Darolutamide Improves Outcomes for mHSPC Patients in ARANOTE Trial - Fred Saad
September 26, 2024
Neeraj Agarwal interviews Fred Saad about the Phase III ARANOTE trial. The study investigates darolutamide plus ADT versus placebo plus ADT in metastatic hormone-sensitive prostate cancer. Dr. Saad discusses the trial's design, patient demographics, and key findings. The results show significant improvements in radiographic progression-free survival, time to mCRPC, pain progression, and PSA responses with darolutamide. Notably, the study includes a diverse patient population from regions where ADT alone is still common. Dr. Saad emphasizes the favorable safety profile of darolutamide, with adverse events similar to placebo. He highlights the importance of having multiple treatment options to tailor therapy to individual patient needs. The discussion concludes by noting the potential for darolutamide to become a new standard of care, offering flexibility in treatment approaches for metastatic hormone-sensitive prostate cancer patients.
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
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
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
Neeraj Agarwal, MD, FASCO, Professor, Presidential Endowed Chair of Cancer Research, Director GU Program, and the Center of Investigational Therapeutics (CIT), Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
Read the Full Video Transcript
Neeraj Agarwal: Welcome to UroToday. Today, we have the honor of having Dr. Fred Saad as our guest. As you all know, he is the Professor and the Chairman of the Department of Surgery at the University of Montreal. He also directs the GU-Oncology program at the University of Montreal. Here, Dr. Fred Saad will be discussing the results of the Phase III ARANOTE trial he just presented at the 2024 ESMO Annual Meeting.
Fred Saad: Thanks, Neeraj, that's a very nice introduction. Thanks very much, Dr. Agarwal. It's a pleasure to just briefly summarize the ARANOTE study that, as you mentioned, I presented at this year's ESMO. It got a lot of very positive feedback. I'm very happy to say that this is a global, randomized, double-blind, placebo-controlled trial that included 669 patients with metastatic hormone-sensitive prostate cancer. They were randomized 2:1 between darolutamide at the dose we're used to giving versus placebo plus ADT, obviously, as a base for all patients. The primary endpoint was rPFS. We chose rPFS because we already had two randomized controlled trials that showed the life-prolonging capability of darolutamide. And we wanted to do this study in a reasonable timeframe within an endpoint that is, I think, considered extremely important. Secondary endpoints, obviously, included overall survival and multiple other important secondary endpoints that I'll briefly summarize.
So going to the type of patients who came in, it's basically what we would expect in the clinic, but we're very happy that this is a diverse geographic group of patients with over 30% of the Asian race and about 10% of the Black race, and the de novo metastatic patients as well as the high-volume patients made up over 70% of the patients who came into the study. So very representative of what we see in our clinics. Jumping straight to the primary endpoint, clearly met its objective with a 46% reduction in the risk of radiological progression or death, hazard ratio 0.54, very statistically significant with a p-value of less than 0.0001. We see that at the two-year time point, 70% of patients on the darolutamide arm had not yet progressed and 52% on the placebo ADT arm had progressed. What we noticed in all the subgroups is that there was clearly a benefit with darolutamide over giving ADT alone, which is unfortunately still widely used around the world, especially in the countries that were included in this study.
These results were maintained whether or not it was high or low volume with a hazard ratio of 0.6 for the high volume and an extraordinary hazard ratio of 0.3 for the low-volume patient. I think one of the striking aspects, and why darolutamide was very much wanted to be used alone without docetaxel, is its safety profile. So the adverse events were actually almost identical between placebo and darolutamide, and in terms of patient discontinuation, was actually lower in the darolutamide arm than the placebo arm. And then the important endpoints that I think we all consider very important, because this is basically the beginning of the end and the need for subsequent therapies, is time to mCRPC, and this was a hazard ratio of 0.4, so a 60% reduction in the risk of becoming mCRPC. There was a delay in pain progression of 28% with a hazard ratio of 0.72. In terms of PSA response, even though the majority were high volume, over 62% of patients reached the undetectable PSA level of below 0.2, whereas only 18% of patients on the ADT arm reached that level.
PSA progression was also significantly improved in the patients getting darolutamide with a hazard ratio of 0.31 in the risk of delaying PSA progression. So briefly, in terms of conclusions, clearly darolutamide added to ADT significantly improved rPFS in these patients with metastatic hormone-sensitive disease, clear benefit across all secondary endpoints regarding overall survival. This is clearly an underpowered study, but we already saw a 19% reduction in the risk of death, but at only two-year follow-up patients hadn't reached median survival in either arm. There was a favorable safety profile, which confirms what we've seen in previous Phase III studies, and adverse events rates were actually very similar between darolutamide and placebo. The hope and the reason behind this study is to be able to offer darolutamide without docetaxel when docetaxel is not felt to be necessary, and that hopefully this will soon become a new standard of care that we can offer patients with metastatic hormone-sensitive disease.
Neeraj Agarwal: Thank you, Fred. Congratulations again for conducting this study and reporting such positive results. Just to summarize for our viewers, the ARANOTE study showed adding darolutamide to ADT compared to ADT significantly delays radiographic progression-free survival, time to castration-resistant disease, time to pain progression, and undetectable PSA responses were quite remarkable at 62% despite the fact that 70% of patients had de novo disease and 70% of patients had high-volume disease. Really remarkable data indeed. So coming back to the population included in the study, I noticed that 30% were Asians, 10% Black, a lot of Latin American patient population, so very diverse patient population. How were you able to achieve this?
Fred Saad: Well, we achieved it because in countries like the U.S., Canada, and Western Europe, availability of an ARPI in the hormone-sensitive setting became more and more widely available. To make this study possible and the results reliable, we had to go to countries where ADT alone was still a widely used standard of care. Brazil is a big contributor to the study, and a lot of the Black race came from Brazil. Asia, including India, were very important contributors to this study, where, as we all know, even though some drugs are approved, access is very difficult. And so they were really happy to be part of this study with two out of three patients getting access to drugs that otherwise wouldn't be accessible for their patients.
Neeraj Agarwal: That's a very important point, and thank you for highlighting that. How do you see this data affecting our practice across the world for people treating patients with metastatic hormone-sensitive prostate cancer?
Fred Saad: Yeah, I think you and I like to have choices, like to have options, because patients aren't one homogeneous group of people. The disease isn't homogeneous. We've got the high-volume, very aggressive de novo disease with liver mets—that's one extreme—and I would propose those patients, unless really contraindicated, need triplet therapy. And then you have the other extreme where you have low-volume asynchronous metastatic disease, and the consensus was almost 99% at APCCC, they need the doublet of ADT plus an ARPI, which I think now is the standard minimum care that we should be offering patients. And then in between that, we have to adapt to patients' needs, realities, capabilities. I think this adds to that doublet treatment option that we can offer patients and might address some of the issues where drug-drug interactions are a common problem, patients with risk of seizure. I think it's nice to be able to have multiple options and try to use what we think is most appropriate for patients.
Neeraj Agarwal: Thank you. So could you please comment on the side effect profile, what you observed in this trial, especially compared to what you have seen in your practice historically?
Fred Saad: Yeah. The striking thing of what we observed is what we didn't observe—it is the very little difference that we actually saw between the placebo and the darolutamide. I have had patients that have had adverse events to darolutamide, like I've had patients that have had serious adverse events to ADT. But this is why it takes randomized trials that are blinded to really see just how little difference we see between darolutamide and placebo. This is, I think, one of the strong points why people were saying we need to be able to access darolutamide without always being obliged to combine it with chemotherapy. Hopefully, this trial will lead to the approval around the world.
Neeraj Agarwal: And any final remarks before we conclude the session?
Fred Saad: Well, the final remarks are clearly that we have multiple options and we need to think of what the patient needs and what they can tolerate. So it's, I think, just great that you and I have lived in an era where we went from almost nothing to offer patients, now to a multitude of options. I think it's great that we can tailor treatment to patient needs, cancer realities, and I think this adds to that. And specifically on darolutamide, what's really nice is if you start darolutamide and ADT, which I think would be the standard for many patients, and we decide after a few weeks of discussion that they need chemo, that transition is a very safe transition to adding chemo to darolutamide if we feel it's needed.
Neeraj Agarwal: Well, thank you, Dr. Saad, again, and congratulations for presenting this remarkable data to all of us.
Fred Saad: Thank you very much, Neeraj, always a pleasure.
Neeraj Agarwal: Welcome to UroToday. Today, we have the honor of having Dr. Fred Saad as our guest. As you all know, he is the Professor and the Chairman of the Department of Surgery at the University of Montreal. He also directs the GU-Oncology program at the University of Montreal. Here, Dr. Fred Saad will be discussing the results of the Phase III ARANOTE trial he just presented at the 2024 ESMO Annual Meeting.
Fred Saad: Thanks, Neeraj, that's a very nice introduction. Thanks very much, Dr. Agarwal. It's a pleasure to just briefly summarize the ARANOTE study that, as you mentioned, I presented at this year's ESMO. It got a lot of very positive feedback. I'm very happy to say that this is a global, randomized, double-blind, placebo-controlled trial that included 669 patients with metastatic hormone-sensitive prostate cancer. They were randomized 2:1 between darolutamide at the dose we're used to giving versus placebo plus ADT, obviously, as a base for all patients. The primary endpoint was rPFS. We chose rPFS because we already had two randomized controlled trials that showed the life-prolonging capability of darolutamide. And we wanted to do this study in a reasonable timeframe within an endpoint that is, I think, considered extremely important. Secondary endpoints, obviously, included overall survival and multiple other important secondary endpoints that I'll briefly summarize.
So going to the type of patients who came in, it's basically what we would expect in the clinic, but we're very happy that this is a diverse geographic group of patients with over 30% of the Asian race and about 10% of the Black race, and the de novo metastatic patients as well as the high-volume patients made up over 70% of the patients who came into the study. So very representative of what we see in our clinics. Jumping straight to the primary endpoint, clearly met its objective with a 46% reduction in the risk of radiological progression or death, hazard ratio 0.54, very statistically significant with a p-value of less than 0.0001. We see that at the two-year time point, 70% of patients on the darolutamide arm had not yet progressed and 52% on the placebo ADT arm had progressed. What we noticed in all the subgroups is that there was clearly a benefit with darolutamide over giving ADT alone, which is unfortunately still widely used around the world, especially in the countries that were included in this study.
These results were maintained whether or not it was high or low volume with a hazard ratio of 0.6 for the high volume and an extraordinary hazard ratio of 0.3 for the low-volume patient. I think one of the striking aspects, and why darolutamide was very much wanted to be used alone without docetaxel, is its safety profile. So the adverse events were actually almost identical between placebo and darolutamide, and in terms of patient discontinuation, was actually lower in the darolutamide arm than the placebo arm. And then the important endpoints that I think we all consider very important, because this is basically the beginning of the end and the need for subsequent therapies, is time to mCRPC, and this was a hazard ratio of 0.4, so a 60% reduction in the risk of becoming mCRPC. There was a delay in pain progression of 28% with a hazard ratio of 0.72. In terms of PSA response, even though the majority were high volume, over 62% of patients reached the undetectable PSA level of below 0.2, whereas only 18% of patients on the ADT arm reached that level.
PSA progression was also significantly improved in the patients getting darolutamide with a hazard ratio of 0.31 in the risk of delaying PSA progression. So briefly, in terms of conclusions, clearly darolutamide added to ADT significantly improved rPFS in these patients with metastatic hormone-sensitive disease, clear benefit across all secondary endpoints regarding overall survival. This is clearly an underpowered study, but we already saw a 19% reduction in the risk of death, but at only two-year follow-up patients hadn't reached median survival in either arm. There was a favorable safety profile, which confirms what we've seen in previous Phase III studies, and adverse events rates were actually very similar between darolutamide and placebo. The hope and the reason behind this study is to be able to offer darolutamide without docetaxel when docetaxel is not felt to be necessary, and that hopefully this will soon become a new standard of care that we can offer patients with metastatic hormone-sensitive disease.
Neeraj Agarwal: Thank you, Fred. Congratulations again for conducting this study and reporting such positive results. Just to summarize for our viewers, the ARANOTE study showed adding darolutamide to ADT compared to ADT significantly delays radiographic progression-free survival, time to castration-resistant disease, time to pain progression, and undetectable PSA responses were quite remarkable at 62% despite the fact that 70% of patients had de novo disease and 70% of patients had high-volume disease. Really remarkable data indeed. So coming back to the population included in the study, I noticed that 30% were Asians, 10% Black, a lot of Latin American patient population, so very diverse patient population. How were you able to achieve this?
Fred Saad: Well, we achieved it because in countries like the U.S., Canada, and Western Europe, availability of an ARPI in the hormone-sensitive setting became more and more widely available. To make this study possible and the results reliable, we had to go to countries where ADT alone was still a widely used standard of care. Brazil is a big contributor to the study, and a lot of the Black race came from Brazil. Asia, including India, were very important contributors to this study, where, as we all know, even though some drugs are approved, access is very difficult. And so they were really happy to be part of this study with two out of three patients getting access to drugs that otherwise wouldn't be accessible for their patients.
Neeraj Agarwal: That's a very important point, and thank you for highlighting that. How do you see this data affecting our practice across the world for people treating patients with metastatic hormone-sensitive prostate cancer?
Fred Saad: Yeah, I think you and I like to have choices, like to have options, because patients aren't one homogeneous group of people. The disease isn't homogeneous. We've got the high-volume, very aggressive de novo disease with liver mets—that's one extreme—and I would propose those patients, unless really contraindicated, need triplet therapy. And then you have the other extreme where you have low-volume asynchronous metastatic disease, and the consensus was almost 99% at APCCC, they need the doublet of ADT plus an ARPI, which I think now is the standard minimum care that we should be offering patients. And then in between that, we have to adapt to patients' needs, realities, capabilities. I think this adds to that doublet treatment option that we can offer patients and might address some of the issues where drug-drug interactions are a common problem, patients with risk of seizure. I think it's nice to be able to have multiple options and try to use what we think is most appropriate for patients.
Neeraj Agarwal: Thank you. So could you please comment on the side effect profile, what you observed in this trial, especially compared to what you have seen in your practice historically?
Fred Saad: Yeah. The striking thing of what we observed is what we didn't observe—it is the very little difference that we actually saw between the placebo and the darolutamide. I have had patients that have had adverse events to darolutamide, like I've had patients that have had serious adverse events to ADT. But this is why it takes randomized trials that are blinded to really see just how little difference we see between darolutamide and placebo. This is, I think, one of the strong points why people were saying we need to be able to access darolutamide without always being obliged to combine it with chemotherapy. Hopefully, this trial will lead to the approval around the world.
Neeraj Agarwal: And any final remarks before we conclude the session?
Fred Saad: Well, the final remarks are clearly that we have multiple options and we need to think of what the patient needs and what they can tolerate. So it's, I think, just great that you and I have lived in an era where we went from almost nothing to offer patients, now to a multitude of options. I think it's great that we can tailor treatment to patient needs, cancer realities, and I think this adds to that. And specifically on darolutamide, what's really nice is if you start darolutamide and ADT, which I think would be the standard for many patients, and we decide after a few weeks of discussion that they need chemo, that transition is a very safe transition to adding chemo to darolutamide if we feel it's needed.
Neeraj Agarwal: Well, thank you, Dr. Saad, again, and congratulations for presenting this remarkable data to all of us.
Fred Saad: Thank you very much, Neeraj, always a pleasure.