Therapeutic Options for Patients with Metastatic Hormone-sensitive Prostate Cancer - Evan Yu

Tom Keane welcomes Evan Yu to discuss the newest therapeutic options for patients with metastatic hormone-sensitive prostate cancer. Dr. Yu details the most crucial studies to date demonstrating improved OS in mHSPC patients, including the ARCHES, ENZAMET, STAMPEDE, and TITAN clinical trials. Additionally, he touches on the survival benefit shown in the CHAARTED trial. Dr. Yu provides a comprehensive review of the mHSPC and provides expert insight into how clinicians can choose between different approved treatments.


Evan Yu, MD, Medical oncologist, treats prostate, bladder, and testicular cancer, and is passionate about providing a personalized medical approach to a selection of novel therapies, as well as understanding the biologic mechanism of drug sensitivity and resistance. Professor, Department of Medical Oncology, University of Washington School of Medicine and Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center.

Thomas E. Keane, MBBCh, FRCSI, FACS, Department of Urology, The Medical University of South Carolina, Charleston, South Carolina, USA.

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Tom Keane: Hello everybody. This is Tom Keane coming to you from UroToday and from the Medical University of South Carolina. Today I have a real treat for you, Professor Evan Yu. He's a GU medical oncology expert who specializes in genitourinary and prostate cancer. He's the Clinical Research Director at the Seattle Cancer Care Alliance. He's a Professor of Medical Oncology at the University of Washington School of Medicine, and a member of the Clinical Research Division of Fred Hutchinson Cancer Research Center. He's also the Medical Director of the Clinical Research Support at the Fred Hutchinson Cancer Center. He's going to discuss metastatic castrate-sensitive prostate cancer, where the state of the art lies now, with particular reference to the newer options that have become available over the last couple of years. Without any more ado, I'll hand you over to Evan. Welcome to UroToday.

Evan Yu: Thanks so much, Tom. It's a pleasure to be here again, and this is a hot topic right now. The reason that we're seeing a lot of this is, I think as you know, we're diagnosing a lot more people with new hormone-sensitive metastatic prostate cancer these days. There's a lot of reasons for that. There's certainly increased awareness, but also there has been for a while less screening that's been ongoing, and so more patients are presenting with metastatic disease. We needed to have newer and better treatment options, and the good news is a lot of therapies that were developed for later-stage disease castration-resistant prostate cancer have shown significant benefit when you import them earlier into the new metastatic castration-sensitive environment, and the impact and the benefit that we're seeing from these agents is much greater when you seem to use them earlier in these disease states. So I just want to go over some of these newer treatment options.

So this is actually a study that was just recently presented by Dr. Andy Armstrong. This is the ARCHES trial, and this was a randomized Phase III trial using enzalutamide in this disease state for new metastatic hormone-sensitive prostate cancer. These were confirmed by traditional imaging studies like bone scan, CT, or MRI, and they did have stratification factors for whether patients had high or low volume disease, and again, when we talk about high or low volume, that's usually using the criteria that they used in the CHAARTED study, and that was using docetaxel where you had to either have visceral disease or four or more bone metastases with at least one outside of the axial skeleton. That being the spine, vertebral column, or the pelvis. So if you had, let's say, a rib lesion or appendicular lesion, humorous lesion, that would qualify, if you had four or more lesions and at least one outside.

This study did allow patients to receive prior docetaxel therapy, and it did randomize patients to either enzalutamide or placebo in this situation, and the primary endpoint was radiographic progression-free survival. As you can see here, the primary endpoint was very positive for enzalutamide over placebo, and you can see here that 18% of the patients did receive prior docetaxel. So they completed docetaxel previously as per the docetaxel CHAARTED study where they might have received up to six cycles of docetaxel, and then they were randomized, and in the patients that received prior docetaxel, it looks like there was still statistically significant radiographic progression-free survival benefit.

This is the ENZAMET study, however, and this was a plenary session at the last ASCO meeting, and the reason it was a plenary session I think is multifactorial. One is the fact that it was a cooperative group study run by ANZUP, Australia New Zealand Cooperative Group, and also the fact that they had a lot more data of combined docetaxel and enzalutamide. So this study randomized patients also to androgen deprivation therapy +/- enzalutamide, and they also stratified based on the volume of disease, planned early docetaxel, et cetera, but the interesting thing with this study is that 40% of the patients received concurrent docetaxel with enzalutamide. So they did have data on whether triple therapy with ADT, docetaxel, and enzalutamide offered any benefit over ADT and docetaxel alone. The additional difference with this study is at the primary endpoint was overall survival. As you recall from the ARCHES study, it was radiographic progression-free survival. They didn't have mature data for overall survival and it wasn't statistically powered that way, but this was powered for overall survival.

Here is the money slide where you can see the overall survival benefit with enzalutamide when added to this situation. This is overall the entire patient study. Now this breaks it down based on progression-free survival and overall survival, on whether the patient's had prior docetaxel or whether they were receiving docetaxel with the enzalutamide, and I draw your attention to the fact that across the board, as you can see here, there seems to be a progression-free survival benefit whether you received docetaxel or not, but when you look to see the difference in the subgroups for overall survival, you only see a benefit for those who didn't receive docetaxel. So for the 40% of patients that received androgen deprivation therapy, docetaxel, and then enzalutamide, there was no benefit over just receiving androgen deprivation therapy and docetaxel alone, and although I'm not going to have enough time to show you all this data, what we did see is more side effects and toxicities, and surprisingly there were more docetaxel toxicities like peripheral neuropathy, et cetera. So those sorts of toxicities were accentuated when you received the triple therapy. So there is no data to support at this point in time triple therapy with ADT, docetaxel, and enzalutamide, but across the board, there is a survival benefit that's clear with enzalutamide.

So this is the TITAN study, and this is looking at apalutamide. This is a randomized Phase III trial also in this setting. So similar disease patients, similar designs, similar patient numbers on over a thousand patients, one-to-one randomization, and what you see here is dual primary endpoints of radiographic progression-free survival and overall survival and ADT and apalutamide dose at 240 milligrams a day. What you see here is a significant survival benefit as well with apalutamide, which similar to enzalutamide is another pure androgen receptor irreversible antagonist, and so very similar results here, statistically significant for overall survival, similar to ARCHES. They did allow patients to receive prior docetaxel, but it was a very small subset of patients, 11% of patients received prior docetaxel and then were randomized.

So hard to say too much about that small subgroup. One thing you might ask is let's look at the subgroups of high volume disease and low volume disease. So in this table, what we've done is we've broken it down based on the ENZAMET study with enzalutamide and the TITAN study with apalutamide, and you can see the different hazard ratios for both low volume and high volume disease being basically on the right side of one on all the different subgroups, but as you can see, very, very dramatic for certain subgroups. I think it's hard to make too much about the subgroup analysis, but certainly, in the ENZAMET study you see the best hazard ratio for the low volume disease groups, and in the TITAN study you see the best hazard ratio and confidence intervals in the high volume disease groups. I think hard to say too much about this. My summary from this is that it seems that there is survival benefit regardless of high or low volume disease with all of these AR antagonists.

We can't ignore the fact that prior to these recent studies that were presented ... that's the latest and greatest data, but prior to that there was a LATITUDE study and this was a similar study design just using abiraterone instead, a CYP17 lyase inhibitor, to inhibit testosterone production, and these patients were randomized one-to-one. They did use some risk criteria for this. You had to have two of three different criteria to be eligible for the study, either visceral metastases, Gleason 8, 9, or 10, and/or you had to have three bone metastases or more. So it wasn't four with one in the appendicular skeleton. It was three bone metastases or more.

So here's the overall survival benefit there. As you can see, abiraterone is clearly statistically significant there, and at the same time as this study, there was a STAMPEDE study which looked at basically using abiraterone in this setting randomized to androgen deprivation therapy, but as you recall, STAMPEDE had many, many different arms. We're going to focus on the abiraterone arm here, and what you see here is this very significant, statistically significant survival benefit as well with abiraterone. And of course, I'd be remiss if I didn't talk about docetaxel chemotherapy as well. This was actually the first study that showed treatment intensification mattered in this setting, and this was six cycles of docetaxel, an ECOG study that would intergroup in the United States and it was added to ADT versus ADT alone, primary survival benefit. Overall survival was the primary endpoint. As you can see, a very significant 13 months median overall survival benefit, which was quite dramatic, but this survival benefit was really restricted to the patients with high volume disease, not necessarily for low volume disease. So the one thing I'll point out that's different with docetaxel is a very clear survival benefit with high volume disease, but with low volume disease, I tend not to use it in this disease setting since we have the AR antagonists and abiraterone that seem to show benefit in those settings as well.

Similar to abiraterone, we also have the STAMPEDE study, and then that STAMPEDE study, what you see is that there are also multiple docetaxel arms, and you can see a significant overall survival benefit here, a median of 10-month overall survival benefit for the entire population. Now the one thing to keep in mind with STAMPEDE is that it was quite, I'd say variable, disease states were allowed onto the study. They allowed patients that had metastatic disease onto the study and they allowed patients who had high-risk features like biochemical returns, node-positive disease, et cetera. So when you look at the 61% of patients who had metastatic disease on this study, the survival benefit is even more dramatic here.

So to wrap up, I didn't talk a lot about toxicities, but that being said and done, it's hard to compare across disease states, across trial to trial. We're not supposed to do that as different patient populations, but that being said and done, there are a few take-homes that I think are important here. When you look at the use of docetaxel versus the use of the oral novel hormonal therapies, it's very clear that docetaxel should probably be reserved for high volume disease patients only. You shouldn't use triple therapy because there was no benefit in the ENZAMET trial at ADT, docetaxel, and enzalutamide, but you should pick one or the other, and if you're going to use docetaxel, you probably shouldn't use it for low volume disease. There's benefit across the board with the oral novel hormonal therapies for low and high volume disease.

One difference is that with docetaxel it is just six doses. So for the patient that wants to be done with it, that's nice. They can just do six IV doses and be done, whereas the orals are daily dosing and can last for years. There are certainly lower costs with docetaxel, as it's only $32,000 for six dose cycles, and the oral therapies can be more expensive. Certainly, financial toxicity is a consideration this day and age, but one thing to consider is it ultimately comes down to a patient's financial toxicity as well. There are copay assistance programs, and it is quite variable to know what a patient's copay will be, we just have to put in that insurance.

There's higher toxicities with docetaxel. It causes mild suppression, peripheral neuropathy, and certainly lower toxicities with the AR targeted drugs. The ones that are listed here are more abiraterone toxicities like hypertension, hypokalemia, edema, and transaminitis. So there are potential toxicities but they tend to be lower than chemotherapy, and with chemotherapy, it is going to require more doctor's visits, more blood draws, more sticks and pokes, et cetera. There certainly still are monitoring issues with the oral agents like with abiraterone well with every two-week blood draws in the first few months. So with that being said and done, I want to wrap up here. Happy to take some questions with Tom and discuss this a little bit more, but that's just a brief overview of what's going on in this metastatic castration-sensitive disease state, and I'm very fortunate that we have so many new treatment options that offer survival benefit for our patients.

Tom Keane: Thanks very much, Evan. That was a very succinct and extensive review of what is becoming in my view more and more of a confusing picture in terms of which agents and when. I'm not talking about the docetaxel, but I'm talking about the other novel anti-androgens that we have. So I'm going to put you on the spot and I'm going to say, okay, if you had to choose between enzalutamide, apalutamide, abiraterone or even darolutamide, even though darolutamide's a more recent arrival, what would be your preference, and if you have a preference, why did you choose that preference?

Evan Yu: Yeah, so first off, before I answer that question, I'll say darolutamide is still being studied in this disease state. Certainly, there's an FDA approval for darolutamide, for M0 castration-resistant prostate cancer, but the ARASENS trial is still ongoing and that is a trial where everyone receives ADT and docetaxel +/- darolutamide. So we don't know the results of that just yet. So I wouldn't include darolutamide in that just yet. I'd just talk about enzalutamide, apalutamide, and abiraterone. I will say this, that I like the fact that all three of these agents offer survival benefit across the board, low or high volume disease. There is more monitoring with abiraterone and there is a need for low dose steroids, but traditionally I've used more abiraterone. Some of that is just because I extrapolate from metastatic castration-resistant prostate cancer where I think the fatigue is a little bit less with abiraterone, but there certainly is more monitoring and there are patients that have issues with transaminitis, and in those situations, I would lean more towards enzalutamide or apalutamide or if somebody showed signs of mineralocorticoid excess, hypertension issues, et cetera, I would lean more towards enzalutamide and apalutamide in that setting.

Now, I will say you're catching me at a time to record during the COVID-19 crisis and I'm here in Seattle and so considerations right now are to try to delay or not use chemotherapy in this situation. So I'm using less docetaxel right now, and there is the consideration that it is a low dose of steroids and it's not clear how much concern there is, but with abiraterone there are steroids and so, for the time being, I'm certainly leaning more towards enzalutamide and apalutamide.

Tom Keane: Very good. That's a very clear answer. Another question that often is asked is how comparable do you think these trials are. I mean some of them are looking at different things, some of them are a different duration. There are different combinations. So I mean it's always been a bother to me that when you look, we compare things, but should they be compared as closely as they are that we're now making definitive clinical decisions based on them?

Evan Yu: Yeah, I certainly don't think you can compare efficacy. I would say that I can't tell that any one of these agents is better than another one of these agents in terms of efficacy. I think the only thing you can do, and it's not even a comparison, is you can just emphasize what the greatest toxicities of each agent are or potential toxicities, and then you can look at your individual patient and look at their comorbidities, look at their medication list, think about drug interactions, think about what potential toxicities might be the most quality of life affecting for that patient, and then try to make your choices that way. At the end of the day, I like all these options, but I don't think you can make comparisons from one to the next. All you can do is really look at the adverse events tables and really recognize that you need to think about that relative to each individual patient sitting in front of you.

Tom Keane: Right. So in summary then, recognizing that the darolutamide trial isn't in and it is looking at a slightly different area, but can we now say that docetaxel should more than likely only be reserved for those patients who have higher stage disease?

Evan Yu: Yeah, I think so. I think docetaxel should probably now only be used for higher volume disease because we have so many other options now that work for patients with low and high volume disease. So I think absolutely, I would not use docetaxel for those with low volume disease at this point in time with all these other options.

Tom Keane: Great. Great. Well, thank you very much, Evan. As usual, it's great talking with you and a lovely talk and I would just like to thank all our listeners and also to encourage everybody that's ... I know things are unsteady at the present time. There's a lot of worry and angst out there, but let's just take the best care we kind of our patients and see how we can get on with this crisis. Having said that, thank you very much for taking the time and we really appreciate you coming on UroToday and giving us this summary.