ARANOTE - Darolutamide in Addition to ADT Vs. ADT in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) - Fred Saad

March 10, 2022

Alicia Morgans and Fred Saad discuss the ongoing ARANOTE trial, assessing darolutamide and androgen deprivation therapy (ADT), as compared to ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC). ARANOTE is an international, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Dr. Saad gives a background on the trial.


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 am a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today a good friend and colleague, Dr. Fred Saad, who is a Professor and Chairman of the Department of Urology at the University of Montreal Hospital. Thank you so much for being here with me today.

Fred Saad: My pleasure.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about a really interesting study that is an ongoing trial in progress called the ARANOTE study. Can you tell us a little bit about it?

Fred Saad: So ARANOTE is a study addressing whether or not darolutamide should be considered as a treatment option in metastatic hormone-sensitive prostate cancer. So we already know we've got several agents that were already in use, but I think there is a need to continue to have different options that maybe have a different profile of adverse events, better tolerated in some patients. The ARANOTE study is trying to find a way to figure this out. We are using darolutamide against a placebo in patients with metastatic hormone-sensitive disease.

Alicia Morgans: Wonderful. So these are patients with mHSPC. All patients are getting ADT and then they are being randomized to darolutamide or placebo. So similar to our prior studies in this setting.

Fred Saad: Exactly. Very similar, with some added effort in looking at the quality of life of this combination, obviously efficacy as we would expect. I think we're not going to have big surprises. We know the drug works in non-metastatic CRPC. We've learned that in combination with chemotherapy, it's extremely effective. But you can't use it until you do a trial that addresses that specific question.

The endpoint is radiographic progression-free survival, and we will probably include a lot of lower risk, lower volume patients. That is good because that's where we really need to have really tolerable treatment options because they are going to be on for quite a bit longer than those very high volumes or very sick patients that are presenting with hormone-sensitive disease.

Alicia Morgans: To that point, ARASENS I think predominantly enrolled patients with de novo disease, high volume disease. So this is looking at a slightly different population potentially that might really benefit more or at least benefit sufficiently from the doublet, or so is the thought.

Fred Saad: Exactly because I think we would all agree, triplet therapy is extremely attractive, but it's not going to be necessarily appropriate for every patient that we diagnose with metastatic hormone-sensitive disease. There is a need to address this doublet. So it's very complementary to ARASENS where ARASENS is really the patients where they can tolerate chemotherapy, where we think it's appropriate for those patients, and where we need this triplet therapy. So that definition is still very questionable as to our individual feelings but there are going to be patients, either because of frailty, because of age, because of the volume of metastatic disease, that might be better suited to a single doublet approach with an AR-targeted therapy.

Alicia Morgans: Wonderful. I love that you and the team are really looking into the adverse event profile, the quality of life. Tell us a little bit about that and why that's important for these patients.

Fred Saad: Well, it's critically important. Already giving them just ADT is sometimes something that patients have a hard time tolerating. So what you really don't want to do is give them ADT and something else that exaggerates the adverse events of becoming castrate overnight. I think what we've learned from non-metastatic CRPC is that this is very reassuring, the added adverse event profile over ADT. It was very nice to see with ARASENS that really even combining it with chemotherapy was really low in terms of adverse events added to what you see with chemotherapy. So I think it's the missing link, patients starting ADT, and I'm going to look forward to you helping us to figure out all of the quality of life issues because you are the expert.

Alicia Morgans: Oh, well, that's very kind of you to say. I look forward to that, and I also think our patients look forward to that because it does, especially as you said, for patients on these treatments for so long, it matters. Every day matters and they want to feel as well as they can feel. So as you think about this trial, can you tell us a little bit about where you are in terms of enrollment and when we can look forward to seeing the results?

Fred Saad: Surprisingly, we thought this would be really hard to recruit to, but it is recruiting ahead of schedule because unfortunately, not much in the States, obviously because there is easy access, but there are many countries where the reality is, there is no easy access to these. So they are very enthusiastic about having at least the opportunity for half their patients to get this kind of therapy and be involved. I think it's great because I think we are hearing a lot about including countries that have been neglected in clinical trials for a long time. I think this is addressing the need that these countries have and these patients have, and also expanding the normality that we've been using in terms of clinical trials and really getting a feel for, that we can probably do clinical trials better and faster by really being international.

Alicia Morgans: I think that's a great goal. I hope that our continued engagement around the world ultimately leads to the approval of these treatments in those places and the familiarity of the physician team so that they can prescribe these drugs and feel confident in doing that and managing the process. So two wins there. Would love to hear your final thoughts on the importance of the ARANOTE trial as we wrap up.

Fred Saad: Well, I think the ARANOTE trial and all the trials we are doing are telling us that we need to do better, earlier in patients who are destined to suffer and die of prostate cancer. I think the recurring theme is every time we have brought in effective therapies earlier in the disease continuum, the better we've had in terms of results. That is pushing us now even to the non-metastatic hormone-sensitive state, where we can start to identify patients truly destined to suffer and die of the disease and intervene earlier. I think you and I would agree that when we're going that early, it would be nice to have a finite amount of time, not lifelong exposure to drugs. That's what we would like to do maybe even in metastatic hormone-sensitive. It would be really nice to say we've cured a patient by hitting them really hard early, and maybe getting them completely off all treatment. I think it would be a great objective.

Alicia Morgans: I love the way that you think Dr. Saad, and I look forward to continuing to change the paradigm of how we approach this disease and how we think about opportunities for a cure, even in patients that today we think are incurable. Thank you so much for your expertise and for giving us that hope, and of course, for sharing your thoughts on ARANOTE.

Fred Saad: Thanks.