Alicia Morgans: Hi. I'm so excited to be at ESMO 2022 where I have the opportunity to speak with Professor Laura-Maria Krabbe, and she's going to review updates and thoughts about non-metastatic, castration-resistant prostate cancer. Thank you so much for being here, Professor Krabbe.

Laura-Maria Krabbe: Well, thank you so much for having me.

Alicia Morgans: Well, wonderful. So we have talked about this several times, and you had a phenomenal presentation also at EAU this year, so I'd love to hear your thoughts. How do you sort of think through the process of treating a patient with non-metastatic, castration-resistant prostate cancer?

Laura-Maria Krabbe: Right. Thank you so much. So, obviously, these are patients who have reached the state of castration resistance. So the first thing, I will think about, well, how did they get there? And obviously to reach the state of castration-resistant disease, first you have to have initial treatment, then you recur, you get maybe salvage treatment or you get ADT. But at some point in time you will have had ADT to reach that castration-resistant state. And obviously some patients will not show any evidence of metastatic disease on conventional imaging, and that would be the person we would consider non-metastatic, castration-resistant. Obviously, at this point, you should always check if they're adequately castrated from the drugs they're receiving because if they're not, obviously that is something that you can tweak a little bit and improve the depths of castration. But if they're adequately castrated, their PSA is rising, and they show no evidence of metastatic disease on conventional imaging, that is someone who has M0CRPC.

And then you can also categorize them into a high-risk category of developing metastases fairly soon or a low-risk category, and that depends a little bit on the PSA doubling time. And if it is less than 10 months, so very short PSA doubling time, that's the people you would consider high-risk M0CRPC, so at high-risk of developing metastases. And these patients, I think, warrant treatment intensification. We've seen this in three phase III trials, and all three of them were designed fairly similarly, including this patient population of high-risk M0CRPC, and then treating them with the continued ADT that they had before.

And in the interventional arm, NHT, a new hormonal agent was added. And in one trial it was apalutamide in one trial was enzalutamide and a third trial was darolutamide. And since the trials were designed fairly similarly, it was really nice to see that they also rendered very similar results. So the primary endpoint in all of those three trials was metastasis-free survival. And we saw in all three trials that the addition or the intensification at that point led to significantly prolonged metastasis-free survival. And in further updates, we also saw that it led to significantly prolonged overall survival. And that, to me, is a very good reason to intensify in this treatment population. And all three drugs are approved for this specific setting of high-risk M0CRPC.

Alicia Morgans: Absolutely. What I think is so interesting, to your point about trying to identify the highest risk patients, in the trials, at least, those patients had a PSA doubling time of 10 months or less, because as you said, those are the patients who are most likely to develop metastatic disease or death from prostate cancer. So really that's the trial for the population in the studies. I would say it's interesting... And those are the patients that I usually use this approach in, but there aren't restrictions, at least in the approvals on the labels of the drugs regarding the PSA doubling time. But an important clinical concept nonetheless, from my perspective.

Laura-Maria Krabbe: Yes. So I think in Europe the approval is a little bit more strict than maybe in the US. So I think it's great that we get the opportunity to exchange these or tweak on these differences. But I totally agree. Obviously, someone who has a PSA doubling time of 10.8 months or 11.2 probably has, maybe at that point in time or at least in a very short time, a very similar risk to someone who has a PSA doubling time of 9.8 months. So sometimes having a little bit of a broader approval basis is easier. However, in Europe it's a little bit more restricted and very strictly enclosed to the study inclusion criteria. Also, the guidelines, and obviously they orient themselves on the trials, stayed specifically or put the PSA doubling time in there. But I agree sometimes the changes are... It is, let's say, more of an arbitrary concept that some the cutoff should be at 10 months exactly. And obviously, that's a continuum as so often in medicine.

Alicia Morgans: So often it is. But again, your excellent points, the guidelines in the US also say the 10 months, and that's what I use in clinical practice. And once again, Europe is a little more discerning about things than we are in the US. But as you think about treating these patients, how do you approach the patient who perhaps has had PSMA PET scans performed or a scan performed, which is very common I think in Europe, really routine at this point in time, and is becoming increasingly common where I practice in the US as well. How do you think about that patient?

Laura-Maria Krabbe: Well, it's a little bit difficult, obviously, because all trials, be it M0CRPC trials but also the MCRPC or even MHSPC trials, have been based on conventional imaging. But sometimes, obviously, the time or the developments are faster than the trials can keep up with. And so, obviously, we see many patients receiving PSMA PET scans, I mean, as they should in certain situations. For example, if someone has biochemical recurrence, so they're even a couple of steps before M0 or potential M0CRPC, I like to perform PSMA PET scans to decipher do they have local recurrence and they could potentially receive a local salvage therapy? Or do they have systemic disease and need treatment intensification at that point already? So this maybe more routine use of PSMA PET scans in biochemical recurrence will lead to a lower proportion of patients reaching M0CRPC at some point because they will show systemic disease at that point already and will get the treatment intensification already at that point in time.

However, obviously, clinical practice is not always perfect, and you will see patients who will receive ADT and who will maybe at some point not have a PSMA PET scan. And if they reach the point of becoming castrate-resistant and I can't get conventional imaging really, really fast and easily, then I mean, I do not press them for PSMA imaging because as they are castration-resistant and they have a short PSA doubling time showing me that their disease is very progressive, then if they show metastases, I will intensify them. If they don't show metastases, I will intensify them. So actually at that point, I don't need this specific imaging to make my treatment decision. And so at that point, if they come to the clinic having not had PSMA PET scans already, I will not push for it in this situation.

Alicia Morgans: And I could not agree more. And I think it's interesting the way that these scans sometimes come when a patient comes from outside or comes from somewhere else, but I myself similarly do not order them. And thank you for the excellent point about biochemical recurrence, because as you said, it may be sorted out even before they would've gotten to this non metastatic CRPC setting, and so this is going to be, I think a population in flux. But on ADT, castrate levels of testosterone, rising PSA, PSA doubling time less than or equal to 10 months, conventional imaging negative, this will be our population regardless of what a PSMA PET shows. So very, very important, and so important to mention too that we would intensify either way, whether that scan is positive or negative. So moving on. Let's talk a little bit about how these patients feel and how they feel when they're on treatment. This is generally an asymptomatic patient population, so why would you want to intensify treatment?

Laura-Maria Krabbe: Well, I mean you're correct, they're asymptomatic, but we know that because of this high risk of developing metastases, they could very well be symptomatic very soon. And as we saw in the trials, delaying metastases meant also prolonging overall survival or delaying death from prostate cancer or actually any cause, because overall survival was that end point looked at. So that's the reason I want to intensify, to prolong the time for them to develop metastases and also to prolong their life. But it always has to be well balanced, because as you say, they're asymptomatic. They're on ADT probably already for quite some time, so they will feel the side effects that you normally feel from ADT, But then by intensifying, I obviously want to get the good effects of the good efficacy of those drugs, but I also want to maintain their quality of life.

I don't want to make them worse by giving them drugs that might help on the one hand, for oncological reasons, and so obviously this has to be very well balanced in an otherwise asymptomatic population. And we've seen this actually with all three drugs, that quality of life was maintained. That was one of the points looked at in all studies. And also, the time to deterioration was pushed back. So despite adding a drug that obviously could potentially have more side effects, quality of life wasn't impacted, and also the time to deterioration, as I said, was prolonged. So that was something good for the patients and therefore not much to worry about by adding another drug.

Alicia Morgans: Fantastic. And again, I could not agree more. So one of the things though that I do think about, and I know you've thought about this a lot too, is that this is an aging population of men who may have other medical problems, may have other drugs that they need to take care of those other medical problems. How do you think through adding an androgen receptor antagonist, one of these agents, when you're also trying to think through their comorbid illnesses and other medicines?

Laura-Maria Krabbe: Yeah, sure. So I mean obviously the first goal or my first priority would be to intensify them. So if I have a limited amount of options, because not everywhere, all three options are available, that will dictate what I can utilize. The second important thing is I think that the treating physicians should feel comfortable with the drug prescribed, because that obviously also leads to better anticipation of potential side effects and also better management so patients can be on drug longer and benefit more. But then the third thing, as you mentioned, these are elderly men and they might have comorbidities, and we saw for example in the study looking at darolutamide, there were many men having six or more comorbidities or having 10 or more medications. And interestingly, they looked at a level of benefit for men with less than 10 comorbidities or less than 10 medications and more.

And they saw that the benefit was equally there, even for those more comorbid and more heavily medicated men. So that shouldn't preclude us from intensifying these patients. However, it is a good point to think about, well, which drug should I use or which drug can I use safely? And within this topic, I think we, for the first time, thought a little bit more about drug-drug interactions. And we see some different drug-interactions with each of the drugs, and there are little tables, which I find extremely helpful, where potential drug-drug interactions and also the direction are mentioned. And that can be a good guidance on which medications to choose for which patient if there are comorbidities or comedications.

Alicia Morgans: Absolutely. I'm so grateful always to our pharmacy as they sort out some of those things. And sometimes you think, oh, I'll try this me medication, but there's a really difficult interaction, and then so switching to another. Given that they all three are very effective in this particular patient population, it's nice to have those options, and switching to another can be a good option. So I'm wondering how do you follow a patient? When you do put a patient on treatment, how do you make sure that the patient's not having progression? Is PSA monitoring enough?

Laura-Maria Krabbe: Well, I mean to that question, I can clearly say no, it's not enough. And I will briefly explain why. So for one thing, obviously, monitoring PSA is something that's helpful because in many patients we see that the PSA will go down, and that will also tell us something about the prognosis of these men, because we know that if they have a PSA drop of 90% or more or if they drop their PSA to 0.2 or lower, that's a very good prognostic sign for them. So that's something for us to kind of, I mean, not plan out, but at least to kind of gauge a little bit what kind of treatment benefit we can anticipate for this man. So that's one thing where PSA helps us. But I look at them clinically. We obviously look at other lab values like alkaline phosphatase, LDH, blood counts, such things like that.

And I mean, clinical appearance is obviously important. However, we've seen from the studies, and especially the one with darolutamide, you actually gave us some great data here at ASCO, which I think is very helpful clinically, looking at, well, how did the people look like when they progressed? And the interesting part was that patients who had remained on ADT alone in the control arm, they had a PSA of about 50-ish, roundabout, when they progressed. And the patients on the intensified therapy with ADT and darolutamide had a PSA of about 16 when they progressed. And you could say, oh, maybe their PSAs at baseline were different, but they were not. So at baseline, they were very similar, but at progression they were not. So we cannot just say, oh, we'll wait until the PSA rises up, and then we'll see. We have to monitor in between.

Then you could obviously say, oh, I'll wait until they have symptoms. Because maybe they will get symptoms, and then I know, okay, I should go image and then I'll find the metastases. But there's no difference in the amount of patients having symptoms, and actually the amount of patients having symptoms is not large. It's maybe one and every five that also has symptoms at the time of progression. So that to me means that I have to monitor them a little bit independently of symptoms and PSA. And therefore, imaging in regular intervals, even though we have no clear-cut guideline on how often that should be, even if they're asymptomatic and PSA is good, should be part of your follow-up plan.

Alicia Morgans: I agree. And to that point, I'm hopeful that our guidelines organizations might make some expert recommendations at some point. So we'll have to continue to see how that progresses. But some interval seems like it would be reasonable, and that may be something, at least until the guidelines suggest, we might have to tailor to our individual patients and their risks. So very, very helpful. So any other thoughts? Anything else you'd like to add on this exciting patient population?

Laura-Maria Krabbe: Well, I think that many physicians or many people kind of dismiss it a little bit as an, oh, this group is so small, we don't want to bother with them. And I would caution against that because while it's true that this patient population will become smaller over time, still the impact you can make by finding a patient with high-risk M0CRPC and intensifying that person and therefore prolonging MFS and, more importantly, OS with a very reasonable side effect profile and a very good maintained quality of life, that should remain, I think, an important point. And therefore I would encourage everyone to have M0CRPC on our minds and to look out for the right patient to intensify at an early point in time.

Alicia Morgans: Well, thank you so much for talking this through. I feel like I could just keep saying, yes, I agree, with all of the points you make. And really, when you're able to prolong metastasis-free survival by almost two years, regardless of the drug you choose, when you're able to prolong overall survival, regardless of what you do between the time they have non-metastatic disease, castration-resistant disease, and ultimately succumb to the disease, I mean, that's a big benefit that we can see there. And it's so important, especially as we maintain quality of life. So thank you for talking us through all of the nuances. I always appreciate your time and your expertise.

Laura-Maria Krabbe: Thank you so much for having me.