Overall Survival Results of Phase III ARAMIS Study of Darolutamide Added to ADT for Non-metastatic Castration-Resistant Prostate Cancer (nmCRPC) - Karim Fizazi

Darolutamide is a structurally unique androgen-receptor antagonist that is approved for the treatment of prostate cancer. ARAMIS is a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer, and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary endpoint was metastasis-free survival, with the presence of metastasis determined by an independent central review of radiographic imaging every 16 weeks. Darolutamide was approved on the basis of demonstrated improvements in metastasis-free survival. While metastasis-free survival has been shown to be a reasonable surrogate for overall survival in this population, there were questions as to whether the benefit of using androgen-axis inhibitors would translate to overall survival benefits, in part due to the differential survival effect seen according to disease burden in CHAARTED. As a result of the treatment benefit of darolutamide demonstrated in the primary analysis of metastasis-free survival, patients underwent unblinding. As a result, there was a cross-over of 170 patients from placebo to darolutamide.

In a conversation with Alicia Morgans, Karim Fizazi discusses the overall survival data assessing darolutamide in non-metastatic castration-resistant prostate cancer from ARAMIS.  ARAMIS was the first Phase III trial testing darolutamide as a treatment option for men with non-metastatic prostate cancer, and it was initially found to postpone the time to metastasis or death. At ASCO, Dr. Fizazi presented positive overall survival data from the trial after a longer follow-up time, showing a reduction in the risk of death.  They performed this reported final analysis after 254 deaths had occurred (15.5% of DARO and 19.1% of PBO patients). While the median overall survival was not reached in either the darolutamide or placebo arms, Cox proportional hazard modeling demonstrated a 31% relative reduction in the risk of death (hazard ratio 0.69, 95% confidence interval 0.53 to 0.88) in spite of the aforementioned cross-over.  Darolutamide showed consistent benefit across the remainder of secondary outcomes including times to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event. It truly shows that earlier intervention in this treatment population is better for overall survival and improved quality of life.  


Karim Fizazi, MD, Ph.D., Head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France and Professor of Oncology at the University of Paris

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, this is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Karim Fizazi, who is a GU medical oncologist and Professor of Oncology at Gustave Roussy in Paris, France. Thank you so much for being here today with me.

Karim Fizazi: Thank you, Alicia, for having me with you today. Thank you.

Alicia Morgans: Wonderful. So we are talking about some ASCO virtual presentations and some simultaneous publications that are really exciting, and that you have had the good fortune to lead. And I'd love to talk with you a little bit about the ARAMIS data, which is data describing the effect of the use of darolutamide, an androgen receptor antagonist, in patients with nonmetastatic castration-resistant prostate cancer. Can you tell us a little bit about the study, why it was so important and what you found?

Karim Fizazi: Sure. Yes, ARAMIS is actually the first Phase III trial for darolutamide. Darolutamide is an androgen receptor antagonist, that we were fortunate enough to develop here at Gustave Roussy in Phase I and II. And so, ARAMIS was really the first Phase III focusing on men with nonmetastatic castration-resistant disease. So in other words, patients with a rising PSA while on androgen deprivation therapy and no detectable disease by conventional imaging using a bone scan and a CT scan. This was a very large Phase III trial, and we had about 1,500 patients randomized. The primary endpoint has been reported last year, and it was obviously positive. It was metastasis-free survival. Actually darolutamide was able to postpone the time to metastasis or death with a median of about 14 months as compared to 18 months in the placebo arm, so clearly a big, big difference.

What we are reporting here at ASCO ... and I'm glad to say that it's going to be also published in the New England Journal very soon, is the overall survival analysis with a longer follow-up, more than a year of additional follow-up. And actually the trial is also positive by overall survival with a 31% reduction in the risk of death, which I think is very clinically meaningful. The median is not yet reached. But if you look at three years' time for example, actually the three-year overall survival rate is 83% in the darolutamide arm as compared to 77% in the control arm. So, a very clear difference favoring darolutamide.

Alicia Morgans: That's fantastic. And as you said, we saw this 22-month prolongation of metastasis-free survival in the last publication. Overall survival is obviously a critically important endpoint and I think it's actually even more meaningful when we expect that the patients who are included in ARAMIS actually had additional life-saving therapies after they had their initial therapy for nonmetastatic CRPC. Can you speak to that a little bit?

Karim Fizazi: Absolutely. You're very, very right, very true actually. More than half of the patients from the placebo arm received at least one life-prolonging drug, such as an AR axis-targeted agent or a taxane, or both, et cetera, which is big. This means that truly these patients were treated a normal way8 if you will. And probably that the overall survival benefit of early darolutamide would have been stronger without that. But of course, we're glad that patients in the control arm were correctly treated. So, that is very important. And on top of that, we see some other clinical benefits favoring darolutamide when used earlier. I'm talking for example, about time to pain progression, which obviously is very meaningful. We observed a 35% reduction in the risk of pain progression with early darolutamide. Time to chemotherapy, approximately a 40% reduction in the risk. Even time to skeletal-related events was reduced by half approximately.

So it would seem that earlier is better, and this is probably even more true with drugs such as darolutamide with a very good safety profile. Actually even with longer follow-up, we didn't see much additional safety concerns. Fatigue is pretty much the same as compared to the placebo. We don't really see hypertension or excess in falls or fractures, or memory impairments or the CNS side effect that sometimes we see with other AR-targeted agents. So I think we will truly have a safe drug, which is very active. Hopefully, we will soon have it all over the world for the patient, I know it's already approved in the US in this indication.

Alicia Morgans: Yes, I mean absolutely. I hope that its availability spreads across the world because it does seem to be a tolerable drug. And as you were mentioning, I think it's really interesting that it is certainly able to affect things like pain. Interestingly when you reported some other quality of life data maybe a year ago or so, it also seemed to improve bowel and urinary complaints, which I thought was really interesting, that many of these patients have had local therapy, but some have not potentially. And so, having a drug that can improve on these outcomes as well seems really important for patients.

Karim Fizazi: I do agree, sure. And actually just to support what you're saying, some recent papers using PET PSMA suggested that part of these patients that we call nonmetastatic CRPC actually do have either a relapse locally or as you said, an intact prostate that was never treated locally so that the cancer is still in there. So due to that, some of his patients will experience some local symptoms. It can be urinary, it can be also GI symptoms. We were surprised to see a proportion of men developing local GI symptoms due to their local progression. And obviously darolutamide can do a good job preventing that. So this is very important clinically, we'll agree.

Alicia Morgans: And I do agree. And to sort of follow up on your comment about more advanced molecular imaging, things like PET PSMA, these more sensitive imaging strategies are certainly coming down the pipeline. They're used much more in Europe, in Australia, than they are used in the US. But we do anticipate that we'll have access to them at some point in the near future. Will any of that imaging actually change your decision-making around this patient population?

Karim Fizazi: I think it may help us, hopefully in the context of clinical trials to address the question as to whether local treatments can help these patients with detectable disease on PSMA PET, but no detectable disease on conventional imaging. But still, I think the data we have interim, and also in other Phase III trials supporting that systemic treatment truly help these men, will still apply in a context of a positive PET PSMA. Then the true question is really, should we add local treatments on top of all the best systemic treatments? Not necessarily, should local treatments replace these very good systemic treatments?

Alicia Morgans: I completely agree. I think as medical oncologists, we can always be biased in the direction of systemic therapies. But we appreciate our colleagues who can provide those local therapies too. And when we can use imaging to understand when that may be most beneficial, that's a really important piece of care. So, I agree with you. I think that in the setting of the trials, they were designed around conventional imaging. And so PET-positive or negative, these drugs should still be effective. As we wrap up, can you give me some final thoughts on the ARAMIS data?

Karim Fizazi: Well, I guess I'm truly happy because this is a nice history of having a drug being developed from very early Phase I. And actually the very first patient responded to this agent in the second and third, et cetera, to now a Phase III trial which is positive and that leads to approval. So, I think this is fantastic. We're also waiting for other trials with darolutamide. For example, the next to come obviously will be ARASENS, which is the purest trial that will address wherever a triplet can help all the patients with de novo M1 disease, castration-sensitive disease, instead of just a tablet with androgen deprivation therapy and docetaxel. So, hopefully, ARASENS will show that darolutamide can also help these men in this context. Stay tuned, hopefully, we'll see the first data later on this year or next year. I'm really, really happy to see this data coming out soon.

Alicia Morgans: I agree, and I sincerely appreciate your time. Thank you for sharing this updated data on ARAMIS. And the way that it not only prolongs metastasis-free survival but despite continued treatments, life-prolonging agents in the control arm have also prolonged overall survival in this nonmetastatic castration-resistant patient population. Very exciting data and very important to patients, thank you so much for your time.

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