Quality of Life and Patient-relevant Endpoints With Darolutamide in the ARASENS Trial - Karim Fizazi

November 10, 2022

Alicia Morgans and Karim Fizazi discuss quality of life and patient-relevant endpoints with darolutamide in the phase 3 ARASENS study and which patient populations benefit most from this data. Dr Fizazi also details the P6 platform. P6 is for all patients with metastatic castration-sensitive disease. There are different phase three trials called P6. Drs Morgans and Fizazi discuss the P6 vulnerable trial, which focuses on the frail population for men who cannot receive chemotherapy and cannot receive abiraterone for hypertension or diabetes or other conditions. When we believe that the current standard of care remains ADT, then we can propose those gentlemen to be randomized to receive ADT plus or minus darolutamide.


Karim Fizazi, MD, Ph.D., is a medical oncologist at Gustave Roussy, and a full professor in Oncology at the University of Paris-Saclay in Villejuif, France.

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, I'm delighted to be here at ESMO 2022 with Professor Karim Fizazi of Paris and Gustave Roussy. Thank you so much for being here, but of course, you're always here.

Karim Fizazi: Thank you, Alicia. Yes, indeed. It's actually weird to have ESMO here in Paris, but it's great indeed.

Alicia Morgans: It is great indeed. It's a beautiful city and a really effective and exciting meeting. I wanted to talk with you about one of your presentations, one of several, in which you discussed the quality of life and patient specific outcomes. Outcomes important to patients and their quality of life in the ARASENS trial. Could you tell us a little bit about it?

Karim Fizazi: Yes, of course. ARASENS, I guess as we call it, is probably one of the purest phase three trials, testing new hypotheses for men with metastatic castration sensitive disease. And here all patients received ADT and docetaxel, and half of them received darolutamide on top of that. The trial is clearly positive by its primary endpoint of all survival and this has been reported. So what we communicated here at ESMO was really data in quality of life, pain, and adverse events in the long term. So to make it easy, basically quality of life for the entire population, which also applies to pain, was maintained. So no treatment to effect of darolutamide versus control. And when we focused on patients who had symptoms at baseline, because the vast majority of men actually didn't have, which is good. But for those who had symptoms at baseline, actually it seemed that darolutamide does better in terms of reducing the pain interference and maintaining better quality of life during time. So this was one part of the story.

The other one was about adverse events, which we see often with other AR targeted agents. So we looked at fatigue, cognitive impairments, rash, most importantly perhaps hypertension and cardiovascular events. And what we found was that there was basically no difference between darolutamide and placebo. The Kaplan-Meier curves were just flat, totally parallel, which is great. We're really supporting all the feeling that darolutamide is a very safe drug, generally speaking, which is really good for this population of men.

Alicia Morgans: Oh, absolutely. And it's interesting, I've heard conversations around ensuring that our older, more frail patients would have access to something that is more tolerable, that does improve quality of life and certainly our more symptomatic patients.

That's really important and so interesting and I've heard conversations around really ensuring that we have access for our older, more frail patients, or as you were mentioning, maybe patients who are more symptomatic. Is this data that you feel should be restricted to those populations or is this suggestive that maybe most patients would have a similarly beneficial tolerability profile?

Karim Fizazi: I agree with you. I think when you have a safe drug, why not use it? Of course, depending you have demonstrated that it's active or less given population. So I'm not typically keeping darolutamide only for frail patients or elderly patients, but also for others. I remember some young patients complaining about cognitive impairments with other drugs and they were in their fifties or something, not the old grandpa. So yes, I think we have quite strong reason to use darolutamide for this indication. The only reason why I would probably not use it if I'm using a triplet is potentially cost, and this is to be balanced with abiraterone, which is generic. But truly otherwise given that, of course, if we don't have direct comparison between all these drugs with regards to [inaudible 00:04:20]. But I think we probably all agree that it's very similar and if we take that, then why not use the safer drug?

Alicia Morgans: Yes, I think that makes sense. And it is important of course, to think about these triplet opportunities for our patients. A lot of our colleagues though also wonder is darolutamide going to always be tied to a triplet as it was in ARASENS? And it looks like there are actually several studies that are looking at it in other places. I wonder if you can comment.

Karim Fizazi: Right. You're very right. I mean, darolutamide, unfortunately, probably arrived a bit late and it was more difficult to find a way to go to CRPC or at least metastatic CRPC. So proven in M0 CRPC, but not in CRPC and it's really difficult to cover. Non-inferiority trials are very difficult to conduct and the agencies don't necessarily like them, but there are other opportunities to test darolutamide. For example, in men with very high risk localized disease, in men with biochemical failures, in men with metastatic castration sensitive disease who are not candidate for chemotherapy and maybe even for average agents. For true frail or very vulnerable populations, we have a trial ongoing here in Europe and some have a trial. So I really think that this agent should be tested more broadly because I mean, it's so active and so well tolerated, generally speaking. So it would really be a waste for patients if we are not able to open more situations for more patients to benefit.

Alicia Morgans: Well, one more question along those lines then. Can you tell us a little bit about P6? Because I do think that's a really interesting study that is focusing on a frail population and trying to get benefit while also of course keeping them safe.

Karim Fizazi: Right. Actually, P6 is a platform. So, P6 is for all patients with metastatic castration sensitive disease. And we have different phase three trial called P6. We have P6 vulnerable, the one you are referring to. So those are men who really cannot receive chemotherapy and for whatever reason, they cannot receive abiraterone for hypertension or diabetes or other things. Enzalutamide or apalutamide may be challenging because of connective impairments, all those things. So for these men, when we believe that the current standard of care remains ADT, then we can propose those gentlemen to be randomized to receive ADT plus or minus darolutamide. So this is the concept of first phase trial. We actually have another P6 oligo trial in manner with oligometastatic disease, where we are randomizing the role of local radiation of a metastasis, metastasis directed radiation. And we have already enrolled approximately 200 men in this one and more is to come. We are trying to set probably one or actually two trials in men according to whether we have a detectable PSA at six to eight months or not.

So for patients with very low PSA at this time, we were going to try to do something about de-escalation. Why should we treat these men forever? Perhaps we don't need that. And while on the other hand, for patients with a still elevated PSA at this time, we very likely going to randomize the role of PSMA targeting on top of ongoing therapies. So this is a broader concept, P6, but you've very right, one of the most interesting ones is really the vulnerable population. And this is just because we don't know what we should do for these men.

Alicia Morgans: Absolutely. But all of this work, this body of work, including the data that you presented from ARASENS at ESMO, is really focused on trying to find that balance between supporting quality of life and ensuring good quality time while we're also prolonging life for these patients. So very, very interesting and so important. So I wonder if you can give us a final thought on the quality of life data you presented from ARASENS. What would your message be?

Karim Fizazi: Well, again, we like to see a trial as a package, or a story as a package I guess. We want to see efficacy, we want to see as lower toxicity as possible, and we also want to make sure that patients clinically benefit. So with ARASENS, efficacy is there, overall survival is improved. Toxicity is very modest, and quality of life, pain control is at the minimum maintain. And for patients with a worst disease, it's actually improved. So I think this is the general message I'd like to say today.

Alicia Morgans: Well wonderful. Wonderful message and wonderful data to present and to share on this particular approach to treatment for metastatic hormone-sensitive disease. Thank you so much for your time and your expertise.

Karim Fizazi: Thank you, Alicia. Thank you very much.