Practice Changing Data from ARASENS - Statistically Significant Overall Survival - Fred Saad, Bertrand Tombal, and Neal Shore

March 23, 2022

Fred Saad, Bertrand Tombal, and Neal Shore join Alicia Morgans in a discussion on the results of the ARASENS trial which examined darolutamide in combination with docetaxel and ADT compared to docetaxel and ADT. They discuss the trial design, its endpoints, how it impacts practice in Canada, the US, and in Europe, and the ideal patient population for this treatment.


Neal Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

Bertrand Tombal, MD, PhD, Bertrand Tombal is Chairman of the Department of Surgery and Professor of Urology at the Université catholique de Louvain (UCL), Cliniques universitaires Saint-Luc, Brussels, Belgium

Fred Saad, MD, FRCS, Professor and Chief of Urology, Director of GU Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Centre (CHUM), Director, Prostate Cancer Research, Institut du cancer de Montréal/CRCHUM

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to talk today with three friends about the ARASENS trial. Let's have them introduce themselves.

Fred Saad: I'm Fred Saad. I'm Professor and Chair of Urology at the University of Montreal.

Neal Shore: Hi, I'm Neal Shore. I'm an uro-oncologist. I'm the Chief Medical Officer of Surgical Oncology and Urology for GenesisCare in the US.

Bertrand Tombal: Bertrand Tombal. I'm also a urologist from Brussels, Belgium, and I'm the Head of the Department of Surgery.

Alicia Morgans: Wonderful. Bertrand, can you tell us a little bit about the ARASENS trial, why you did the trial? Tell us a little bit about the design and a brief overview of the results.

Bertrand Tombal: So we should go back almost five, six years now, where you remember it was the first results, we had the results of CHAARTED. So docetaxel was slowly becoming the standard of care for patients with newly diagnosed metastatic disease. At the same time, we had the results with abiraterone. We started to have more data on apa/enza. So the idea came that we should define a new standard and that in our view at that time, that standard of care should incorporate docetaxel. So there was no study specifically designed for testing the addition of an AR pathway inhibitor in patients receiving ADT plus docetaxel. So then came the idea of ARASENS to make ADT plus docetaxel compulsory as the standard of care, and then randomized placebo versus darolutamide. We had a lot of discussions, but we wanted to make the trial simple and pragmatic. When we started discussing this with Matt Smith, we said we just go for overall survival. Because I know there is a lot of discussion on the endpoint, but in the end, this is what is practice-changing.

So we did the trial very simply. And also because there was a lot of, I would say contamination by second-line treatment, we wanted to make it double-blind. I still remember an epic discussion about having a placebo or not, but we are so happy today that we chose that design. It is a quite large trial. And what we've learned yesterday actually is that the results are outstanding. So that darolutamide very significantly increased overall survival in patients receiving ADT plus docetaxel. That was not granted for success. I can tell you that when I saw the result of ENZARAD, ENZAMET sorry, I had a few white knights saying that my large big trial would be negative, but then finally, I've seen that we have the confirmation. So we can today, and it is a big day because it means that in any situation, whether you use ADT alone or ADT plus docetaxel, we are back to maximal androgen blockade, we should add an AR pathway inhibitor and darolutamide, for sure. I'm sure my colleagues will speak about that, is a very elegant and attractive option for these patients.

Alicia Morgans: Well, thank you for that. And I really appreciate that you reviewed how you thought through the eligibility criteria and really that it was for any chemo-fit patient. You weren't selecting high volume, low volume, de novo, or recurrent disease. Because we weren't really thinking about every patient like that, given the time when all of this was developed. And the high volume, low volume was still a little bit controversial. STAMPEDE data suggested the benefits across that subgroup. So really this was for all-comers who were chemo fits and then plus-

Bertrand Tombal: Chemo candidates.

Alicia Morgans: And chemo candidates, plus or minus darolutamide, really showing the benefit there. So great design, I commend you. And I also commend, of course, the overall survival endpoint. And I'm curious to hear what you think, Dr. Saad. When you think about the data, and of course, you've been involved in this trial for a long time, how does it impact your practice in Canada? What are you thinking about when you see a patient in the clinic?

Fred Saad: Well, I'm thinking that for a long time, it's been disappointing that we had to choose one or the other because, at the time of this study, we had four active agents, docetaxel plus three ARPIs. And the problem is we had to choose. So obviously, when you have to choose, patients were more inclined to choose an ARPI, a hormonally based therapy, and avoid chemotherapy. But I've always thought that it made biological sense to treat, obviously with a hormonally based therapy, but we knew there are hormone insensitive or ADT insensitive clones from the beginning. And the biggest opportunity is upfront rather than sequential. Because in my experience, and I think in many of our experiences when you wait for them to fail the ARPI and then introduce docetaxel, it's very disappointing. They do not respond very well.

And every time we've checked, the earlier you introduce effective therapies, the better the long-term results. And so this study actually shows that we maintain the standard of care. I think everybody agrees that ADT plus an ARPI should be the standard of care and what we are saying is to add six cycles of docetaxel upfront to get rid of as much as possible of those clones that are going to give us grief down the road and that are going to cause the death of the patient.

Alicia Morgans: I appreciate that perspective. And I wonder from your view, Dr. Shore, really to build upon one of Dr. Saad's points, in this trial, and I've heard him say it in other trials too, the earlier intensification is better. What was interesting about the ARASENS trial, certainly we looked at subsequent therapy use and a very large proportion of those patients in the control arm received subsequent disease-directed therapies at over 70%. And so of course, if we are seeing a survival benefit despite that, that suggests that those patients who got AR targeted agents, they got them later, most of those patients got AR-targeted agents in addition, and they weren't able to make up the difference with getting that drug later, rather than that early intensification. What are your thoughts on that? Does that affect you in your clinical practice?

Neal Shore: Well, it does. And first, let me say congratulations to Bertrand and Matt Smith for their leadership on this study. This was a bold and courageous study to do. And here we are at ASCO GU and seeing the plenary presentation and the simultaneous New England Journal publication. This is a really important achievement and an accomplishment. I absolutely echo Fred. And in my experience in treating patients with advanced prostate cancer, arguably bladder cancer, and kidney cancer, too, I think your window of opportunity is to be as aggressive as possible when patients have good performance status and combine novel mechanisms of action, when they have good performance status, in my years of doing this, they do better. They delay the progression of the disease. And in ARASENS in particular, they delayed the progression of the disease. They delayed PSA progression. They delayed the conversion from sensitive to CRPC and clearly survival, the primary endpoint was made.

And notably, the long-term adverse event safety profile in both arms was essentially the same, which really speaks very nicely to the use of darolutamide. It complements the long-term data that we saw with the ARAMIS trial. So it's not in the concept that, oh, just more is better, more actually is better for these patients. And I completely agree with Fred, combining novel mechanisms of action is so imperative. We have data in some developed countries that our patients succumb to mCRPC and on average, see less than two novel mechanisms of action. So that's kind of a shame on all of us as healthcare providers, whether you are urology, medical oncology, radiation oncology, we have to do better. So I think this is a tremendous accomplishment, the ARASENS trial.

Alicia Morgans: Well, I think we would all agree and I think the patients are certainly grateful. And thank you for raising some of that real-world evidence information that helps us understand what things look like out in the communities. And I wonder from your perspective, Bertrand, as a European, where more being better isn't always enough. It has to be better sufficiently, or it has to be also better in terms of health economics, in terms of quality of life. What are your thoughts when you look at the ARASENS data? Is it going to move the needle or potentially change the way things are done in Europe?

Bertrand Tombal: Yes and no. And I would say quick, probably more quickly than anywhere else, because as Fred mentioned, there are countries today that do not have access to AR pathway inhibitors. I'm going to take the example of Italy, Spain because there is that choice and that choice between chemotherapy and an AR pathway inhibitor is not fair when it comes to economics. So for this country, it is very important that we show that, actually saying that we only give docetaxel in the first line, now, that is not sustainable anymore. So for all these countries, it will open renegotiation about having the possibility of using this agent. Then the second and most important thing is that today in the landscape of prostate cancer, you are going to have to receive docetaxel at some time. So to me, except for some very low burden diseases where we may have a chance to cure them, but that's the guy with a single metastasis.

Many of these patients will receive docetaxel. And when we speak about ARASENS, we also have to speak about PRESIDE, the data with enzalutamide that clearly showed that once you have received one of these AR pathway inhibitors, as you mentioned, docetaxel doesn't work well. So if you believe in taxane, you have plenty of arguments to demonstrate that the best time to give it is at the start of the disease. So that is why also, people say there is no volume in your trial. No, because at that point we believe that, keep in mind that the volume was chosen initially for registration and discussion purposes to have something which is clear cut, but it's not, it doesn't necessarily reflect the biology of cancer. So it is a really short view.  So that is why we decided we were going to get the data, but we decided not to go that way.

And then the third thing to ARASENS, because that is what I call the hidden world of a clinical trial, where you can influence the results, is that in contrast to what was done with other drugs, we have chosen the country and the site, being sure that it was a high-quality center so that the patients would have a chance to receive the drug at progression, rapidly. Because that criticism has been made over and over and over again.  If you look at the LATITUDE trial, for instance, and you go in the appendix, you are going to see that there was an eight-month difference in survival between Eastern European countries and Western European countries.

Here, we wanted to be sure, as they both mentioned, that we would conduct the trial in countries where there was no limitation in access to drugs. So we really answered, not the question about is darolutamide better, no, it's really more about intensification. So this means, giving your two agents at the beginning and not after. So that is very important. I think that we managed to have a trial, which is the closest to what real-world can give you today. And I think that is very important because we knew that convincing physicians to go back to the triplet will come with some hurdles.

Alicia Morgans: Absolutely. So as we start to wind down, I'm going to give each of you the opportunity to tell me who is a patient, who is the ideal patient, who do you see in your clinic that you would want to use the approach used in ARASENS? And I'll start with Dr. Saad.

Fred Saad: I'm going to be provocative because we are hearing the patients that are most likely to benefit are the worst patients. And I would disagree, that they shouldn't be limited to those patients. What I would simplify is if we have a patient in front of us and we are convinced that the patient is going to die of prostate cancer, consideration absolutely needs to be given to triplet therapy. So I do not believe it is only the high volume that dies of prostate cancer. In my experience, the only ones that might not die of prostate cancer are when there are only some small lymph nodes in the retroperitoneum. All the others that have distant mets, whatever we do, are going to end up progressing quickly and they are going to end up dying of prostate cancer. So our opportunity is upfront. So I would give it to somebody who is fit enough and is likely to die of prostate cancer. So there are some patients that are frail, very elderly that might not have time to die of prostate cancer and they would not be good candidates. But most people in my experience should be considered for triplet therapy.

Alicia Morgans: All right. Thank you. Dr. Shore?

Neal Shore: Yeah. Well, let me stay with the theme of being contrarian because that's why Fred and I are good friends, and also Bertrand, he's extremely contrarian. So the question is why do so many of our colleagues still do monotherapy ADT for patients with metastatic hormone-sensitive prostate cancer? Whether it's high volume or low volume, the data is really frustrating and offensive, frankly. So we have this fantastic data from multiple arms of STAMPEDE, CHAARTED, LATITUDE, TITAN, ARCHES, ENZAMET, and now ARASENS. ARASENS, I think should catapult the enthusiasm to recognize that first of all, couplet combination therapy with an ARPI and ADT or ADT and DOCE, clearly is life-prolonging. It clearly delays the progression of the disease. It is overall very well tolerated. Now we have triplet therapy, which further takes it to a whole other level. But yet we see data all the time, in North America and other places where less than 50% of patients are receiving combination treatment.

And you and I did a program on this for ASCO in 2020, and it's really mind-boggling. And we frequently ask well, why is that? Well, I think what happens is our colleagues give a testosterone suppressant medication, whether it's an agonist or an antagonist, we see the PSA go down and say, I declare victory. That's not victory. That is missing all of the level-one evidence. And now ARASENS just augments that. So at the very least, you should be doing a doublet with an ARPI or DOCE. And now clearly there is level one evidence for a triplet. I agree with Fred that, tell me why you shouldn't be getting the triplet, you are chemo ineligible, or you have some other issue. It's the vaunted and important patient-physician, shared decision-making discussion, which we all have to be better at. And so I think ARASENS, to congratulate Bertrand on this and everybody else who was involved in it really is taking this educational opportunity to improve care.

Alicia Morgans: Well, thank you. And Dr. Tombal?

Bertrand Tombal: The same. And I think that there are a lot of misconceptions in the field today and the volume is one of these. And I mean, to me, there is already plenty of good reason not to be a candidate for docetaxel. And that's enough, like this, we have a very old patient, we have patients with some form of toxicity. But volume to me is not a good excuse because I've been privileged to be the chair of the IDMC of STAMPEDE for nearly 10 years now. And they have a huge number of patients and they believe a lot in what they call interaction tests when it comes to low volume, high volume. There has never been evidence of an interaction between volume and efficacy of the treatment for systemic treatment. It was only for local treatment and because of that, many people extrapolate that interaction. They see from the local treatment for systemic treatment.

That is not supported by STAMPEDE and by other trials. So I think that they are the occasional patient that we call metastatic disease, which everybody would say, the guy which is 75 years old, which has a Gleason 7, a PSA 21, and has what looks like a metastasis on the prostate MRI, which is one centimeter in the pubic arch. Technically that guy [inaudible 00:17:32]. He could be, I would say that occasional guy, maybe yes. But for the rest, if you are 55 and you've got one bone metastasis, unfortunately as of today, you are going to die from prostate cancer. Fred and I remember very well, also the denosumab prevention trial, where Matthew and I were PIs. We looked a lot at what was the number one biomarker of [inaudible 00:18:00] lethal disease that was developing bone metastasis and not one, two, three, four. One single bone metastasis was a signature that you would die from prostate cancer, meaning a signature that you are going to get docetaxel one day, meaning a good reason to discuss with the patient let's say let's hit it bad, and then we are going to see what's going to happen.

Alicia Morgans: Well, thank you. I sincerely appreciate all of your perspectives and thank you so much for your time and for sharing those with us today.