Read the Full Video Transcript

Neeraj Agarwal: Welcome to UroToday. Today, we have the honor of having Dr. Fred Saad, one of the most well-known GU oncologists in the world from the University of Montreal joining us. Welcome, Fred.

Fred Saad: Thanks, Neeraj. Thanks for having me. Always great.

Neeraj Agarwal: So we'd love to have your take on your EAU presentation. Can you please tell us more about the data you presented at the European Association of Urology meeting in 2025?

Fred Saad: So it's going to be my pleasure to explain what I presented that I think is really quite interesting and I think quite novel. So what I presented at EAU is really the PSA response with darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer that we saw in the ARANOTE study.

So just as a brief introduction, ARANOTE was a phase III randomized, placebo-controlled trial of darolutamide plus ADT versus ADT plus placebo that showed a significant reduction in the risk of radiological progression or death by 46%.

And it confirmed the low adverse event rates in using darolutamide compared to ADT without any other treatment. So this was quite reassuring. And we had reported that achieving an undetectable PSA of less than 0.2 at any time, these patients had better ECOG performance status at study entry, lower Gleason scores, lower baseline PSA values versus patients who did not achieve that level of less than 0.2.

And here we report the post-hoc analysis of ARANOTE correlating PSA response with outcomes overall and by PSA level at study entry. So just as a reminder, we saw throughout the study more than a threefold increase in achieving 0.2 nanograms per milliliter with darolutamide compared to patients that were on ADT alone.

And this was throughout the study, always at least three times more patients achieved this level. And overall at any time was 62.6% versus 18.5%, even though more than 70% of patients were high volume de novo metastatic disease.

And patients who achieved this level of less than 0.2 compared to not achieving less than 0.2 had a very significant, about a 90% reduction in the risk of RPFS in patients on darolutamide. And patients who achieve this undetectable level of less than 0.2 had a much longer time to mCRPC and time to PSA progression—again, in the range of a 90% reduction in the risk of progression to mCRPC and PSA progression.

As you would expect, the darolutamide arm always had better PSA responses, whether it was high or low volume. In the low volume patients, it was over 80% of patients that achieved this undetectable level versus only 25% with ADT alone. And even in the high volume, 54.6% achieved this level versus only 15.5% on ADT alone.

What we looked at that’s a little bit more unique is that we looked at what PSA entry level patients came in with. And as you recall, several studies had PSA entry levels that were quite low, under 10 or even in the range of 5. Here in the ARANOTE study, we had a PSA median entry of 21, just showing, I think, reflecting that in ARANOTE, most patients were exposed to ADT for a very short amount of time before coming in. But it gave us the opportunity to look at how significant entry PSA when you start a drug like darolutamide has on an impact in terms of outcome.

So we would put it below the median: less than 4.1, 4.1 to 21, and then above 21. And you see that the patients who came in with PSA levels lower had lower incidence of de novo disease compared to patients that had PSAs above 21.

And when looking at entry level PSAs and outcome in terms of reaching undetectable PSA, a much larger proportion of patients achieved this PSA of below 0.2 if they came in with less than 4.1 of a PSA level. And here it was over 85% of patients achieved that level of less than 0.2 versus about 50% of patients if the PSA was above 21 when they came into the study.

And what does that translate to? Well, numerically, there was a longer time to RPFS or death in the patients with levels of 4.1 or less compared to patients with PSA of above 21. In terms of becoming mCRPC, time to PSA progression—again, numerically, patients with less than 4.1 had better outcomes than those with above 4.1.

So again, I think reconfirming that the lower the PSA level when you start an ARPI, the better. And so darolutamide, I think we now confirm, provides deep and durable PSA responses in the overall population—very much like we saw with ARASENS when we added darolutamide to ADT and docetaxel—more than a threefold likelihood of reaching that level compared to patients who were on placebo and ADT. And undetectable PSA was achieved in a greater proportion of patients, regardless of baseline PSA.

An undetectable PSA with darolutamide correlated with clinical benefit in terms of radiological progression or death, longer time to mCRPC, and PSA progression. And again confirming that regardless of PSA entry levels, the safety profile was maintained across all subgroups, regardless of PSA response and baseline PSA. Thanks, Neeraj.

Neeraj Agarwal: Thank you, Fred. This is amazing. Congratulations, first of all, to you and to your team for successfully conducting a large phase III trial which was happening worldwide. And it takes years of time and efforts and hard work. So really fantastic job. And we really hope to have another option in our clinic without having to use concurrent docetaxel based on these data.

So these are practice-changing data. And the PSA values, especially the data you showed on lower the PSA values, higher are the chances of undetectable PSA rates of less than 0.2 nanograms per mL. Longer is the time to castration resistance, longer is the time to PSA progression. And hopefully, ultimately, all of this hopefully will translate into overall survival down the line. And we are looking forward to those data.

I’ll ask you a few questions regarding the data and how does it apply to our real-world population. First of all, undetectable PSA or PSA of less than 0.2 nanograms per mL—what is your take on patient counseling and prognostication in the clinic? How do you use these data to talk to patients when they achieve a PSA of less than 0.2 nanograms per mL?

Fred Saad: Yeah. So obviously, the discussion is much more optimistic when they reach that level of 0.2, because I can say with a lot of conviction that they’re likely going to do well for a longer amount of time.

And the practicality is, the way I follow a patient who reaches below 0.2 is more spaced out in terms of imaging, in terms of coming back to the clinic, in terms of follow-up, because I know that they’re going to remain responsive for much longer. This is very different than a patient who doesn’t get to below 0.2 or stays quite high. We have to be very conscious that those patients are likely to progress earlier, need closer follow-up so that when they become mCRPC, we react quicker.

Now I think your question is, in those who don’t reach that 0.2, should we do something more? That’s still a question that I think is being addressed in ongoing studies. But I think this data helps us maybe to understand that if you’ve got high-volume disease—high PSA—maybe you need to consider the triplet approach from the beginning. That these patients, yeah, we’re getting 50% response, but 50% are not getting to below 0.2. So do we need to wait, or should we act early? And I think there’s more data supporting acting early, getting that synergistic effect rather than taking six months to realize they should have gotten docetaxel or some other option that is being developed.

Neeraj Agarwal: That’s a great point. And I was going to ask you the question regarding monitoring—how do you monitor these patients who achieve a PSA of less than 0.2 nanograms per mL? And you already answered.

And I practice the same monitoring pattern in my clinic. I agree with you. If PSA is less than 0.2 nanograms per mL after six months, if I feel relieved, feel happy for the patients, and let them not be seeing us for three months or even four months, allow them more time, more local labs, less frequent scans. Those are really great points for our colleagues out there across the world.

Regarding the clinical trial you mentioned, we discussed this in the APCCC meeting regarding de-escalation, especially in those patients who are having or experiencing side effects, especially severe side effects. Do you feel more comfortable—admittedly, we don’t have the trial data yet, we are still waiting for de-escalation trial data—but a patient has achieved a PSA of less than 0.2 nanograms per mL and is experiencing severe side effects—fatigue, hot flashes. And we have a lot of those patients, especially younger ones.

Do you feel more comfortable de-escalating the therapy in those patients, taking a break? If you de-escalate, how do you de-escalate? And what are the practical implications for our colleagues out there in the community who are listening to this podcast?

Fred Saad: So, Neeraj, you want me to be shot if I say something that is not evidence-based. But I agree with you—these are the realities in the clinic. Now, obviously, I tell the patient we don’t have the data of what happens if we de-escalate, because all the trials continued until they started to fail.

But this is a shared decision, and this is part of our responsibility—to say that things that we don’t know, we have to make a decision with patients. But I definitely would not de-escalate before at least a couple of years. I mean, we have the data that two or three years of hormone therapy in the non-metastatic high-risk population with radiation is what’s proven to help. So in a metastatic patient, I wouldn’t de-escalate after six months or a year.

Let’s talk about it in a couple of years is what I tell patients. We have to get them to go through these adverse events and help them to cope with it because their life is at stake. Now, in a patient who has a complete response that’s long-term, that on imaging, there’s no question they are getting a really good response because sometimes there’s a discordance between PSA response and we start seeing progression. We know from multiple studies that it does happen. So we have to be sure that nothing else is abnormal in terms of imaging, alkaline phosphatase, LDH—something that would tell us this is becoming a less friendly prostate cancer. But if everything is aligned, this is a shared decision. And I have, in some patients, stopped after two or three years of being in that kind of situation of a complete response type of patient.

Neeraj Agarwal: Thank you. I agree, there are no data to support de-escalation right now, but what to do with those patients who have severe side effects? I think I personally feel more comfortable talking about taking a treatment break with them if they have achieved a PSA of less than 0.2 nanograms per mL, like you said. And we look forward to the data from those de-escalation trials which have already started recruiting patients.

Fred Saad: And volume is important, right? I mean, I would be more favorable in a low-volume patient that we’ve treated—the prostate and sometimes in studies with oligometastatic treatment. I mean, we’re going to get to that point where we will have to consider de-escalation.

Neeraj Agarwal: Fantastic. Any summary, any message for our audience from these data—final message?

Fred Saad: Yeah. Final message, I think we owe it to our patients to try to personalize as much as we can in terms of their treatment. Not all metastatic hormone-sensitive patients fit in the same box. So we need to, I think, personalize in how we treat. So more aggressive patient, more aggressive treatment. Less aggressive, we can probably get away, as much as you said. But really, I think that’s what we’re trying to get to, is personalizing as much as we can. And these patient responses, I think, help us to personalize care and follow-up.

Neeraj Agarwal: Absolutely. Thank you so much for joining us today.

Fred Saad: It’s a pleasure, Neeraj. Always fun.