Time Course Profile of Adverse Events With Darolutamide in the ARAMIS Trial – Christian Gratzke

October 27, 2021

Alicia Morgans is joined by Christian Gratzke to discuss data presented at the European Society of Medical Oncology (ESMO) 2021 annual meeting around the time course profile of adverse events with darolutamide in the ARAMIS phase 3 trial. The ARAMIS trial was a phase three multicenter randomized control trial, comparing darolutamide versus placebo in combination with ADT in non-metastatic castration-resistant prostate cancer. Dr. Gratzke highlights that during the first 24 months of the double-blind period, the incidence of adverse events of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue.  The rate of initial onset and cumulative incidence of grade 3/4 adverse events and serious adverse events were similar for darolutamide and placebo groups over 24 months.


Christian Gratzke, MD, Urologic Surgeon and Chair, University of Freiburg, Freiburg im Breisgau, Germany

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 have here with me today, Dr. Christian Gratzke, who is a Professor of Urology and the head of the Department of Urology at the University of Freiburg in Germany. Thank you so much for being here with me today, Dr. Gratzke.

Christian Gratzke: Thank you for inviting me. It's a great pleasure.

Alicia Morgans: Wonderful well professor, you and your team presented some very interesting data at ESMO 2021 around the safety and adverse events of treatment with Darolutamide in the ARAMIS trial. Can you please tell us a little bit about what you reported and start just by reminding everyone what the ARAMIS trial was?

Christian Gratzke: Well, thank you very much. So the ARAMIS trial was a phase three multicenter randomized control trial, comparing Darolutamide versus placebo in combination with ADT in this space of non-metastatic castration-resistant prostate cancers we've seen three trials, they were all quite similar with regard to study side, the SPARTAN PROSPER in the ARAMIS trial Apalutamide Enzalutamide and Darolutamide. Now Darolutamide is a bit different because it's structurally distinct. It's a highly potent androgen receptor antagonist. And in a nutshell, it was leading to a very good efficacy, leading to a metastasis free survival rate of almost three years and reducing the risk of death by 31%. So that was with regard to efficacy. In general, the rate of adverse events was very low. There were almost all in the range of placebos. So we were wondering whether we could have more information about the onset of those adverse events within this clinical trial.

Alicia Morgans: I think that's so important when we really think about how we use these medications in practice. So what did you find and what did you report?

Christian Gratzke: The adverse events of interest in general are fatigue, rash, fractures and falls, hypertension and mental impairment. The most pronounced adverse event that we have seen in ARAMIS was fatigue. That was the only adverse event that was above 10%. It was actually 12% versus 8% with regard to placebo. So we looked at the onset of all these adverse events in our analysis. What we found was that in general, apart from fatigue, all the other adverse events were occurring at a very low prevalence. They were all around 1% or less. So for example, fractures, falls, mental impairment around 0.2% 0.4%, 0%, very low. They were also not very much different compared to placebo, not more than 2% different from placebo and that's I think good news. That's a good message. The only adverse event of interest above that was, as I said before, fatigue. Now, if you look at fatigue, we realize that almost half of those patients experience fatigue did experience it in the first month.

And that was very striking. So if you prescribe this drug you could expect this adverse event to kick in very soon. When you look at other side effects though, for example, fractures and falls, they did occur later within the study. On the other hand, rash did occur in the first four months. So there's a difference towards the onset of these adverse events over the time course of 24 months. Mental impairment and hypertension did occur at a very, very low rate. Very few patients experienced it. And what's even more important I guess, is that the patients that withdrew from the study were not different in numbers compared to placebo.

Alicia Morgans: Yeah, I think that's so useful and really important as a clinician who might use these types of drugs for their patients with non metastatic CRPC fatigue might be if a patient experiences it, something that he would notice within the very early days of starting his treatment and so interventions to support him and encourage him through that so that he can achieve the benefits in terms of disease control would have to happen early. And I think that's really, really helpful. So when you look at all of this data and really think about the use of this medication in your clinical practice, what would your message be to clinicians?

Christian Gratzke: I would have a very clear message. The space of non metastatic CRPC is a rather new field, right? And there has been much discussion about imaging and whether or not we should use PSMA PET scans. And now in Europe, we use it more and more. In Australia, I think every patient with prostate cancer will have PSMA PET scan, there's nothing else that they use. It's not quite the same here, but it's changing a little bit. And of course we know from the SEP analysis, especially from the Spartan trial, that if you did PSMA imaging on these patients with a high w times less than 10 months, so they're having a pretty aggressive prostate cancer. The likelihood of detecting prostate cancer is rather high, but I would say that, that doesn't even matter because, and that's also written by the authors in their publications.

If you have a patient, not every patient will be able to receive a PSMA PET scan, then you have three options of prescribing a drug to a patient who can actually expect to have no metastases for almost two years. And who has also reduction in the risk of dying from the disease of more than 30%, which I think good news given the very low side effect profile of the drugs, especially Darolutamide.

Alicia Morgans: I would agree, for all of these men, most are already experiencing some effects, even if they're minimal from the androgen deprivation itself. And if you really add to that minimally, I think that makes a difference when you can provide that kind of a disease control. So very, very important. I really appreciate you and the team characterizing this and helping us understand the temporal relationship of these events to the way that patients might experience them in the clinic. That's very, very helpful. I congratulate you and your team, and also of course the patients and thank you for your time today.

Christian Gratzke: Thank you very much for inviting me. Thank you.