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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I am delighted to be joined, as always, on UroToday by Dr. Alicia Morgans, who is a medical oncologist at the Dana-Farber Cancer Institute. Alicia, how are you?

Alicia Morgans: I'm well. Thanks so much for having me today, Zach.

Zachary Klaassen: Great. So we're going to talk about ARASTEP, which is a really important phase III trial that's ongoing and we've covered on UroToday. But there's always important updates, always important angles to talk about. So maybe just take us through the GU ASCO 2025 trial and progress that you presented.

Alicia Morgans: Great. Thanks again, Zach, for asking to hear about this. So ARASTEP is really a registrational phase III trial, international phase III, that's really looking at darolutamide plus ADT in patients with high-risk biochemical recurrence of prostate cancer identified by PSMA PET.

So in terms of background, really, this is a patient population that doesn't necessarily have a defined treatment algorithm at this point in time when they have PSMA PET positive disease. But they really do need some form of intervention. And we know that this is a disease state where we can define things. Luckily, the EMBARK trial showed us that we can impact metastasis-free survival in a PSMA PET agnostic population. So this is really focusing on that PET positive population.

Darolutamide did significantly improve metastasis-free survival and overall survival in some other disease states, so nonmetastatic CRPC, and in the metastatic hormone-sensitive prostate cancer population. And it's distinct from other androgen receptor antagonists in terms of its structure. And it does have a favorable safety profile.

So this trial, which is ongoing, is really evaluating darolutamide plus androgen-deprivation therapy versus ADT and placebo in patients with this high-risk biochemical recurrence state when they have PSMA PET positive lesions. So let's look at the schema here. This is the study design.

All patients who enter this trial have to have a high-risk biochemical recurrence state, so no metastases on conventional bone scan, CTs, MRIs. They have to have a PSA doubling time of less than 12 months. They have to have a PSA that reaches threshold for recurrence—so over 0.2 after radical prostatectomy, or over 2 if they have primary radiation therapy.

And they have to have PSMA PET positive lesions. And this is really, really critically important because it does differentiate them from the EMBARK population. And of course, that's because, in EMBARK, there weren't PSMA PETs used in practice at that period of time.

Patients also have to have a normal serum testosterone level. They are randomized one to one to receive darolutamide and ADT for 24 months or ADT and placebo for 24 months. And for patients who are able, they also can receive SBRT to any PSMA PET-identified lesions. They continue to be followed in active follow up, with PSMA PETs happening every six months, so that they can identify that metastasis-free survival primary endpoint by PSMA PET. And there are also conventional imaging scans built in.

One important thing I would say about this study is that it is really going to provide us that ability to have a crosswalk between our PSMA PET scans and our conventional imaging strategies. So I think we'll have a much better sense of what progression looks like, at least from a biochemical recurrence to initial radiographic recurrence by PET, by the end of this study. And we'll hopefully also understand what kind of lead time we might see in terms of PET versus conventional imaging.

So lots of information to learn beyond that metastasis-free survival primary endpoint. And we also, of course, are looking at things like quality of life, overall survival, and others. And currently, the study is open. It is enrolling around the world.

I did just learn that the 500th patient was enrolled, so really excited that we are doing well. And it's expected that it will continue to enroll until later this year, hopefully finishing up by the end of the year. And we're just really excited and appreciative for all the investigators, all the patients who are continuing to put patients on the trial.

So the take-home message is that high-risk PSMA PET positive biochemical recurrence is a disease state without a currently defined optimal treatment approach. It's a bit of the Wild West in terms of what people are doing, how long they're using systemic therapy, how they're integrating SBRT or metastasis-directed therapy. And we really need data to ensure that patients get effective and tolerable treatment that makes sense and is data driven.

ARASTEP is a phase III for patients with high-risk biochemical recurrence that combines PSMA PET imaging, metastasis-directed therapy when appropriate, and two years of systemic therapy with ADT versus ADT and darolutamide to really determine whether this multimodal treatment approach, with a discrete duration of 24 months of therapy, can improve PSMA PET defined metastasis-free survival. And so thank you so much for your interest in this study, Zach.

Zachary Klaassen: Excellent. So Alicia, great overview. It's exciting to see that we're getting relatively close to the finish line of accrual for this study.

I think whenever I look at this study, a couple of things jump out. The first one is that this is a little different than the EMBARK trial design, greater than or equal to one PSMA PET positive lesion. In your mind, how does this population maybe differ from an EMBARK from a clinical perspective?

Alicia Morgans: Yeah, I think it's really the PSMA PET here defining this novel group and also the integration, at least in the US, of patients getting SBRT. I think the reason that it's not mandated for every patient is because, in truth, around the world, it's not always something that people have access to. And so one of the stratification factors is intent to use SBRT or not. So that will be included in the analysis.

But I think in the US, that combination of being able to hit with metastasis-directed therapy and then also using that discrete-defined duration of treatment, whereas, in EMBARK, there was a holiday built in. But then when that treatment was restarted, that would continue indefinitely. So it's a similar population offset by this new imaging strategy with the goal of hopefully not treating patients forever and maybe rendering some patients free of disease. We just don't know.

Zachary Klaassen: Yeah. Great answer. I think you mentioned that nine months for EMBARK on enza, plus or minus ADT. Whereas here we're looking at two years of daro plus ADT. We all know daro is very well tolerated. How have you seen this two years for patients? Are they excited about just that two-year discrete time frame? What's the patient feedback on that?

Alicia Morgans: Yeah, one of the most controversial things that we had in designing this trial was, how long do we have that systemic therapy duration? And I think some people wanted 12 months. Some people were happy with 24. It ended up that we based this on other study data that was coming out around a similar time period.

The PRESTO study did inform this and other information. But I think, from a patient perspective, shorter is always better. And so that's always a goal. But I think that there is an understanding that our best data suggested and the consensus among experts was that we would aim for 24.

If they can't make it to 24, it's a trial. It's not a jail sentence. They can discontinue if they need to, if that's clinically the best thing for them. And we document all of that in these clinical trials anyway—what proportion of patients made it through the entire proposed treatment regimen.

And we'll have the data on the back end. If a large portion of patients make it through 50% of the treatment duration or 75% of the treatment duration, we'll know that. If most of them get through all of it, we'll know that as well. And then when we apply the data in clinic, again, the patients will make the choices for themselves. But at least we'll have the information to inform those decisions.

Zachary Klaassen: Yeah, absolutely. Great update on ARASTEP. Alicia, anything we didn't hit on, anything you want to cover before we wrap up?

Alicia Morgans: Yeah, no, except to just say that this study, I mentioned, will really help us, I think, also better understand PSMA PET metastasis-free survival. And as a field, we need to understand that. It's not been used as a registration endpoint before. And my hope is that this will stand as a solid registration endpoint. But that's something to learn as well and, again, just sort of meeting the needs of our community, of our patients, and our practice patterns where they are currently.

Zachary Klaassen: Yeah, it's great to have it built in as that trial design because we know it's everywhere. And we'll have some data on how this looks. Great job as always, Alicia.

Alicia Morgans: Thank you so much, Zach.