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Zach Klaassen: Hi. My name is Zach Klaassen, I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are in Chicago for ASCO-2024. I'm delighted to be joined by Dr. Alicia Morgans, GU medical oncologist at Dana-Farber. Alicia, thanks so much for joining us.

Alicia Morgans: Thank you for having me, Zach.

Zach Klaassen: So we're going to talk about an exploratory analysis of the ARAMIS trial, and we've heard a lot about darolutamide over the last five, six years. Just walk our listeners through where we've been with darolutamide in this exact disease space of non-metastatic CRPC.

Alicia Morgans: Sure. So based on the ARAMIS trial, which was of course a Phase Three international registration trial, darolutamide was approved for the treatment of non-metastatic CRPC. This was really based on a 22-month improvement in metastasis-free survival and a 31% reduction in the risk of mortality or death in patients who were treated with ADT and darolutamide versus those patients who had continued ADT and received a placebo.

Again, this was in non-metastatic castration-resistant prostate cancer so patients didn't have conventional imaging evidence of metastatic disease, but this was really before the era of PSMA PET scan utilization. I think, in our practices we can absolutely use these medications in patients who have PSMA PET scans that are positive as long as their conventional imaging is negative. At least that's how we've interpreted it to this point, though there are certainly investigations to try to understand that better. But this was an exploratory analysis to look within the population of treated patients.

Did it make a difference if you had a really deep PSA response, less than .2 versus over that or not, to try to understand who are the best responders and what are the outcomes in these two different groups?

Zach Klaassen: Yeah, it's important because we see these deep responders. These are the patients that are happy, their PSA goes down within three to six months. But this analysis really does look at how does the radiographic progression differ between these two groups, right?

Alicia Morgans: It does, and I think among those patients who have that really deep response, the radiographic progression is pretty minimal, even at the follow-up of about three years. I think what's also really important is that there's very little progression, in terms of radiographic progression, in the setting of a low PSA. For those patients who don't have as deep of a response, there seems to be clearly a higher rate of radiographic progression. There can also be progression in the absence of PSA rising, which is important to know, but it's actually a very low number of patients throughout this study.

Zach Klaassen: Right. And just by way of background, maybe take our listeners through the ARAMIS trial design and how this specific analysis was set up.

Alicia Morgans: Sure. So the trial included patients who had no evidence of metastatic disease by conventional CTs, MRIs, and bone scans. PET scans were not included in this study. Patients did have to have a PSA of about two, I believe, and they had to have a PSA doubling time that was less than 10 months so it was identified as a high-risk, non-metastatic, castration-resistant prostate cancer population. All patients had to have been on ADT while the PSA was rising and have a castrate level of testosterone less than 50. In this study, patients were randomized to receive ongoing ADT plus placebo or ongoing ADT plus darolutamide. And, it was in that context that we found that 22-month prolongation of metastasis-free survival for patients who got that darolutamide addition. And, of course, the reduction in mortality.

So this study was looking at, within that study population, how did things fall out for different groups who had maybe that more substantial PSA response versus those that did not. And what is evident in the poster, and certainly we can have a QR code or a link to that poster here, is that those patients who have that really low PSA had minimal progression, even at three years, versus what seemed to be a relatively steeper amount of progression in patients who did not get down to that low level. And, importantly, a much greater population is going to achieve that very low, less than .2 PSA response in patients who received darolutamide versus nearly no patients who were receiving placebo reached that level.

Zach Klaassen: Right. I think too, and you had mentioned 24 months darolutamide treated patients, only 9% radiographic progression versus 33% that didn't reach that PSA of .2, and then 36 months it goes up to 50%.

Alicia Morgans: Yes.

Zach Klaassen: So how does this information, when we're sitting there with patients, we're following PSAs every three months, how do you counsel your patients based on this new data in terms of what our goals are for their PSA?

Alicia Morgans: Yeah, so I actually try not to give my patients a goal for PSA. I think that's undue pressure on a person who has absolutely no control over that. Certainly, they can take their medication, which I encourage them to do, and I think most patients do. We have discussions about side effects to try to ensure that patients are continuing to feel well while they're on their medication. And, if not, we try to mitigate those or we try to take them off the medicine if it's really causing complications.

But I do think that it's a lot to put on a person, to achieve this PSA less than .2. When patients do get to that less than .2, I congratulate them and say, "Here's the data, this is really encouraging," but otherwise, I think as a clinician I may watch them more closely. And we've had multiple pieces of data suggest that the lower our PSA goes, and there are multiple thresholds in different disease situations where we are looking for different thresholds, where we keep a closer eye and especially with the potential of progression without PSA progression, we might scan them more often.

So I might scan a patient who has a higher PSA a little more often and I think there's not necessarily guidance on exactly how often we do that. Generally, I would scan patients probably once a year at a minimum, but if they do have a higher PSA I might do it every six months or maybe every nine months, certainly with symptoms, but those unprompted scans I would do more often.

Zach Klaassen: I think you bring up a great point. I mean, we know this is conventional imaging, they're followed with conventional imaging. Does that all go out the window now that PSMA PET is so prevalent? Are you basically just incorporating PSMA PET if that PSA is starting to rise or they're having symptoms?

Alicia Morgans: I think in the era of 2024 and moving forward, and even 2023 for patients with biochemical recurrence, PSMA PET has become standard and we are doing that for the majority of patients. When patients have an extremely low PSA, I have a low suspicion that that PET scan is going to be positive and so, in those situations, again, I would wait longer. But when patients have a PSA that is over .2, especially if it's rising, even if slightly, that's going to be a situation where I think a PSMA PET scan may be positive. And generally, as I'm doing serial imaging, as long as I don't have challenges from an insurance perspective or coverage perspective, that's the scan that I would commonly do.

Zach Klaassen: And we're seeing that in other darolutamide trials, right? ARASTEP incorporating PSMA PET imaging into that trial design as well, right?

Alicia Morgans: Absolutely. So what I love about that particular trial design is that patients are getting a PSMA PET and, as long as they have identifiable lesions, they're having metastasis-directed therapy, and then everyone, and this is in a hormone-sensitive setting. Everyone's getting ADT for two years versus ADT and darolutamide for two years in combination with that metastasis-directed therapy. And I think there's a real possibility that in this extremely low volume oligometastatic state we might cure some people.

Zach Klaassen: Sure.

Alicia Morgans: So I love that and I think these PET scans in the biochemical recurrence space in particular are giving us the opportunity to see things we couldn't see before and potentially act in ways that may be really, really powerful for patients.

Zach Klaassen: And I think too, we just saw at the AUA a few months ago that in the new guidelines for AUA, for salvage, PSMA PET is recommended at the time of biochemical recurrence. So we're really seeing some ... Hopefully, that helps with some of the approvals too in terms of getting the imaging for these patients. If it's negative still treat them, but if it's positive then we can move on to some of these other options.

Alicia Morgans: Absolutely.

Zach Klaassen: Great discussion as always. Any take home messages for our listeners today?

Alicia Morgans: Well, I would say that when it comes to non-metastatic castration-resistant prostate cancer, we should keep in mind that metastasis-directed therapy, if we see something on a PET, is always attractive. But, most of the patients who are enrolled in these non-metastatic CRPC trials probably had things we could see on a PSMA PET. If we are doing metastasis-directed therapy, we should not forget that we should intensify by adding darolutamide or one of the AR antagonist agents to the ADT in that setting because we know we're not only improving metastasis-free survival but also overall survival in that setting. And so, regardless of what we do in terms of directing therapy at the metastasis we need to do that. And, if we can achieve those really, really low levels of PSA, we are probably going to be controlling the disease for quite a prolonged period of time and we can be confident in that and share that with our patients as an encouragement.

Zach Klaassen: Yeah. Great summary, thanks so much, Alicia.

Alicia Morgans: Thank you so much.