Fred Saad: Thank you very much. And I am the chair of the GU oncology. So I share a title like yours. It's rare for a urologist to be chair of GU oncology, but it's a pleasure to be here and it's always enjoyable discussing with you.
Neeraj Agarwal: Thank you, Fred. So this is not really a specific abstract today, unlike we have done in the past. You have led so many practice-changing trials in patients with metastatic hormone-sensitive prostate cancer. And I'll just bring up two of them here, ARANOTE trial, phase three trial with ADT plus darolutamide and the ARASENS trial, phase three trial of ADT plus darolutamide plus docetaxel. I would like to take a step back and ask you about your experience with these two trials, the therapies you have used. But before that, when you see a patient with metastatic hormone-sensitive prostate cancer, how do you start the workup?
Fred Saad: Yeah, that's a good question. I mean, when they come in the door, obviously first we want to get an idea of the extent of the disease. So you need to have imaging on top of the PSA that we obviously get and the biopsy that proves that they have cancer. After that, knowing ... And we're still doing mainly conventional imaging at diagnosis of mHSPC. So I wouldn't get into the molecular imaging, but obviously we want to know the extent of bone metastases, if there are any, whether or not they have visceral metastases, especially liver metastases. And so conventional CT scan, chest and abdomen plus bone scan is still our standard of care upfront imaging. And then we discuss with the patient, and I'm upfront with the patient. This is incurable disease. We have to be clear with the patient. This is incurable, but we can hope for many years of survival with good quality of life with all that we have to offer these patients. And so we sit down and discuss the options. And like you said, the options are really a doublet, ADT plus ARPI. And our now choice of darolutamide has added to our capabilities of treating patients and obviously the triplet approach of combining ADT plus ARPI plus docetaxel. And this is a discussion we basically have with all patients. And triplet is discussed with all, not only the worst of the worst. We really have to be upfront with patients to help them make the decision that's most appropriate for them.
Neeraj Agarwal: So when you choose triplet over a doublet, what are the factors which make you choose a triplet therapy?
Fred Saad: Yeah, that's a great question. And that comes up all the time. So obviously if a patient has high-volume disease, especially if there's any evidence of visceral metastatic disease, I really try to encourage them to take the chemotherapy earlier at the beginning rather than waiting for the disease to become resistant to an ARPI, where both of us know, and everybody who does this knows the response rate with the taxane after failing an ARPI is not great. So why not hit them early when they have the lowest amount of castration-resistant clones sitting there? We know they always have, but the proportion of those clones goes up with the volume of disease. So I'd rather hit them hard early. And then some patients, even with low-volume disease, we're going to discuss triplet, probably a younger patient, just somebody as young as you, I'm obviously going to discuss with them triplet therapy to try to hit them as hard as possible early and add treatment to the prostate with radiation therapy, even consider metastasis-directed therapy. I want the kitchen sink in a young, healthy patient to try to put them in complete remission and the hope of maybe going with de-escalation if we hit them really hard. But I have to admit, most patients really want to stick to the doublet therapy because of the fear of chemotherapy. And so this is a discussion that I help the patient make the decision, but ultimately the decision comes down to the patient.
Neeraj Agarwal: So for our audience today, when you're doing the ARASENS trial with ADT plus darolutamide plus docetaxel chemotherapy, what was the breakdown of high-volume disease versus low-volume disease? And what has been your experience in high-volume disease versus low-volume disease or de novo disease versus metachronous disease with the ADT darolutamide plus docetaxel triplet?
Fred Saad: Right. So obviously ARASENS was biased more towards the higher volume disease. We didn't stratify based on volume, but obviously because of the fact that all patients got docetaxel, whether they got ADT docetaxel as the base plus or minus darolutamide, over 80% were high-volume, high-risk disease, and the majority were de novo patients. And so that was obviously the worst kind of patients with the fastest progression to metastatic CRPC. And that's what we want to delay, really. That's an endpoint we'd like to delay as long as possible because you don't die of prostate cancer until you're castration-resistant. As long as you remain castration sensitive, you simply don't die of prostate cancer. So we'd like to park them in that space of sensitivity for as long as possible and hope they die of something else. That's the next best thing to cure, right?
Neeraj Agarwal: Absolutely. To make them alive for as long as possible while maintaining quality of life so that they don't die of prostate cancer.
Fred Saad: Exactly.
Neeraj Agarwal: That's a goal for the field. So coming to the doublet therapy with ADT plus darolutamide, you led the ARANOTE trial and it was again a big trial, hundreds of patients. What has been your experience with the doublet of ADT plus darolutamide?
Fred Saad: Right. So the fact that we did the study, because there are already three very effective other ARPIs for hormone sensitive diseases, but we felt there was a need to do a study where darolutamide could be used without docetaxel. So that was the basis of doing ARANOTE. And since we were already the fourth and there were a lot of other subsequent therapies, we did an RPFS primary endpoint. And the experience here led us to realize that darolutamide can delay radiographic progression, delay mCRPC, greatly improve PSA declines below 0.2, but also allowed us to really get a sense of just how tolerable the drug is because in combination with the docetaxel, it was hard to figure out the adverse event profiles of darolutamide because it's combined with docetaxel. So this gave us really the opportunity to realize that we're not adding much in terms of adverse events over ADT alone.
In fact, there were more patients who complained of fatigue in the placebo arm than in the darolutamide arm. More patients discontinued therapy in the placebo arm than the darolutamide arm. So that was very reassuring. And now more recently, and we're in the process of publishing, we looked at patients with multiple comorbidities, multiple other co-medications, and we realized it doesn't matter. They do well on the darolutamide in terms of efficacy, but also in terms of tolerability. And we also presented at ESMO the age, we had 30% of patients over 75, and the patients did just as well and didn't have more adverse events than the younger patients in terms of proportion with the placebo patients.
Neeraj Agarwal: So it looks like efficacy was maintained despite being older and high volume versus low volume, de novo versus non-de novo, did you find any difference in efficacy of ADT plus darolutamide in ARANOTE trial?
Fred Saad: Great question. So surprisingly, we had 70% of patients with high volume, even though they weren't getting chemotherapies. Just to show you that patients want to avoid chemotherapy. But when we looked high volume, low volume, they both had significant benefit. The low-volume patients actually had the most benefit. So this is where we're going to have the biggest impact in avoiding chemotherapy. So I think some of the high-volume patients in retrospect would have probably been better served with a triplet regimen. We got really good responses, but it was 55% getting to below 0.2. If we had given chemotherapy, could we have pushed that up? Could we have further delayed RPFS? Could we have further delayed the appearance of mCRPC? And so that's why I think it's good to have the options, know what we can expect when we're talking to patients.
Neeraj Agarwal: Absolutely. Before we conclude, Fred, what is your experience with quality of life when you are treating patients in the ARANOTE trial?
Fred Saad: Yeah. So it's one of the few trials that actually we spent a lot of effort in quality of life. And we saw that quality of life deterioration was much prolonged with the darolutamide compared to the control arm. And this is coming out now in Lancet Oncology. It's just been accepted and it should be coming out in the next few weeks. And so we're very happy that this quality of life is unique enough and studied well enough that it made it as a paper on its own. And surprisingly or not, you know this because you did a lot of work on PSA declines, the ones who get to below 0.2 maintain quality of life much longer than those that don't get to below 0.2. So we're learning a lot on what to do and how to follow these patients. What we still don't know is what do we do with patients who don't get to below 0.2? Should we further intensify? Because we're seeing that really is a dichotomy. If you don't get to below 0.2, you're going to progress much earlier and unfortunately your survival is much worse. We've got that in the clinical trials, we've got that in the IRONMAN registry. So we really have to start figuring out what do we do with these patients that don't get to below 0.2 after about six months.
Neeraj Agarwal: And that's a question which is being answered in TRIPLE-SWITCH trial by SWOG and Canadian trial cooperative group. In PEACE trial, when lutetium is being tested in these patients, I'm sure more trials will come for these patients.
Fred Saad: Absolutely. Yep.
Neeraj Agarwal: Well, it's such a pleasure to learn from your experience and thank you for sharing your time here.
Fred Saad: Thanks for the opportunity.