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Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I am joined on UroToday by Dr. Fred Saad, who is a urologic oncologist at the University of Montréal. Today, we're going to be discussing a case-based discussion with Dr. Saad, looking at recent advances in real-world decision-making for treating de novo metastatic hormone-sensitive prostate cancer. Fred, thanks so much for taking time out of your busy day to discuss metastatic hormone sensitive prostate cancer with us.

Fred Saad: Always a pleasure.

Zachary Klaassen: So this is a case that I put together. This is a 64-year-old healthy Caucasian male presented to his urologist after a screening PSA with his primary care physician, PSA notable for 35 otherwise unremarkable labs. And if you look a little deeper into his history, a healthy gentleman, an active gentleman, medical history included hyperlipidemia, hypertension, a couple of orthopedic surgeries, as you can see listed here. He's adopted, so we have an unknown family history.

But again, he lives in Montréal. He plays hockey in the men's league twice a week. He's married for 30 years. He's sexually active. He's a long-haul pilot for Air Canada.

So in terms of thinking about what we're going to do, this gentleman, he's very busy. He's very active. He's a never smoker, social alcohol.

So at the urology clinic, he undergoes a 12-core guided TRUS biopsy of two cores of Gleason grade group 5. 7 cores at Gleason grade group 4 is a PSMA PET scan, as you can see here, representative of left hip bone metastases as well as a T10 and an L2 metastases. He does have somatic genetic testing, no actual mutations. And so when we look at this gentleman, what he really has is de novo metastatic hormone-sensitive prostate cancer presents with metastatic disease. He's CHAARTED low volume, but he's LATITUDE high risk.

So, Fred, when we look at these patients, there's a lot of options we have in 2025. This is truly shared decision making. Maybe just walk through some of these criteria or discussion points that you have with patients for this guy specifically.

Fred Saad: Yeah, so-- so this gentleman has a good life expectancy-- probably excellent life expectancy. He's my age. So he's a really young guy. So we have to be careful and treat this guy properly.

Zachary Klaassen: Yes.

Fred Saad: But obviously, we need to think of all the options, whether-- the only thing that is clearly not an option is ADT alone. I hope that's not a discussion point anymore. You have to really explain why you would give ADT alone for any de novo hormone-sensitive metastatic disease. And what we're left with is the decision.

The new ADT in 2025 should be ADT plus an ARPI. That should be the standard base therapy.

And then the question is, should we give this guy chemotherapy or not? And that's really part of shared decision making. I mean, there are some patients where I would really push for chemo if this guy had liver metastases, if he had widespread metastatic disease with a very low PSA. But other than that, we really have to explain the pros and cons of chemotherapy in this kind of patient. And high-risk disease, three bone mets, Gleason 8 or more, that's a given that almost all patients with de novo hormone-sensitive disease are going to be high risk. So I think we really should look at the low and high-volume categories, rather than use their risk score or category to decide on what we should be doing.

Absolutely. I mean, that should be part of standard of care, at least a discussion. I think the data is very convincing.

Even though people might say it's not level 1 evidence, I think there's little harm in treating the prostate. I wouldn't necessarily treat the whole pelvis because we want to think of long-term chemotherapy. Eventually you want to preserve as much bone marrow. But I think the data is very convincing that you can probably delay the progression of the disease and probably improve overall survival by just treating the prostate and controlling the local disease.

Zachary Klaassen: Yeah, absolutely. And so after discussion, this patient, he's interested in a tolerable efficacious doublet therapy. I think that discussion about chemotherapy is important.

As I mentioned, this gentleman is probably gone for a week at a time flying. He's playing hockey twice a week. So he's interested in something that's not going to drastically affect his quality of life, but certainly something that's going to take care of his prostate cancer. So, Fred, I'd love for you to walk us through some of the options, maybe focusing on efficacious doublet therapy, specifically possibly darolutamide plus ADT through the ARANOTE trial.

Fred Saad: All right, so ARANOTE is the most recent trial looking at a doublet approach of maximal hormonal therapy of ADT, plus an ARPI versus ADT alone. So the nice thing is this is a recurring theme. We've got multiple ARPIs that have shown to be effective over ADT alone, and ARANOTE just builds on that basis.

And so ARANOTE was a randomized placebo controlled trial-- 2 to 1 randomization of darolutamide plus ADT versus ADT and placebo in hormone-sensitive metastatic disease. We did have some patients that were asynchronous-- so patients who were treated for prostate cancer earlier and develop metastatic disease. And the majority of those patients are going to be low volume.

But we had a significant proportion of high-volume disease in this trial, so really representative of the real world with an RPFS primary endpoint, since overall survival has already been shown with darolutamide in two previous phase III studies. So we didn't feel we needed to do a study that would be much longer and much larger to document the role of darolutamide without chemotherapy, because we already had ARASENS that adding darolutamide to chemotherapy and ADT significantly improved overall survival. And that overall survival advantage is coming certainly from darolutamide because the base was ADT and docetaxel in both arms. So there's no other explanation for the overall survival advantage that was seen in ARASENS.

Zachary Klaassen: Yeah.

Fred Saad: So the results basically are a very statistically significant reduction in the risk of radiographic progression or death, a 46% reduction, which is clinically meaningful. And all the other secondary endpoints were met time to metastatic castration resistant disease, time to pain progression, time to PSA progression. So all of the endpoints point to a very significant improvement over ADT alone in these patients.

And it wasn't powered for overall survival. But what we did look at and spend a lot of time analyzing is PSA response, because I think we all know now that the depth of PSA response is a good predictor of outcome. And here with darolutamide added to ADT, we went up to about 63% of patients reaching undetectable PSA less than 0.2, compared to only 18.5% with ADT alone. And this is, I think, very much in line with what we've seen with other ARPIs, even though over 70% of patients were high-volume disease.

So this is, I think, really important information in terms of efficacy of this ARPI that is really in line with the others. And why this is important is if you reach below 0.2, you have an 81% reduction in the risk of radiographic progression compared to not reaching below 0.2-- so very important for patients because that's what they would like.

But also for us as clinicians that if you reach under 0.2, you probably don't need to follow these patients as intensely because they're going to be progressing much later. But if you don't reach below 0.2, you probably have to follow them a little closer. Or in some circumstances, consider early additional therapy, which is something that's being looked at in clinical trials now. And again, time to metastatic castration resistant disease, which is the lethal state of prostate cancer, 84% reduction in the risk of mCRPC and a 92% reduction in time to PSA progression.

And just look at those curves. You're about 90% free of any PSA progression beyond three years. So this is really something because that's the first sign that things are starting to fall apart is when PSA starts to progress. But, looking at these patients, we're-- we're likely going to see patients dying of other causes besides prostate cancer, which is the next best thing to curing patients.

Zachary Klaassen: Right. No, these are absolutely powerful for explaining to patients why we're looking to get that PSA less than 0.2.

Fred Saad: Yeah, and we said 63% with darolutamide and 18% with placebo. And you see that here summarizing all the benefits of being below 0.2 in one single graph or slide. And the next slide, if we go to-- now looking at high volume, this is unpublished data yet, but we see that in the high volume, you're at 55% undetectable PSA, which is very good. But maybe these are the patients we'd consider chemotherapy because we'd like to get higher than 55% undetectable PSA.

But again, if you do get a darolutamide, you do much better in terms of rPFS in the high-volume patient with a 54% reduction in progression and a 40% reduction in the risk of mCRPC in the high-volume patient. Now, the low-volume patient here, we're up to 83% undetectable PSA rates, compared to only 25% with ADT alone. And here, clearly, look, 70% reduction in RPFS.

And with darolutamide, it's over 85% of patients are not progressing. And same thing for mCRPC, over 85% are not progressing to mCRPC in the low-volume stage. So this is why in a low-volume patient, it's probably reasonable to be giving darolutamide alone based on this kind of data.

And the point of trying to do cross-trial comparisons we have to be very careful about because entrance PSA is not diagnostic PSA. So this gentleman had 35 of PSA, had diagnosis. But when patients come into clinical trials, they're exposed to ADT prior to coming in. Almost all the studies had PSA between 4 and 6 at entrance.

In ARANOTE, the baseline median PSA was 21. So if we look at the group that came in with PSA of below 4, here we're at 88% undetectable PSA. Whereas those that came in with PSAs above 21 after having been exposed to ADT prior to coming into the study, it's a 51%, which is excellent, but obviously, we'd like to have patients coming in with lower PSA after a month or two of ADT.

So the time it takes to get to undetectable and how many patients will get to undetectable is clearly related to the entrance PSA in clinical trials, so be careful when you try to do these cross-trial comparisons in terms of time to PSA reduction and undetectable PSA. Now, this is just maybe to come back to ARASENS. And you see that undetectable PSA in the high-volume patient. We're getting more undetectable PSA when we add chemotherapy to darolutamide and ADT.

We're having a much better time to PSA progression with the addition of darolutamide to ADT and docetaxel. But in the low volume, here we're above 80%, and we're almost identical to ARANOTE with darolutamide alone.

This is why I say that in the low-volume patients, I'm very comfortable if the patient doesn't want chemotherapy to go with a drug like darolutamide or any other ARPI as a doublet formula for those patients. And look at time to PSA progression. 92% are not progressing at four years. This is unbelievable for patients. So that's why I wouldn't totally exclude chemotherapy, but this is a shared decision-making with the patients.

Zachary Klaassen: Yeah, absolutely, Fred. I think when you point out that comparison with ARASENS is powerful because you mentioned off the top that the baseline should be ADT plus an ARPI. And we saw an error. In those low-volume patients specifically, we're not getting a ton, at least on these metrics, by adding the chemotherapy. So for this gentleman, again somebody who's active, traveling a lot, this doublet therapy seems to be exactly what would be ideal for him-- so just a great, great discussion. Just a couple of Q&As to wrap things up.

When we look at these patients, we have a plethora of options, many doublet options, a triplet option as well. How much does the side effect profile and tolerability fit into your decision for what type of treatment you're going to give these metastatic hormone-sensitive prostate cancer patients?

Fred Saad: These are patients that are not going to be living only for six months. These patients are going to be-- we're starting to create a chronic disease out of metastatic prostate cancer, especially in the low volume. So, side effect profiles, tolerability have to be taken into consideration because they're going to be on these therapies for multiple years, we hope. And so they have to be able to tolerate them, continue to function to live with a good quality of life. And so that really does play into our decision making.

And so far, I mean, without doing cross-trial comparisons, at least compared to placebo, what was really interesting, especially in ARANOTE, was that the side effect profile of darolutamide with placebo, there was very little difference. And even in terms of fatigue, we actually saw slightly less fatigue in the darolutamide arm than in the placebo arm. So really, fatigue is largely explained by ADT. And we're not making it worse by adding darolutamide, which is really important for this gentleman who's working and wants to continue to work, which is what we want our patients to do.

Zachary Klaassen: Absolutely. In your opinion, Fred, who would-- who's the ultimate patient for doublet therapy? You kind of alluded to it a little bit during the discussion, but maybe just bring it back together for our listeners.

Fred Saad: Yeah, well, the optimal patient-- I would favor doublet for patients who have low-volume disease, that are well controlled, obviously no visceral metastatic disease because that would exclude the low-volume category, and patients that really prefer not getting chemotherapy, which is great since we don't have a head-to-head study of doublet hormonal versus triplet. So the patient has to have the last word. But the optimal patient, PSA. That's in relation with the volume of metastatic disease. I don't like it when it's discordant. Very low PSA in the presence of metastatic disease.

I think we have to be careful about very bulky local disease. Gleason 910, very bulky local. Those patients, we shouldn't underestimate their resistance to therapy. And obviously, we're talking about doublet. But really, it's triplet because we have to add radiation therapy to these patients when they're low volume to really optimize their long-term outcome.

Zachary Klaassen: Yeah, great point. And just to wrap it up, when discussing the benefits and the risks of darolutamide, as part of treatment intensification, we talked about it in the discussion quite a bit, but just the importance of not getting to a PSA of 0.1 or 0.5, but really hammering this PSA down as low as we can as quickly as we can get it. Maybe just wrap that up for our listeners as well, Fred.

Fred Saad: Yeah, well, that should be now our early signal that we're going in the right direction. So patients like it. But it's not only because patients like it. It really does translate to better outcomes. So we should be always trying to have the goal of getting to below 0.2.

Now the question of below 0.02 that we use in surgery is another area because when the prostate is still intact, it's hard to get to 0.02 because the prostate, even with benign tissue, is going to have some PSA. So at least getting to below 0.2. And if we're not, then I think we have to have that discussion and maybe consider further intensification after three to six months of therapy if they're not getting to below 0.2. But that's a research question.

Zachary Klaassen: Yep, absolutely. Fred, as always, a high-level discussion. Really enjoy your time. Any final concluding remarks or anything we need to hit on that you want to discuss?

Fred Saad: Well, the only take-home message is that we can do much, much better than ADT alone. That should be banned from our vocabulary. The new ADT for metastatic disease is ADT plus an ARPI.

Zachary Klaassen: Absolutely. Well said, Fred. Thanks so much as always.

Fred Saad: Thanks, great talk.