Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Chuck Ryan, who is the Director of the Hematology, Oncology and Transplantation Group at the University of Minnesota, where he is also a GU medical oncologist. Thank you so much for being here with me today, Chuck.

Charles Ryan: Pleasure to be here.

Alicia Morgans: Wonderful. So I wanted to continue our conversation as a look back on all of the things that have really transformed prostate cancer care in 2020 and a look forward, of course, as to where things might go in 2021 and beyond. And I think we could start this portion of that conversation, really focusing on making the old new again or this relugolix story. The HERO trial was a Phase III trial that was looking at a GnRH antagonist and the way that it could lower testosterone in patients, and really comparing that to the efficacy of testosterone lowering by leuprolide. What are your thoughts on that trial?

Charles Ryan: Right, so HERO looked at an LHRH antagonist, relugolix, as you pointed out. And looked at its ability to induce castrate levels of testosterone and testosterone suppression persistently, and it was compared to leuprolide in a 2:1 randomization. And impressively, this oral therapy led to a very quick and sustained castration that occurred within a week in most patients. And then when treatment was discontinued after 48 weeks, testosterone levels rose back quite nicely. So that is a very good set of evidence. This is an active form of androgen deprivation. But there are really sort of two nuances perhaps, or two headlines to this study that we should highlight. First, it's oral, and I think that is going to present a lot of opportunity. And it will be really interesting to see how we can sort of play with that in a way, in terms of patient convenience, perhaps adherence issues, and perhaps even moving forward with clinical trials to try to refine how precisely we're able to lower testosterone and to time it. And I look forward to those potential studies.

The other angle that we saw in the HERO study that was published in the New England Journal of Medicine was the selection of patients who had, many of them had had major adverse cardiac events. And over time compared to leuprolide, the reduction in these events in patients with a history of cardiac events was about 50%. So, that's quite interesting. This has been something that has been touted with regards to the LHRH antagonist for some time that they may in fact have beneficial outcomes with regards to cardiac and cardiovascular disease. So that's another arena in which patients may find this to be the preferred agent.

Alicia Morgans: Yeah, I thought that was really interesting. And so, of course, relugolix was recently approved by the FDA. I have not actually seen it available yet though. I know it's in process. And I know that I do have patients who are interested, particularly those patients who have a high cardiovascular risk because they're interested in trying to reduce risk in any way that they possibly can. I think it will be interesting for us to see how combinations of relugolix and our other oral AR targeted therapies that may have an elevated cardiac risk in themselves. Things like abiraterone or enzalutamide, how they, when combined with relugolix then may hopefully have a lower risk than when they're combined with things like GnRH agonists. So I think that there's still more to tell of this story and interesting that label, as far as I could tell, did not have a specific mention of any elevation of risk of cardiovascular disease or cardiovascular events, which we do know, those warnings or mentions are present on the other GnRH agonist labels.

And there was an American Heart Association statement on the risk associated with those agents. So it'll be interesting to see how those come into use in our clinics. The other thing that I do think we should mention, and you alluded to this is that it does look like testosterone may recover more quickly after cessation of treatment by that 90-day time point or so. Many men had recovered well out of that 50 level, which is our level of quote-unquote castration. So, this low testosterone that we're aiming for... So, for those patients who need short and specific durations of androgen deprivation therapy, this may be a way for them to have a recovery that's more effective or at least more consistent and more rapid, hopefully when they do choose to stop their therapy. So in settings, like when used with radiation therapy, for example, I think this could be an important advance for our patients.

Charles Ryan: Yeah, no, I agree. And I think that there's a lot of opportunity for further study, and the type of work that you do around survivorship and quality of life analysis and cardiovascular outcomes. And this is just a proof of principle study that show that it will reduce testosterone in this sustainable and reversible way. Checkbox that, if it is, yay, got that job done. It's now out on the market. And it opens up a lot of possibilities for secondary tabular analysis that could broaden the benefits for patients.

Alicia Morgans: Absolutely. And really important and interesting that this was a Phase III with a direct comparison that showed this, but I would also mention it was certainly not the primary end point of the trial, these cardiovascular events, but it was a pre-planned assessment that they did between these adverse events at these adverse cardiovascular events. So very interesting data. And I guess we'll see in 2021 and beyond where we find this oral GnRH antagonists actually landing in our therapeutic option list.

Charles Ryan: Yes.

Alicia Morgans: So moving along, I think we had some other real targeted approaches to therapy that included things like a ipatasertib IPATential150 trial. What are your thoughts? Can you tell us a little bit about that study and what your thoughts are on this drug?

Charles Ryan: So ipatasertib is an orally available AKT inhibitor, and it was a very rational thing to test it in prostate cancer. Because prostate cancer is a disease that has a very high prevalence of PTEN loss. And in some studies in CRPC it's upwards of 70% or so of tumors will have PTEN loss. When PTEN which has a negative effect on AKT is lost, AKT is upregulated and is essentially a cell cycle agonist. And thus a really good idea to be targeting PTEN. And it's been something that has been talked about for years in my whole career, in fact. And so what this study did, the IPATential150 did is it looked at a PTEN loss population and compared ipatasertib plus abiraterone to abiraterone alone.

And what we saw was a modestly positive data hazard ratio of 0.77 for RPFs. So about a 20 plus percent reduction in the risk of radiographic progression. What the conversation is going to shift to, I think in the coming year is how do we determine PTEN loss? Because there are several ways you can do it, immunohistochemistry, other modalities. And I think that the robustness of the clinical data is going to be driven in part by how well the patients are selected for this biomarker. So, there's going to be further publications that are coming out on this I think. I had further conversation in our field about this process. But as you point out Alicia, this is a targeted therapy, targeting AKT in a precision medicine context in which we select the patients for the targeted therapy. And we've got the targeted therapy kind of down, and now we need to figure out the precision medicine context. And, we use those terms interchangeably, targeted therapy and precision medicine. But this is a really good example of how they're actually two concepts that can be married to one another and need to be done so thoughtfully.

Alicia Morgans: Yeah, just to comment on that. And the difference between these words. I remember learning as a fellow that you could have drugs that are incredibly precise and hitting that target, but sometimes you're so precise that you're ineffective because you're only hitting one area and there are compensatory mechanisms that are not being hit by a particular drug that may upregulate, and then be a way to sort of get around that pathway that you're inhibiting. And sometimes for TKIs, for example, you want to have a little bit of more of a broad suppressive or inhibitory effect so that you can sort of affect these compensatory pathways. 

Charles Ryan: Sorry to interrupt. A great example of that is cabozantinib. And we could actually mention that cabozantinib had some data out in prostate this year in combination with immunotherapy. And cabozantinib is a study that was first developed as a met inhibitor. And we thought we want to precisely target met, but there were all these off target effects. And now it looks like some of those off target effects may actually drive some of the clinical benefits of this drug. So cabo is moving into more advanced studies again in prostate cancer in combination with immunotherapy and maybe its role is going to be in targeting the extracellular matrix. The tumor micro environment. So we'll look forward in 2021, perhaps hopefully to more conversation and more data on that front.

Charles Ryan: It's very early days, but I think that your point is that AMG 160 kind of opens the door to the T-cell specific therapies, having a role in prostate cancer. AMG 160 is a anti PSMA BiTE. It's a bi-specific T-cell enabler. So for those not familiar with this concept, you have a molecule that has a two attachment sites. One is PSMA, so it attacks the prostate cancer and the other attracts and attaches to a T-cell. So it's really bringing the T-cell close to the tumor. This is something that has been explored in a variety of other malignancies, as you can imagine, we can just replace the PSMA target with something else. And we did see some PSA responses and objective responses presented this year. And it is very interesting that agent, I believe, is moving into more advanced studies and we'll have to see what comes of it, but it is exciting that, not the first time, but we're now seeing a new novel approach to immunotherapy coming down the pipeline.

T-cells are challenging. T-cells are the target of BiTEs. T-cells are the targets of CAR Ts. And when activated they can do wonderful things in an anti-tumor context, they can also be quite toxic. So there's a lot of groups, ours here, and others looking at NK cells, which are potentially as effective, but have certain logistical issues that are easier than T-cells. So the cellular therapy revolution that's happening across oncology and in hematology is going to be tested in prostate cancer. And it will be really exciting to see how these things play out in particular, as we think about other PSMA targeted therapies, like we talked about earlier with lutetium and actinium and these kinds of things. Whether delivering a radioisotope is going to be as good as delivering a cell or a T-cell is another thing altogether. So, exciting times to be moving into an arena where we can think about these approaches.

Alicia Morgans: I am in complete agreement. I think it's also really important for us to recognize our limitations and also then to try to mitigate those issues. So when we start getting into these cellular based therapies, there has been actually quite a significant amount in some settings of cytokine release syndrome. It's expected. It's what we see when we rev up these systems. And what I thought was really impressive and important about the AMG 160 trial as was presented, there were strategies including using slower rates of infusion, using steroids, for example, where they were able to actually decrease the occurrence of this cytokine release syndrome and keep patients from having to have ICU admissions and those kinds of things. So, if we can use effective therapies, we do need to use them safely. And having those strategies gives me some confidence that it won't hopefully only be at main major inner city cancer centers where we end up being able to use these therapies, but we may be able to eventually roll these out even to our community practices where so many patients need to get their treatments as well.

Charles Ryan: Yeah. On the one hand, we have the HERO study with relugolix which is an oral therapy that it will open up many doors to who can treat prostate cancer, perhaps with androgen deprivation therapy. And then on the other end of the spectrum, we have cell therapies, which even as an experienced clinical trials through prostate cancer, as we do cell therapy trials, the patients are taken care of by a bone marrow transplant doctors. And that's opening up a whole new arena. And as you point out that the CAR T studies and other studies do demonstrate that there's a really a real potential for life-threatening toxicity from these agents. So, it's moving forward, really exciting stuff, grateful to be part of it. And looking forward to future discussions about how it's going.

Alicia Morgans: Wonderful. So as we wrap up, I just want to make a final comment on what I see one of the biggest themes of 2020 is really that we as a community have a growing community. And that multidisciplinary care is so, so critically important. Whether we're engaging as medical oncologists with urologists and radiation oncologists, as we always have been. Or whether that's engaging with nuclear medicine physicians, or perhaps our transplant doctors or our doctors who are more skilled or more experienced, I should say in using these therapies that we use in the hospital that have these sort of more difficult to manage side effects, it's a growing community and a community that I think will be best served by working together. And that's one of the things that I really see as coming out of 2020 and of course, moving forward, what is a major theme that you see from the year as we kind of wrap it up?

Charles Ryan: A major theme for the year of 2020? I don't know that all of the new studies are linked in a thematic way, but these are, we're seeing the maturation of projects that have been underway for quite some time with the PARP inhibitors and other approaches. I guess maybe your question is a challenging one, but as I'm thinking about it, this issue of targeted therapy, precision medicine is coming along. Because imagine if we come down the road take a patient who unfortunately developed CRPC and we can use a sequencing method, and we can determine whether his PTEN is lost or not. We can determine whether he has a DNA repair alteration or not. And we're going to determine, as we've pointed out with the PET scan discussion earlier, we can determine whether he has PSMA expression or not.

So there you have PSMA expression, PTEN expression, and DNA repair alterations as three sort of distinct pathways of therapeutic approaches in prostate cancer that maybe they're mutually exclusive and maybe they're not. And so I think that that may be the theme of the future. And that may be the thing that we continue to see develop. And it's the challenge for those of us who are charged with the translation of these therapies into the clinic to try to define these things. And I think that the conversation about the PTEN loss and how you measure that, or the DNA repair alterations.

We had a lot of these conversations about, well, what does it mean when you have a BRCA2 variant of undetermined significance? What is loss of heterozygosity? All of these molecular questions that you and I are asking each other, as we talk about patients that was previously something that was taking place outside of the labs by groups of PhDs. And so I think that's the definition of translation and that's the excitement. And that's why it's so fun to work in cancer research right now. And so, as we look forward to 2021, I'm not sure what the new theme will be, but it's certainly fun and exciting to be working along the development and the evolution of these things.

Alicia Morgans: Well, I think if nothing else, we could certainly take a message of hope, of innovation, of excitement, for a community that was not stopped by a very difficult year. And that community of course, is supported not only by investigators, but by those patients who gave their time, braved coming into clinic, continuing those clinical trials. And that's what we have to keep doing. So I thank everyone in the UroToday community. And I certainly thank you for your time. And I look forward to not only 2021, but all the years to come. So, thank you very much.

Charles Ryan: You, too. Look forward to this conversation in a year.