Maha Hussain: Okay. Good morning and bonne journo, everybody. I'm learning my Italian. Not Swiss yet, but almost there.

Silke Gillessen: Amazing speed, I have to say

Maha Hussain: Exactly. Thank you so much. My name is Maha Hussain, and on behalf of myself and Dr. Castro, we welcome you to this session. This is going to be focusing on the management of the non-metastatic castration-resistant prostate cancer. I have to say, it's kind of a goofy terminology, because we obviously know there is micrometastatic disease. So just to clarify. And I do think this is a very interesting disease space, specifically as we get into the sort of more newer imaging technologies. Our first speaker is Dr. Elaine FTA, who will be discussing the overview of treatment options. Good morning.

Eleni Efstathiou: Thank you. Good morning. In fact, you were right about training a little bit in Italian. First, you start with a little bit more of a singing accent. I think that's the first step.

Maha Hussain: Show us how.

Eleni Efstathiou: I will do it in Greek in a little bit. It actually feels like I'm in Greece. It's a wonderful feeling and I've missed it for a while. Sleeping with your windows open and listening to the birds in the morning, and even at night sometimes. Welcome, everyone, and indeed, I loved what Dr. Hussain said. A goofy terminology. That was really upsetting me last night, so I just scratched it out and put early CRPC there. You know how I get sometimes. I was given the option and the opportunity to speak about the overview of treatment options, so the hard work is coming after me, of course. Thank you for this opportunity of having me here to our host. It is not just a great pleasure, but a great honor, and congratulations on what you've done over the years in making this the most prestigious consensus meeting, not to put down any other consensus meetings, of course, in our field. These are my disclosures.

The considerations for what we call non-metastatic, goofily so, CRPC evolution are as follows. There's a definition threshold when it comes to testosterone, and that could also be called a little bit old fashion, that less than 15 nanograms of per dL or 1.7 nanomole per L would define your threshold of castration. And then what you also need would be a biochemical progression of three consecutive rises of PSA with a PSA over 2, and this has been adapted in different ways, of course. That would be enough to call it a non-metastatic CRPC. And if you have an absence of imaging, conventional imaging, and I will leave it at conventional because some guidelines do include magnetic resonance imaging, which is not that conventional, and it is a higher level of granularity of anatomic imaging as we can get.

Now, I put in the bottom of this slide, a very simple trivia question that we may or may not address. There is a country in the world that has actually overcome this obstacle of non-metastatic and metastatic CRPC early on, back in the 2010s when they, in fact, approved, collectively, the agents abiraterone and enzalutamide back then for all CRPC. We didn't pay a lot of attention to it, but it was groundbreaking and it was way before the trials that followed.

Progression to CRPC. It comes also with a toll. It is the time when we look at the patient in the eye and we admit to the failure to cure, because even when you have biochemical recurrence, we heard yesterday wonderful discussions regarding potential salvage options, and we know how these discussions translate when you're in the clinic, we usually tell a patient, "We've got one more chance at this." That's what we usually do.

So we need to keep in mind that in order to be clean in our definition of non-metastatic CRPC, ideally, we must have exhausted the opportunities to cure early on, but we know that this is not the case, and we saw it with hard data when we looked at the phase III trials that have been conducted recently, and all three of them included patients that participated in phase III trials, hence had expectation for long-term survival, but about 20-25% of men who participated had not, for one or other reason that were not carefully explained, received treatment of their primary. So, the concept of undertreatment or even non-treatment of the primary is there and needs to be addressed as an educational level, at a practice level. I will not go onto that in a very long description.

We have, of course, the other issue that is the moment that CRPC ensues, either non-metastatic or early, however you call it, there has already been variable exposure to androgen deprivation therapy, along with a more advanced age in our patients. We know that well.

So what are the strategies available for men with non-metastatic or early CRPC? First and importantly, interrogation of the disease. Number two, interrogation of the patient's status, which probably is the most important. The second part is, what are systemic treatment options? The third part, what are local treatment options, especially for those patients who have been not treated before or undertreated? I will defer that to Dr. Blanchard's presentation. And the fourth part that we may not touch upon enough is the monitoring tools. Finally, what we need to all discuss together at the end of the session is, what do we stand to gain in the mix and what, importantly, to lose?

Interrogation of the disease. I know this will be touched upon in a bit. The advent of advanced imaging is here. We heard multiple esteemed principal investigators from the phase three trials that have been conducted, saying, do not perform advanced imaging, do not perform PET PSMAs or other PETs. I don't think I'm in any position to tell others what to do. That will be a decision that needs to be made based on their understanding of the data, the guidelines, of course, and their own practices. But, the reality is that when the disease starts getting to that early mCRPC, it is not just about advanced imaging. It is where you pause and think, "Have I done everything I should have done and should have conducted, potentially, earlier on when it comes to germline testing?" Or archival, let's call it somatic sequencing, since you may not have access currently to what you would need to do an adequate assessment for this patient.

We, again, need to remember, the non-metastatic CRPC is only early CRPC. And I know we will go into detail into this data that is already 3 years old, that represents that on advanced imaging, 50% of these men who were considered non-metastatic CRPC already may have had distant metastases. But the question here is, are these findings only reflective of heterogeneity, or are they also reflective of aggressiveness of disease? Meaning, since we don't have a baseline from before, how do we not know that these were lesions that were there before? And why would such a finding make us more aggressive in the way that we treat the disease, given the consideration of all the comorbidities of our patients?

How about in the interrogation of the patient status? Beyond germline and somatic sequencing, we have to take serious consideration of the long-term exposure to antigen deprivation. If you recall, the numbers showed a median average, I believe, of about 6 years prior exposure. And translate that to the impact on cardiovascular disease, the impact on metabolic status, the impact on bone health and musculoskeletal health, and why not emotional health. So right now, this is where, what we would call the healthcare corporation, becomes more intimately involved in the treatment of our patients. And these are multiple disciplines that need to be called in to have an opinion to also contribute to the management.

Let's go on to what is expected to be the discussion of this first presentation. The systemic treatment options. Well, obviously, you know me, you know that I will say strength is in data reproducibility. And if anything, these three trials have, and I'm sorry that the third, darolutamide, I promise I did not do it on purpose, is bolded. In fact, I would have to here disclose that I was part of the PROSPER trial, the enzalutamide. But what comforts all of us is that all three trials that are reproducible and very close in their design.

Similar trial design across registrational trials. Now, the devil is in the details, and there are some details that are different, but for this high-level understanding of the discussion, we know that all trials included men who had what was defined as non-metastatic CRPC, per my primary slide, had no findings of metastasis by conventional imaging, had a PSA doubling time that was less than 10 months, very important, and a PSA baseline equal or over to 2. The randomization was 2:1 to treatment plus ADT versus placebo plus ADT, and the main primary endpoint for all three trials, metastasis-free survival. Key secondary endpoints, overall survival, amongst the others.

I'm saying that first, because if you recall, when we all heard the three trials report positively on the primary endpoint, a lot of us scratched our head and said, "Well, we won't believe it until we see overall survival data." And guess what? All three trials met, triumphantly, the primary endpoint, obviously, and there was reproducibility of results across the trials, and they also all met their overall survival benefit secondary endpoint with very good profiles that can be, of course, debated and discussed further. I actually retrieved this from a metanalysis that reinforces the overall survival benefit consistency across all three trials, and I think it needs to be taken into consideration.

Of course, the safety signal becomes important, but here detail also becomes important. Three trials with different monitoring approaches. Let's recall that the SPARTAN trial involved every month visits, the PROSPER trial and the ARAMIS trial involved every 4 months visits and assessments of adverse events. And these, of course, differences in numbers actually see into these analyses. But all in all, you can see that there is comparable findings.

Now, the granularity of adverse event collection is actually represented in this very nice slide here. What becomes important is to look within the groups for the delta, and you can come to your own conclusions on that. I really also enjoy those spider plots that come for all studies when it comes to the adverse events. You can see on the left, the total AEs kind of having a degree of overlap, and on the right, when it comes to the adverse events, grade 3 and 4, it would seem in the gray that darolutamide is performing a little bit better. And of course, real-world practice is where the differences will be seen.

Monitoring tools. I took the liberty, and I apologize, this is the manuscript that Hussain et al and I'm part of is in review and soon to published. This has been reproduced by the other trials, I believe as well, especially the SPARTAN trial, where the association of PSA with decline with the outcome becomes a very important consideration. It is not enough to just see that PSA 50. You would wish to see an undetectable PSA to maximize the outcomes that you anticipate. flip it around. If you do not reach that amazing PSA 90 plus, keep an eye open because we have seen progression. Up to 15% progression that can be seen only on imaging and not by PSA criteria. Very important for the next step.

Finally, the whole goal of this discussion, of this meeting, is how to maximize therapeutic index in CRPC across the board. Those are a therapeutic strategy towards the most efficacious and the least toxic for the specific patient. And I said, strategy, I didn't say specific treatment option. I will stop here, and thank you.