ARAMIS - Efficacy and Safety of Darolutamide in nmCRPC - Karim Fizazi

Karim Fizazi discusses the efficacy and safety of darolutamide with Alicia Morgans.  The ARAMIS trial evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer (nmCRPC).  Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001).  Karim discusses darolutamide as a potential new standard of care in the treatment of nmCRPC.  

The conclude their conversation discussing the final analysis of the LATITUDE study in patients with newly diagnosed high-risk metastatic castration-naïve prostate cancer treated with abiraterone acetate + prednisone added to androgen deprivation therapy (ADT). The updated findings indicated that abiraterone plus prednisone in combination with ADT continues to offer a survival advantage to men with newly diagnosed, high-risk metastatic castration-naive prostate cancer (mCNPC) or mHSPC.


Karim Fizazi, MD, PhD, 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. I'm thrilled to have here with me today Dr. Karim Fizazi, who is a professor at Gustave Roussy in Paris, France.  Thank you so much for coming to speak with me today.

Karim Fizazi: Thank you Alicia.

Alicia Morgans Of course. So, thinking back about GU ASCO you had some really big presentations that I think are going to impact the clinical care of men with prostate cancer moving forward, and I'd love to hear your thoughts particularly on the first presentation that you did in non-metastatic castration-resistant prostate cancer (CRPC). Can you tell us a little bit about it?

Karim Fizazi: Right. This was the ARAMIS Phase 3 trial. The first trial looking at darolutamide for men with the castration-resistant disease, and actually those men had high risk non- metastatic CRPC. So, the design is pretty much the one we saw already with PROSPER or SPARTAN. A big trial, 1500 men were randomized, plus or minus, and the primary endpoint was metastasis-free survival. Darolutamide has a big difference as compared to the other drugs we've seen in the past. And very different is that it doesn't penetrate the blood and brain barrier.

So we heard from Phase 1/2  development, and also from the preclinical experience that we had, was that we might see fewer side effects with that drug as compared to others. And also the preclinical data supported quite potent activity against the AR and against xenograft. So, in the trial what we saw was that the primary endpoint of metastasis-free survival was very clearly and significantly improved with about 60% reduction in the risk of metastasis, or death. So this was very, very clear. It came together with another secondary endpoint. For example, overall survival we saw this favored darolutamide with a 29% reduction in the risk, and same for pain, pain progression. About 35% reduction in the risk was observed with darolutamide. So, I think strong efficacy data was reported, and again, this is really the first Phase 3 for the trial we had with this agent. 

Now, regarding the other side, which is safety. I think this is really interesting too because the theory again predicted that this agent might be better tolerated than others, and it really seems to be true indeed. And actually, side effects, such as CNS related side effects such as cognitive impairment, fatigue, seizures, memory troubles, etc, were not seen in excess as compared to placebo, which was really impressive, and for example, patients with a past history of seizures were actually allowed to be included in the trial. Even with fatigue actually disappears when adjusted by the duration of exposure. So it's truly well tolerated with regards to the side effects. Also, we saw falls and fractures with other agents. Here it's exactly the same rate between darolutamide and placebo. And finally, cardiovascular side effects, or at least events, are absolutely not seen in excess when compared to placebos. A very safe drug.

So, effective, it's very well tolerated. The primary endpoint is met together with secondary endpoints supporting efficacy. We believe that this should become one new standard of care for these men.

Alicia Morgans Absolutely, and I thought it was really interesting, the hazard ratios may be not exactly the same as the other studies, but the prolongation in MFS was 22 months, which is what we saw before.

Karim Fizazi: Absolutely. 

Alicia Morgans And I think it was about 15 months until pain progression, or difference in time to pain progression, which is also really-

Karim Fizazi: Quite big.

Alicia Morgans ... really big, and really, really intriguing all without some of the safety issues, or tolerability issues that we've seen with other agents. 

One of the other things I think is interesting and unique about darolutamide, and that I've encountered with other agents, generally, in my clinical practice is that sometimes it can be a challenge when we have patients with comorbid illness, that hopefully is being managed actually quite effective, and they're on a stable drug regimen. Sometimes we try to add an additional agent for their non-metastatic CRPC, and find that there's a drug-drug interaction that then requires us to think through what am I going to do with this other agent that's actually controlling x, y, or z. Their comorbidity. 

With darolutamide, it does not look like there are necessarily as many drug-drug interactions, and I think that's going to be a positive thing too as-

Karim Fizazi: I agree. 

Alicia Morgans ... we actually put this drug into practice.

Karim Fizazi: Absolutely. Actually, in the perconate experience that was conducted with darolutamide, drug-drug interaction was very low. Clinical data will come soon supporting that, and in ARAMIS, actually, this was very reassuring to me. They're right. Indeed in many of these men who are typically 75 year old, they already have quite a long list of drugs, so it can be alarming to have a drug with strong drug-drug interactions. So yes, that's also a very good thing with darolutamide and it's again, supporting this as potential alternate healthcare for these men.

Alicia Morgans Absolutely. One other piece that I want to flush out a tiny bit, was an apparent trend at least to improved overall survival. This was an early analysis, so the data is not yet mature, but the curves actually separated nicely. I think that one of our fears is that we are potentially just moving a drug earlier but not changing the trajectory of the disease. At the end of the day, we want to not only prevent metastasis, we want to help people live longer, give them time to have additional therapies, and change that disease trajectory.

This is the closest we've seen of any of the drugs to really, kind of, needing that statistically significant endpoint. Though it wasn't quite significant, because it's still in interim analysis, but I'd love to hear your thoughts on that.

Karim Fizazi: I totally agree with you actually. So, the three-year overall survival rates that we saw were 73% with placebo over 83% with darolutamide. P value was .04 basically, .04 or .05, whatever. So because this was an interim analysis, we cannot claim victory and say this is significant, but it's a strong trend very obviously. It actually supports more generally the concept of treating earlier with those agents, something that we've seen also in the castration sensitive metastatic setting, where we're using, targeting strong the AR pathway in those men with bad cancers, might make a difference, not only as you said, in terms of first endpoints, either MFS or radiographic progression-free survival in the castration sensitive metastatic setting, but also in terms of overall survival, which is eventually what we want to do.

So, for ARAMIS, and that's true also for PROSPER and SPARTAN, more time will tell. Where we receive a case, that I think it will eventually be the case that we knew our survival will be significantly improved with these agents in M0 CRPC.

Alicia Morgans: I hope so, for everyone's sake.

Karim Fizazi: Me too.

Alicia Morgans There was another presentation that I wanted you to comment on, and that was the LATITUDE update. So you've also been really a key player in that study. What did we find? What was the updated data kind-of punch line?

Karim Fizazi: Sure, so when we reported the first interim analysis, almost two years ago at ASCO, of two co-primary endpoints of rPFS and OS were met and I think very clinically significantly met with, let's say, almost a 40%, let's say a 35% reduction in the risk of death. Something around that. With early abiraterone in men with high-risk metastatic castration sensitive disease. Now one criticism that was made at that time was that in the control arm, patients didn’t really have the time to receive more active agents for CRPC, which was true. Now with more or longer follow up, almost two years of additional follow up, actually 57 of men in the control arm have received at least one life-prolonging therapy for CRPC when progressed to that, including abiraterone, enzalutamide, docetaxel, and some others. 

So, it's really comparable to what we've seen, for example, in CHAARTED or in STAMPEDE, or docetaxel, it's actually even higher, to be honest. And even though we still see, a strong difference in overall survival, the hazard ratio remains almost the same. It's .66, a 44% reduction of the risk of death. The curves are really very, very parallel, and it's almost a year and a half of additional life as a median that we're providing with earlier abiraterone to these men when we're treating them early. So it's big, it's really big. 

Now the question is whether this is the new standard of care or whether the taxanes remains, and of course, this is highly debated. My gut feeling is that abiraterone probably provides more activity to these men. Slightly more but still more of this is true for progression-free survival very clearly. Unfortunately, many men who received ADT tend to progress quite rapidly when they have a high volume or high risk disease. While with abiraterone, it takes much more time. And even for overall survival, of course, it's very difficult to compare trial to trial. But here we're seeing at least a 34% reduction of a risk of death in LATITUDE and in STAMPEDE with abiraterone for these men it's basically 40% while for the docetaxel with the updated analysis of CHAARTED or STAMPEDE etc, it's more about a 20-25% reduction of the risk of death, no more. 

So it could well be that actually, we're more impacting of the duration of life the good way with abiraterone, which actually makes sense, I mean the AR is the main oncogenic driver of disease for many of these men. So when you have a good drug with targeting strong oncogenic pathway, it makes a difference in oncology. 

Alicia Morgans: Absolutely, well I think that speaks to my interests and understanding what might happen if we combine these therapies. So the ARASENS trial is coming out at some point in the future with chemotherapy and darolutamide, +/- darolutamide essentially. And that's going to be a combination approach, and so we can see at least ... not a head to head, but we can at least see is there synergy or potentially something additive that we can get by making these drugs a combination and really hitting home any of the clones that may be escaping one mechanism or the other. So more data to come and I have so appreciated your time today. Thank you so much.

Karim Fizazi: Thank you, Alicia.

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