Efficacy and Safety of Darolutamide in Combination with ADT and Docetaxel by Disease Volume and Disease Risk in the ARASENS Trial - Karim Fizazi

March 5, 2023

Alicia Morgans and Karim Fizazi discuss the ARASENS data and how it relates to whether patients with high-volume or low-volume metastatic castration-sensitive disease should be treated differently with systemic treatments. They explain that while historically, CHAARTED showed benefits in high-volume but not low-volume disease, STAMPEDE showed benefits for all patients regardless of volume. The recent STOPCAP meta-analysis suggests that we should count our metastasis and pay attention to whether patients are metachronous or synchronous. At ASCO GU, the ARASENS data showed that the efficacy was similar in men with high-risk disease as compared to those with low-risk disease.


Karim Fizazi, MD, PhD, Medical Oncologist, Head of the Department of Cancer Medicine at the Institute Gustave Roussy (IGR), Villejuif, France and a Professor in Oncology at the University of Paris

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 so excited to be here to talk to Professor Karim Fizazi and we're discussing the ARASENS data, really that extra data on volume and how that may influence the outcomes or how we think about the outcomes in the context of disease volume and disease risk. Thank you so much for being here.

Karim Fizazi: Thank you Alicia. Yes, indeed. We know for about a year now that triplet therapy for men with metastatic castration-sensitive disease is better than a doublet. And when I'm speaking about triplet, this is ADT, docetaxel and an AR pathway inhibitor such as darolutamide in your example. It can be also abiraterone, for example.

The question is who should we treat? And in the last, what, seven or eight years there's been quite intense debate as to whether patients with high volume or low volume should be treated the same with systemic treatments. We know that only patients with low-volume disease benefit from radiation therapy to the prostate in terms of overall survival, but what we don't really know whether they also benefit in terms of controlling the local symptoms.

But for systemic therapy, there's been intense debate as to whether chemotherapy, for example, should be used. This is because in CHAARTED historically we saw benefit in high volume, but not necessarily in low-volume disease, while in STAMPEDE actually all patients tend to benefit regardless of volume.

Actually, I think a very important piece of data came out, say six months ago, with a STOPCAP meta-analysis looking at this data and telling us that not only we should count our metastasis for decision-making, but we should also pay attention to whether patients are metachronous patients or synchronous patients with metastasis. Indeed, in this meta-analysis, patients with low volume and relapse, so metachronous, just don't seem to benefit from docetaxel chemotherapy, zero person, very clear data, explaining probably why CHAARTED was negative for these men.

On the other hand, if you take patients with de novo disease, they actually benefit pretty much the same when they have low volume versus high volume, explaining the STAMPEDE data, which are mostly for men with de novo disease.

So I think this is very informative for us with regards to the use of triplet therapy now because triplet means that you have docetaxel component and actually, yes, at ASCO GU yesterday, we saw data from ARASENS which is one of these trials by volume analysis and what was reported was that the efficacy seems to be very similar in men with high-risk disease as compared to those with low-risk disease.

Now if you look at the volume by the CHAARTED definition, you go to a small subgroup of men so men with high volume, which whereby in obviously the majority benefited from the triplet as compared to the doublet. With the subgroup of men with low volume was very small, just 20%, we saw the same trend but not significant, probably because they were just too small. But I think, again, what's this is telling us is that for men with de novo disease, counting the metastasis is probably not the most important thing.

Of course, we will be probably all keen to go for triplet therapy and not doublet if a patient has multiple disease everywhere because we know that we have to be very active at first shot. Otherwise, the patient might just die from his disease.

But even for patients with a lower volume, we should actually discuss probably on a one-by-one basis whether the triplet is also a good option and very often we see patients on the fence. What is low volume? What is high volume? Patients with just two, three, four bone metastasis and how accurate his all accounting, I just don't know. So simply probably adopt should benefit the patient and if he's a fit gentleman and keen to go for chemo, very often I would go for triplet therapy in that situation.

Alicia Morgans: Yeah, I think that's such a rational way to do it and is really the way I apply the data in my clinic, too. For those patients who are sort of in the middle in terms of their volume status, as you said, the de novo metastatic status is often driving that recommendation, at least in my practice, and that, I would assume, is influencing yours as well.

Karim Fizazi: Absolutely. I do exactly the same.

I should say also that we should not make chemotherapy necessarily a drama because, I mean, we use the stupid name of chemotherapy as medical oncologist for decades, but we're speaking about hundreds of different drugs with hundreds of different side effects and doses as well. If we're speaking about docetaxel 75 milligram per square perimeter plus GCSF support upfront as I do, I'd be curious to hear what your practice is, generally speaking, it's very well tolerated. We give only six cycles, so we're speaking about four months of treatment in the life of men. In the few patients where it's actually not well-tolerated, you can just stop and this is fine.

This is what I'm telling patients, give it a try. If you feel comfortable, if it's not terrible to you, which is very likely to happen, we will carry on with a six cycle. Otherwise, that's fine. We will stop and we will carry on with darolutamide or abiraterone and that's totally fine.

Alicia Morgans: I think another area in which we agree, I think that patients actually receive that very well and emphasizing the opportunity to stop if things don't go as they wish is also a way to help them understand that they are ultimately in control.

Karim Fizazi: Absolutely.

Alicia Morgans: And when they see that it's not so bad, I think many, most, at least in my practice, continue on and get the entire six cycles.

Karim Fizazi: Absolutely.

Alicia Morgans: There is something attractive to having that six cycles and being through with it, rather than having more prolonged duration in the metastatic CRPC setting in which setting that patient may be more debilitated, more frail, may have more comorbidities, there are other social complications that can make it more challenging.

Karim Fizazi: I agree. And because typically the next step, if you're not using chemotherapy upfront and if your patients eventually progresses will be docetaxel chemotherapy, these patients then are older, were sicker because their cancer is progressing while in the mCSPC, the cancer is under control, thank to the ADT that you typically have started couple of weeks before. And it's much more difficult to treat these men with actually a much lower efficacy reported in trials. In men with CRPC, the benefit was, what, three month, four month of survival, something like that. While in the mCSPC setting, it's more an additional year or year and a half of additional lifespan. So I think this is very important also to understand for our decision-making.

Alicia Morgans: Absolutely. And certainly to address the disease heterogeneity that we know exists in so many of these patients and really hopefully get them off to the best start possible.

Karim Fizazi: Absolutely and more and more data are supporting what you're saying. This is an heterogeneous disease amongst patients, patients versus patient. But even in a one gentleman, we see different disease in the same man. So if we are just trying to address this issue with one drug or even two drugs, that's probably not sufficient and three might actually not be enough. And perhaps in the future we'll go for four or five if it's well tolerated and more active.

Alicia Morgans: Well, we'll look forward to that conversation when the time comes. But for now, I really appreciate you talking this through.

What would your message be on this ARASENS data in general, but then also in the context of the updated disease volume/disease risk information?

Karim Fizazi: Well, I was fortunate enough to do the phase one trial of darolutamide some years ago and at this time I was thinking, "Hey, you may have missed something" because there was just no toxicity reported in the phase one. We stop with dose escalation for PK reasons, not for toxicity reasons, and I thought to myself, "Hey, you're going to be ridiculous when the phase three read out because we will see this or that toxicity that you have missed."

But it was not the case and eventually it's now confirmed across two randomized phase three trials, ARAMIS and ARASENS, that it's a very safe drug so it's really good for patients. It's also great to see that ARASENS confirms the data from PEACE-1. We have at least two phase three trials pointing to the same direction, three drugs clearly better than two, and I think the magnitude of the benefit is clearly worth it.

So for patients it's really showing, especially for those with the worst disease, high volume, de novo, when you think about it, Alicia, less than a decade ago, these men had less than three years of overall survival in median with ADT alone. We see now this man living more than five years. So in just a decade we've completely changed the way they're living and probably the quality of life is also dramatically impacted the good way. So we are making progresses. We should not deny this to patient. We should apply this evidence in our clinic. And as I said, I really hope that this is one step and we will do even better tomorrow.

Alicia Morgans: Wonderful. Well, thank you so much for talking that through and for your time today.

Karim Fizazi: Thank you very much.