that are being [included] in this study?

Dr. Gilligan: Absolutely. Chemotherapy for germ cell tumors has been one of the huge success stories of modern oncology, and the cure rate is extremely high. Overall, [we cure about 96% of men with testis cancer.] However, when you start to look at advanced stage disease in intermediate and poor risk patients, the success rate goes down. It's about a 75% cure rate for patients with intermediate risk tumors and 60% for [those with] poor risk tumors. The standard of care has been the same for a long time. It's 4 cycles of chemotherapy called BEP, and that's what has produced those results. And while those results are good, we would like them to be a lot better.

Dr. Pal: So Dr. Gilligan, you've used this term intermediate and poor risk in the context of patients with germ cell tumor. Can you tell us a little bit about what intermediate and poor risk [means]?

Dr. Gilligan: Yes, it's based mostly on where the cancer has spread to and how high certain blood tests are. There are things called tumor markers which are proteins in the blood that are made by the cancer, and the higher those levels, the worse the prognosis. Similarly, if the cancer has spread to certain organs, such as the liver or the bones or the brain, organs other than the lungs, then patients have a poorer outcome and a poorer prognosis. The last category is men and women who have certain germ cell tumors that grow in the chest called extragonadal tumors. They also have a prognosis that's not as good as other germ cell tumors. So it's a little bit complicated, and for patients, when you see your oncologist, they can clearly tell you which prognostic category you fall into.

Dr. Pal: How does this study aim to improve or change the standard of care?

Dr. Gilligan: So mainly we'd like to get those numbers better. And I think the key idea in this study is that with chemotherapy, which is different than the kinds of drugs we talked about in the prior conversation, the philosophy is to basically give patients as much of a dose as they can safely tolerate. And the idea of this trial is that if we give the chemotherapy more frequently - if we kind of squeeze together the cycles so that rather than every 3 weeks we're repeating it every 2 weeks - can we get a better response in killing the cancer without having too much toxicity?

Dr. Pal: So they use this term in the title “accelerated.” Is that what you're referring to there?

Dr. Gilligan: Yes. So if you think of chemotherapy as something that is repeated, we're repeating it sooner. And we used to give the patient 3 weeks to recover. On this trial, they're comparing that standard approach every 3 weeks to giving it every 2 weeks. In other words, we're making it denser. You get the chemotherapy faster. And the question is, will we cure more people that way or not?

Dr. Pal: And Dr. Gilligan, any known risks that patients should be aware of as they [consider] a study like this?

Dr. Gilligan: Well I think the risk with this approach is that we may increase toxicity without improving outcomes. Past attempts to do better than the standard treatment have not been successful. And the current standard treatment has been the standard for a long time as a result. We are hoping the new approach will be better, but we don't know until we try it, and it's possible that it will be more toxic.

Dr. Pal: When do you think we might see some results from this?

Dr. Gilligan: I don't know when we will see results. My guess is that it will be within a few years. Germ cell tumors grow quickly; they're aggressive cancers, so you tend to get your results pretty quickly, but I don't know exactly.

Dr. Pal: Dr. Gilligan, thank you for that excellent overview. Last, but certainly not least, we're going to turn our attention to Dr. Tian Zhang for discussion of a very important study in kidney cancer. [A Study of Bempegaldesleukin (NKTR-214: BEMPEG) in Combination With Nivolumab Compared With the Investigator's Choice of a Tyrosine Kinase Inhibitor (TKI) Therapy (Either Sunitinib or Cabozantinib Monotherapy) for Advanced Metastatic Renal Cell Carcinoma (RCC)] Tell us a little bit about this study and who it's designed for.

Dr. Zhang: PIVOT-09 is a study of a combination of a [novel] immunotherapy called bempegaldesleukin in combination with nivolumab compared to investigator-selected sunitinib or cabozantinib. So these are standard blood vessel blockers. The study is designed for patients with metastatic clear cell kidney cancer who have had no prior medication treatments and also measurable disease that can be followed on subsequent scans.

Dr. Pal: And when you're seeing these patients in clinic with metastatic kidney cancer, what is the current standard of care? What are you using to treat patients these days?

Dr. Zhang: We've known for a long time that kidney cancer will respond to these immune activating therapies, and [it has been demonstrated that a drug called IL-2, when given in high doses,] improved the overall survival for a subset of patients with metastatic kidney cancer and [produced] really durable complete responses for a small number of patients. However, it was highly, highly toxic, and there were lots of patients who ended up in the hospital. It had significant toxicities and patients were treated in the hospital for about a week at a time. So since about 2018, our standard of care immunotherapy options [have included] agents like ipilimumab and avelumab or the combination of pembrolizumab or avelumab with a blood vessel blocking agent. This is an easier way to give immune activating treatments in a more targeted fashion. [With this study we are testing] whether the IL-2 cytokine can be modified and given more in a more safe and effective manner.

Dr. Pal: This is an interesting drug. If I understand it correctly, we're taking IL-2 from yesteryear, a drug that we used more than a decade ago to treat patients with advanced kidney cancer, and we're retooling it a bit for patients to really enhance the efficacy, maybe really enhance the safety of the compound as well. Can you tell us how this compound's doing that?

Dr. Zhang: Right so bempegaldesleukin is a special formulation of IL-2. It's actually a pegylated form of the IL-2 cytokine, so it includes this polyethylene glycol molecule around the IL-2. And this pegylation allows that cytokine to be released slowly [in the bloodstream] so that in itself may improve the side effect profile. And then it also activates the tumor fighting subset of immune cells, T cells and natural killer cells in the tumor microenvironment, without activating other suppressive T cells. So the thought from preclinical studies is that bempegaldesleukin, because of its pegylated form, will actually decrease the side effects while activating the tumor fighting cells in the tumor microenvironment.

Dr. Pal: And in this trial, how will success be evaluated? How will we know the treatment is working, that it's positive?

Dr. Zhang: So the primary objective for this particular trial is a composite of objective responses as well as overall survival, and then secondary objectives include progression free survival - so lengthening time until disease progression - as well as evaluating the safety of the combination and the quality of life for patients who are treated on this combination.

Dr. Pal: Now I remember IL-2, the drug that you referred to, from more than a decade ago, giving it to patients and certainly it came with a lot of toxicity. What are some of the toxicities of patients receiving bempegaldesleukin should be aware of?

Dr. Zhang: Some of the early phase 1 trials that evaluated bempegaldesleukin found that some of the toxicities included low blood pressure as well as syncope where patients would feel lightheaded [or faint,] headaches, edema, swelling in their legs and fluid buildup, as well as infusion reactions. And I think we should also think about the immunotherapy-related toxicities of nivolumab where we're giving it in combination. So diarrhea, rashes, endocrine dysfunction are pretty common. So those would be some of the expected side effects of the immunotherapy cohort. And then we shouldn't forget about the control cohort treated with standard sunitinib or cabozantinib, and those side effects would include hypertension, hand foot syndrome or other rashes, diarrhea, nausea, hypothyroidism, and loss of protein in the urine.

Dr. Pal: Right. Well a final question for you Dr. Zhang. Is this trial still open to patients, and if it is, when do you think we might see some results from it?

Dr. Zhang: Yes, the trial is still open. It's enrolling up to 600 patients total and it's currently open globally in the U.S., Mexico, South America, Asia, Russia, and Australia. I'm hoping we will see results from this phase 3 trial in the next 2 to 3 years.

Dr. Pal: Well thank you very much, Dr. Zhang, Dr. Gilligan, Dr. Agarwal. 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. Thanks so much for listening.

ASCO: Thank you, Drs. Pal, Agarwal, Gilligan, 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.

And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at