ARANOTE Trial Explores Darolutamide’s Role in High and Low-Volume Metastatic Prostate Cancer - Fred Saad
February 24, 2025
Fred Saad discusses data from the ARANOTE trial. The phase III study examines darolutamide plus ADT versus ADT alone in metastatic hormone-sensitive prostate cancer, showing a 46% reduction in the risk of radiographic progression or death. Dr. Saad highlights new volume-based analysis showing a 70% reduction in risk for low-volume disease and 40% for high-volume patients. The treatment demonstrates impressive PSA response rates, with 83% of low-volume patients reaching undetectable levels compared to 25% with ADT alone. The discussion explores treatment selection considerations based on disease volume, with Dr. Saad suggesting doublet therapy for most low-volume patients while considering triplet therapy for high-volume disease.
Biographies:
Fred Saad, MD, FRCS, Professor, Department of Surgery, Raymond Garneau Chair in Prostate Cancer, Director of Prostate Cancer Research, Director of GU Oncology, Université de Montréal, University of Montreal Hospital Centers (CHUM), Montréal, QC
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Biographies:
Fred Saad, MD, FRCS, Professor, Department of Surgery, Raymond Garneau Chair in Prostate Cancer, Director of Prostate Cancer Research, Director of GU Oncology, Université de Montréal, University of Montreal Hospital Centers (CHUM), Montréal, QC
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Well Star MCG, Georgia Cancer Center, Augusta, GA
Related Content:
ASCO GU 2025: Darolutamide + ADT in Patients with mHSPC by Disease Volume: Subgroup Analysis of the Phase 3 ARANOTE Trial
ESMO 2024: Efficacy and Safety of Darolutamide plus ADT in Patients with mHSPC from the Phase 3 ARANOTE Trial
Advancing mHSPC Treatment Options: ARANOTE Trial Analysis - Neal Shore & Fred Saad
ASCO GU 2025: Darolutamide + ADT in Patients with mHSPC by Disease Volume: Subgroup Analysis of the Phase 3 ARANOTE Trial
ESMO 2024: Efficacy and Safety of Darolutamide plus ADT in Patients with mHSPC from the Phase 3 ARANOTE Trial
Advancing mHSPC Treatment Options: ARANOTE Trial Analysis - Neal Shore & Fred Saad
Read the Full Video Transcript
Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologist in Augusta, Georgia. We are live at GU ASCO 2025 for UroToday. I'm delighted to be joined by a good friend of UroToday, Dr. Fred Saad from Montreal. We're going to be discussing some new data from ARANOTE. Fred, thanks so much for joining us, as always.
Fred Saad: Always a pleasure, Zach.
Zachary Klaassen: So ARANOTE made a big splash a few months ago. Maybe just take our listeners through the highlights of your presentation from ESMO 2024 before we get into the new data.
Fred Saad: OK. My pleasure. So what we did is a phase III study, randomized, in patients with metastatic, hormone-sensitive prostate cancer, randomized to darolutamide plus ADT versus ADT alone, which is still, unfortunately, the standard of care in many areas around the world and in practice.
But what we did was take an RPFS primary endpoint, 2-to-1 randomization, 669 patients. And the results were positive—46% reduction in the risk of radiographic progression or death, very statistically significant, and all the other secondary endpoints of importance—time to mCRPC, time to PSA progression, and PSA response—were all positive in favor of adding darolutamide to ADT. And, obviously, it was an underpowered study, but overall survival showed a 19% reduction in the risk of death, going in the direction that we had expected.
Zachary Klaassen: And very tolerable, like we've seen in ARASENS and ARAMIS as well, right? I mean, some of those side effects were actually a little bit better in the darolutamide group, correct?
Fred Saad: Absolutely. That was one of the important aspects of ARANOTE is to be able to test it without combining it to chemotherapy. Very hard to figure out how tolerable it actually is when you're combining it to an elephant called docetaxel. So here, we saw really almost identical adverse event profiles compared to placebo. And actually, more patients discontinued the placebo arm than the darolutamide arm. Fatigue is one of the most common complaints, which was actually slightly less in the darolutamide arm than in the placebo arm.
Zachary Klaassen: So let's pivot to what you presented at GU ASCO 2025, and this is really interesting data looking at volume—so high versus low volume. We've seen this in some of the other trials. What was the rationale to look at it in the doublet with darolutamide plus ADT?
Fred Saad: The patients who came into ARANOTE were as we would expect: 71% were high volume, 29% low volume. De novo disease was the majority of patients, over 70%. So we wanted to figure out just how effective this doublet is in the presence of high or low volume. And the results were as we would have hoped.
Both groups benefit significantly in the sense that the hazard ratios are below 1 in the confidence interval. There was a 70% reduction in the risk of radiographic progression in the low-volume group, which is really impressive. And in the high-volume group, it's actually a 40% reduction—so very effective in both groups, which is reassuring.
Time to mCRPC was significantly improved in both arms, but obviously more so in the low-volume group. PSA response was 83% in the low-volume population getting to undetectable, versus only 25% in ADT alone. And still, 55% of patients got undetectable in the high volume compared to less than 15% with ADT alone.
Zachary Klaassen: So this is really interesting. We know we have very good data from the intention-to-treat that you presented a few months ago. Now we have good data with volume as well. And so I think, at least in my mind, I've always rationalized, “OK, high volume—we're still going to give chemo because we know it works.” ARASENS is a great trial design with overall survival. As we mix this new data in, how are we— I mean, I think with low volume, it's pretty clear this is going to be a nice go-to. But let's say the high-volume patients—who are we going to give chemo to, who are we going to give double to?
Fred Saad: Yeah. So this is part of the analysis. You're perfectly right. I mean, we did really well in the high volume, but we can do better. Clearly, a 55% PSA response—we can do better than that. And by adding docetaxel, we expect much more, as we saw in ARASENS, but also delaying the lethal form of prostate cancer, mCRPC.
That's what we really want to do up front. And so this reconfirms that we can do better in high volume, but in low volume, for the vast majority, doublet is enough. But I still do think we need to consider triplet even in some low-volume patients—younger patients, bulky local disease, Gleason 9s and 10s. These patients don't necessarily do well. And so I wouldn't say never triplet for low volume, but for the majority of patients, doublet in low volume looks really good.
Zachary Klaassen: Well, I think to take a term from one of your previous presentations that I use a lot, we’re not trying to get the PSA and the disease volume low—we're trying to get it as low as we can get it. And I think that's important for those younger patients who may be low volume, or those super-high-volume patients where, again, it's just six cycles of docetaxel. It's not docetaxel forever; it's just the six cycles. So I think it's a very good point.
Fred Saad: And, you know, I'm starting to think we can use that four-letter word called “cure” in some patients. And this is the first step of doing it right up front to hopefully maybe even stop therapy after two or three years of undetectable PSA, which is not unreasonable in this day and age.
Zachary Klaassen: Great discussion, as always, about ARANOTE. Any take-home message from your most recent analysis of ARANOTE?
Fred Saad: Well, there's going to be more data presented, so look forward to it in the next few weeks—looking at more details in PSA response and outcome based on PSA response. And we're going to be looking, and we've looked at, ultra-low PSA responses and how that works out. So more and more data coming out of this paper.
Zachary Klaassen: Wonderful. I know we're getting to the point, hopefully, where it's in FDA review, so I think the 2025 landscape for darolutamide is going to be exciting. Fred, always great to have you on UroToday. Thanks for your time and expertise.
Fred Saad: Thanks for having me.
Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologist in Augusta, Georgia. We are live at GU ASCO 2025 for UroToday. I'm delighted to be joined by a good friend of UroToday, Dr. Fred Saad from Montreal. We're going to be discussing some new data from ARANOTE. Fred, thanks so much for joining us, as always.
Fred Saad: Always a pleasure, Zach.
Zachary Klaassen: So ARANOTE made a big splash a few months ago. Maybe just take our listeners through the highlights of your presentation from ESMO 2024 before we get into the new data.
Fred Saad: OK. My pleasure. So what we did is a phase III study, randomized, in patients with metastatic, hormone-sensitive prostate cancer, randomized to darolutamide plus ADT versus ADT alone, which is still, unfortunately, the standard of care in many areas around the world and in practice.
But what we did was take an RPFS primary endpoint, 2-to-1 randomization, 669 patients. And the results were positive—46% reduction in the risk of radiographic progression or death, very statistically significant, and all the other secondary endpoints of importance—time to mCRPC, time to PSA progression, and PSA response—were all positive in favor of adding darolutamide to ADT. And, obviously, it was an underpowered study, but overall survival showed a 19% reduction in the risk of death, going in the direction that we had expected.
Zachary Klaassen: And very tolerable, like we've seen in ARASENS and ARAMIS as well, right? I mean, some of those side effects were actually a little bit better in the darolutamide group, correct?
Fred Saad: Absolutely. That was one of the important aspects of ARANOTE is to be able to test it without combining it to chemotherapy. Very hard to figure out how tolerable it actually is when you're combining it to an elephant called docetaxel. So here, we saw really almost identical adverse event profiles compared to placebo. And actually, more patients discontinued the placebo arm than the darolutamide arm. Fatigue is one of the most common complaints, which was actually slightly less in the darolutamide arm than in the placebo arm.
Zachary Klaassen: So let's pivot to what you presented at GU ASCO 2025, and this is really interesting data looking at volume—so high versus low volume. We've seen this in some of the other trials. What was the rationale to look at it in the doublet with darolutamide plus ADT?
Fred Saad: The patients who came into ARANOTE were as we would expect: 71% were high volume, 29% low volume. De novo disease was the majority of patients, over 70%. So we wanted to figure out just how effective this doublet is in the presence of high or low volume. And the results were as we would have hoped.
Both groups benefit significantly in the sense that the hazard ratios are below 1 in the confidence interval. There was a 70% reduction in the risk of radiographic progression in the low-volume group, which is really impressive. And in the high-volume group, it's actually a 40% reduction—so very effective in both groups, which is reassuring.
Time to mCRPC was significantly improved in both arms, but obviously more so in the low-volume group. PSA response was 83% in the low-volume population getting to undetectable, versus only 25% in ADT alone. And still, 55% of patients got undetectable in the high volume compared to less than 15% with ADT alone.
Zachary Klaassen: So this is really interesting. We know we have very good data from the intention-to-treat that you presented a few months ago. Now we have good data with volume as well. And so I think, at least in my mind, I've always rationalized, “OK, high volume—we're still going to give chemo because we know it works.” ARASENS is a great trial design with overall survival. As we mix this new data in, how are we— I mean, I think with low volume, it's pretty clear this is going to be a nice go-to. But let's say the high-volume patients—who are we going to give chemo to, who are we going to give double to?
Fred Saad: Yeah. So this is part of the analysis. You're perfectly right. I mean, we did really well in the high volume, but we can do better. Clearly, a 55% PSA response—we can do better than that. And by adding docetaxel, we expect much more, as we saw in ARASENS, but also delaying the lethal form of prostate cancer, mCRPC.
That's what we really want to do up front. And so this reconfirms that we can do better in high volume, but in low volume, for the vast majority, doublet is enough. But I still do think we need to consider triplet even in some low-volume patients—younger patients, bulky local disease, Gleason 9s and 10s. These patients don't necessarily do well. And so I wouldn't say never triplet for low volume, but for the majority of patients, doublet in low volume looks really good.
Zachary Klaassen: Well, I think to take a term from one of your previous presentations that I use a lot, we’re not trying to get the PSA and the disease volume low—we're trying to get it as low as we can get it. And I think that's important for those younger patients who may be low volume, or those super-high-volume patients where, again, it's just six cycles of docetaxel. It's not docetaxel forever; it's just the six cycles. So I think it's a very good point.
Fred Saad: And, you know, I'm starting to think we can use that four-letter word called “cure” in some patients. And this is the first step of doing it right up front to hopefully maybe even stop therapy after two or three years of undetectable PSA, which is not unreasonable in this day and age.
Zachary Klaassen: Great discussion, as always, about ARANOTE. Any take-home message from your most recent analysis of ARANOTE?
Fred Saad: Well, there's going to be more data presented, so look forward to it in the next few weeks—looking at more details in PSA response and outcome based on PSA response. And we're going to be looking, and we've looked at, ultra-low PSA responses and how that works out. So more and more data coming out of this paper.
Zachary Klaassen: Wonderful. I know we're getting to the point, hopefully, where it's in FDA review, so I think the 2025 landscape for darolutamide is going to be exciting. Fred, always great to have you on UroToday. Thanks for your time and expertise.
Fred Saad: Thanks for having me.