ARAMIS Trial in Prostate Cancer: Impact of Darolutamide on Pain and Quality of Life - Karim Fizazi

June 5, 2019

Karim Fizazi and Alicia Morgans discuss a follow-up on the quality of life parameters evaluated in the ARAMIS trial. Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal-related event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo. Dr. Fizazi also elaborates on patient-reported quality of life which was similar in the darolutamide group and placebo group. Differences in least-squares mean time-adjusted AUC scores consistently favored darolutamide and were significant for BPI-SF (pain severity and pain interference scores), FACT-P (Physical Well-Being, Emotional Well-Being, PCS, General, FACT-P total, and Trial Outcome Index), and the EORTC-QLQ-PR25 urinary symptoms subscale.


Karim Fizazi, MD, Ph.D. Dr. Karim Fizazi is Professor of Medicine of Institut Gustave Roussy, (IGR) in Villejuif, France.

Alicia Morgans, MD, MPH, is an Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Read the Full Video Transcript

Alicia Morgans: Hi, and welcome to ASCO 2019. I'm delighted to have here with me today, Dr. Karim Fizazi, who is a medical oncologist and Professor at Gustave Roussy in Paris. Thank you so much for being here, Karim.

Karim Fizazi: Thank you, Alicia, for inviting me today.

Alicia Morgans: Of course. So I wanted to talk with you a little bit about your oral presentation and would love to hear about the study design, the study, what the implications might be. So can you fill us in?

Karim Fizazi: Sure. We've tried to provide more details regarding the ARAMIS trial that we presented at ASCO GU and published a few months ago. So, just briefly, this is a trial testing darolutamide in men with non-metastatic castration resistant prostate cancer, and obviously, a poor risk population of men, because they had a rapidly rising PSA. Less than 10 months for PSA doubling time. So that trial randomized darolutamide with placebo on top of continuous ADT. Primary endpoint was metastasis-free survival, like other trials. Other trials is obviously positive with a super big difference, about 60% reduction in the risk.

Alicia Morgans: Mm-hmm.

Karim Fizazi: This was the main data that we presented some months ago. At ASCO this year, we've tried to provide more data regarding the trial. For example, we provided data on pain progression or pain deterioration, and this was based on the BPI SF questionnaire. What we were able to show is that darolutamide, indeed, succeeded with better outcome with regards to pain in the vast population of men. We also provided data regarding skeletal-related events. This is probably still major because of the number of events is still low, about 30 events, but still, we clearly see a trend fairing darolutamide again. So this is for efficacy. Also, regarding overall survival, this is also probably major, after 3 years we have about 73 percent overall survival of the control arm versus 83 percent in darolutamide on, so again strong trend favoring darolutamide. We've tried to dig into toxicity data, it really seems to be a very safe agent, probably because it doesn't cross the blood-brain barrier. We don't see an excess in the falls, an excess in fractures or hypertension or cardiovascular disorders, such as we see with other AR-targeted agents. 

Even fatigue, for example, we saw a slight difference of 16 percent versus 11 percent but when this is being assessed with adjustment with the duration of exposure it totally disappeared, no difference at all. So really no side effect that we can tell is associated with darolutamide, which is just good for the patients. 

We've also tried to asses quality of life using the FACTP questionnaires, the EROTC questionnaires, and basically what we saw is that quality of life is maintained. Actually, when we're looking at this data in terms of time consideration and quality of life, it seems to be also supporting that darolutamide is better than placebo. Approximately 20 percent reduction in the risk for the FACTP questionnaire, and when we looked at the ERORTC subscale questionnaire, we don't see a difference for different subscale. But we do see the difference for bowel symptoms or urinary symptoms, very clearly a 36 percent reduction in the risk which actually makes sense. 

Alicia Morgans: Wow, Yeah. That's great. 

Karim Fizazi: So, altogether, we do see efficacy for various endpoints and safety is just neat. So it's a very safe drug as far as we can tell. I think we have a quite nice story to report. 

Alicia Morgans: Absolutely. I think it's just, it's wonderful that you're providing the longer term outcome data on metastasis-free survival and certainly some updated overall survival, but trying to round out the rest of the picture for patients and for clinicians who are trying to make choice because this is not yet an approved agent in the non-metastatic CRPC setting, but certainly we anticipate that in the United States at least, it will be available at some point. I imagine coming to Europe and other places too, as it goes through the process. When you're thinking about decision making in this patient population, assuming that you're not PSMA PETs and not finding these patients in the first place, but when you are making those decisions, what do you think about and how does the date from the updated ARAMIS data, how does that help you make those choices?

Karim Fizazi: I can see it's always difficult to compare a drug versus another one versus a third one actually.

Alicia Morgans: Absolutely. 

Karim Fizazi: The good thing here is that the three trials are very similar and they are placebo-controlled. Comparing the drugs one versus the other one is out of a discussion, but looking at the data between placebo and drug is probably something more appropriate. With darolutamide basically for safety, we don't really see much difference as compared to placebo. While enzalutamide and apalutamide we do see some differences of again regarding falls, fractures, cognitive impairments, which can be really important and really annoying in some patients in the elderly or hypertension. So those are very important things to look at. Again, this population of men is mostly asymptomatic. Of course, we want to have active drugs, we want to postpone cancer progression but we also want to protect the quality of life of all the patients and we want safe drugs. So this is why it's so important. 

Having said that, on top of all these things, cost will be very important and we will have to look at what the cost of these drugs are to make our decision because that can be a very, very important thing all of societies will look at before allowing us to use the A, B or C drugs. 

Alicia Morgans: Absolutely. One thing I also wanted to get back to that you mentioned earlier, were the skeletal-related events or I don't know if they were skeletal-related or they were symptomatic skeletal related.

Karim Fizazi: Symptomatic. 

Alicia Morgans: Which I think are more clinically important. There was a difference at least emerging there that darolutamide may be less associated with that, which I think as we are reflecting as a field on the importance of bone health is really important. When you have patients with non-metastatic CRPC, it's kind of an interesting patient population, where we have the metastatic hormone-sensitive patients or patients with long term ADT having guidelines in place regarding fragility fractures, and we have metastatic CRPC where we're trying to prevent the symptomatic skeletal events. This is sort of this carve out in between and so I'm curious were there many patients who were on bone-targeted agents because I would imagine it's few given the population and the locations where this study was done? Where do you see darolutamide fitting into the area of preventing these skeletal events?

Karim Fizazi: You are very right. Actually, only a minority of men, actually in the three trials in ARAMIS, but also in the two other trials PROSPER and SPARTAN, were on denosumab or a bisphosphonate, which my question is how best we should handle these patients, try to protect bone health. This is one thing. What we saw in ARAMIS is at least a trend, because it's major for SSE prevention, actually, the risk is reduced by half, so it's obviously a very nice trend we'll see with longer follow up visits, whether it's a true finding, yes or no. 

I agree with you on top of that we now have emerging data indicating that in this metastatic CRPC setting denosumab was indicated that it should be used broader, especially the PEACE 3 data that are presented here at ASCO are telling us that if you're using enzalutamide plus or minus radium, you probably should use these drugs to prevent fractures or other risks of this disease. I think we have these drugs on the market denosumab basically a decade ago that because the other drugs came, abiraterone, enzalutamide, chemo, radium, et cetera, and we're postponing death, probably these drugs were put on hold and we should rethink how best to use them. Of course, it's a balance between efficacy and risk of osteonecrosis of the jaw, but still, the efficacy is there, we should not forget it, and we should perhaps learn better how to use them. I'm not totally convinced that the monthly regimen is the best one.

Alicia Morgans: Yeah, agreed. 

Karim Fizazi: I was obviously involved in the Phase 3 development of denosumab but perhaps we might think about a better balance between efficacy and safety. Maybe a trimester of three-month use of those drugs is a good balance, we don't really know. So we need the data and I will be keen to see more trials looking at these questions. 

Alicia Morgans: Absolutely. Anything Silke Gillessen has Swiss study not nearly reporting at this point but hopefully, we'll have some answers around that at some point in the future. 

Karim Fizazi: Absolutely, very important Swiss trial indeed. 

Alicia Morgans: Absolutely. Well thank you so much for sharing your insights and your data and I appreciate your time today. 

Karim Fizazi: My pleasure. Thank you.