Read the Full Video Transcript

Oliver Sartor: Hi, I'm Oliver Sartor. It's an incredible pleasure for me to welcome Dr. Alicia Morgans to UroToday. And no stranger, Associate Professor at Dana-Farber. Prostate cancer doctor extraordinaire. Welcome, Alicia.


Alicia Morgans: Oh, thank you so much, Oliver.


Oliver Sartor: You have a really interesting new trial, the ARASTEP, and we've had a little bit of conversation about it. But I want you to talk a little bit about the trial design, and how you came to put this trial together because I think it's really fascinating.

Alicia Morgans: Oh, thank you very much. So this trial is really meant to focus on patients with high-risk biochemical recurrence in the hormone-sensitive biochemical recurrent disease setting. And all patients who are enrolled in this trial have to have a baseline PSMA PET that is positive. So this is selecting a different population than we might say would be in the EMBARK type of population, where at that point in time, of course, they didn't have PSMA PET scans. So this is PSMA PET positive, hormone-sensitive, high-risk biochemical recurrence.

Patients are enrolled, and they are randomized to receive treatment with ADT for two years, or ADT and darolutamide. And all patients are encouraged, if it's feasible where they live, in whatever part of the world, to get SBRT to all visualizable lesions. This is a really important component because I think we have some evidence, actually multiple pieces of evidence, that suggest that SBRT to all PET-identified lesions can actually change the trajectory of the disease itself. And when we add on the systemic therapy, we're hoping that the intensified ADT/darolutamide prolongs metastasis-free survival, as compared to ADT alone in that setting.

The primary endpoint is metastasis-free survival, but this is a little unique. It's metastasis-free survival by PSMA PET, and these are actually covered by the company, by the sponsor, to ensure that all patients are able to get these over time, which is not something that we can reliably do in all parts of the world.

We also have key secondary endpoints that include conventional imaging, so CTs and bone scans, so that we can actually find metastasis-free survival by those imaging strategies as well. So if patients hit a PSMA PET positive MFS endpoint, follow-up continues until they ultimately have conventional imaging MFS as well, as long as that's consistent with the way that they're being treated in their local facility. So that's a key secondary endpoint. We, of course, have other disease control endpoints, and quality of life endpoints as well.

But the goal is maybe to shift the trajectory of the disease for some patients. And after the two years, stop all systemic therapy and see what we see.

Oliver Sartor: A lot of the trial design, there are a couple of elements I want to drill down a bit deeper on. So high risk. Define high risk for me because I mean, it means different things to different people.

Alicia Morgans: So they do have to have a PSMA, or a PSA doubling time that's less than 10 months, I believe. And so we really want to see that rapid trajectory. And then the other way that we're really defining this is by the PET-positive disease.

Oliver Sartor: And the PET-positive disease, could it be in the pelvis, like a pelvic lymph node, or does it have to be metastatic? Because it could be one, or is it multiple? How did you define the PSMA PET positivity?

Alicia Morgans: It has to be extra-pelvic PSMA PET positive. They can have just one, they can have multiple. It does have to be a patient whom the investigator thinks it's reasonable to do SBRT to all of those lesions. Now, I would say that the restrictions around SBRT are pretty limited because it is delivered differently in all areas of the world. And it is not a requirement that patients have SBRT. Though, I think in the US, these patients will have SBRT. But trying to be inclusive of other areas where this may not be possible, we did allow patients who do not have SBRT into this study.

Oliver Sartor: Interesting. Now, with two years of hormonal therapy being sort of the norm with SBRT, you're going to end up really pushing out those endpoints. What is the frequency of scanning? Because it's going to take a while for these patients to relapse. That, I'm pretty sure.

Alicia Morgans: Yeah. So they're every six months. And if patients have a rapidly rising PSA, certainly as someone who puts patients on trials all the time, if you have to do a trial, or do an imaging study outside of the standard parameters, because it's the right thing for the patients, these things do happen, but it is mandated to be every six months.

Oliver Sartor: So one of the things that could potentially be a problem is that when the PSA begins to rise, people restart on ADT. So you get two years of ADT, all of a sudden the PSA is going up, and maybe you get a PSMA PET, but it doesn't show anything. Are people going to be starting on ADT, and how will that disrupt the endpoint? Or how have you thought to manage that particular scenario?

Alicia Morgans: Yeah. I think in those settings, when people sign up for the trial, and they recognize that it's a PSMA PET negative recurrence and a PSA rise only, my hope is that, when they reach out to the sponsor and talk to the medical monitor, that they feel confident that PSA alone is not going to harm an individual. Really, we know that PSA is just a protein circulating in the blood. It is a canary in the coal mine, if you will, telling us that you will see something positive in the future. But my hope is that, if there's a negative PSMA PET, they will feel comfortable enough to continue to monitor the patient. Because again, the PSA is not going to be something that in itself will harm the person, and within the next six months, when they get their next PSMA PET, maybe that one will be positive.

I think, in clinical practice, we have seen this over time, and you and I have both been in that setting, but all of the patients in this trial need to have a maximally treated pelvis. So it's not that we're going to be in a situation where you have a rising PSA and the PSMA PET is negative, and now we're withholding salvage radiation. All patients must have a maximally treated pelvis, so salvage radiation, if that patient was eligible, was already given. So we're really talking about a potential withholding of, until we see PSMA PET positive disease, SBRT to a lesion. And if we can't see it, then you can't radiate it anyway. So there's no, I don't think there's a harm in continuing to monitor, and then applying that SBRT, or whatever management strategy is needed, at the time of the PSMA PET being positive.

Oliver Sartor: This is a potentially practice-changing trial at multiple levels. Not only would you have a therapeutic intervention that a positive would be a practice change, but also, the utilization of PSMA PET as a regulatory endpoint would be practice-changing.

I'm sure you've had discussions about the correlation between the MFS with conventional imaging and the PSMA, obviously the PET imaging. And I'm just curious if you might give us a little bit of insight about how those discussions sort of played out, and the confidence that you have that the MFS biomolecular imaging will actually translate into regulatory approval.

Alicia Morgans: So I think this is such a fascinating question because we've had a lot of back and forth and discussions as the study was being designed. And what I would say is that no one really knows what the correlation between PSMA PET positive disease and conventional bone scan, CT scans, MRIs, will actually be. And so, that's why it is one of the most fascinating parts of this study, from my perspective, that it is built in that we will get the PSMA PET, and when positive, it will meet that MFS endpoint for the primary, but patients will continue to be followed for that conventional imaging positive.

Now, we know that this will be muddied because people will potentially do things to stop that progression. But we're hopeful that we'll have enough evidence and information to help us understand a crosswalk between what's the timing that someone may have MFS by a PSMA PET and the development of metastasis on this conventional imaging, or older imaging strategy that we used to use. And at a minimum, this will inform us on what that crosswalk might be, and how we can better understand PSMA PET as a potential endpoint in the future.

Oliver Sartor: I think it's fantastic. Like I said, practice-changing trial potential on multiple fronts. Anything else you wanted to mention before we wrap up?

Alicia Morgans: I would just say that this study is absolutely actively looking for sites. So if people are interested, I feel like there are so many parts of this trial that are very consistent with what we're doing in practice. Right now, we try to be pragmatic about the design, to ensure that physicians who put patients on this study feel confident that they're doing what they would do in normal practice, and maybe just amping it up a bit by adding darolutamide to one of the arms.

And I'm really hopeful that we might find that we are meaningfully changing the trajectory of the disease for these patients. And I really hope that when we do stop all systemic therapy, for at least some of the patients, at the end of this trial, we don't see that everyone relapses. That there might be some patients who continue to have disease control, and that would be fantastic.

Oliver Sartor: Congratulations for leading a really important trial. Thank you, Alicia.

Alicia Morgans: Thank you so much for the time.