Alicia Morgans: Hi, I'm so excited to be joining you today from APCCC in Lugano, Switzerland, where I am talking to Dr. Piet Ost, who is a professor of radiation oncology at the University of Ghent, and a radiation oncologist at the Iridium Network in Antwerp, Belgium. Thank you so much for being here with me today.

Piet Ost: Thank you for having me.

Alicia Morgans: Wonderful. So I wanted to speak with you about the broad topic of biochemical recurrence, focusing a little bit on the systemic treatment aspect of that, as well as metastasis-directed therapy. So let's get started. What are your thoughts on systemic treatment in the context of salvage radiation and biochemical recurrence?

Piet Ost: Yeah. It is a question that pops up almost every week, because we have a lot of patients requiring salvage radiotherapy. They've got a rising PSA following radical prostatectomy, for example. And the question is, when do we add androgen deprivation therapy? The second question, for what period of time? And there are very nice studies. There's the American study with 24 months of bicalutamide. We've got a French study with six months of ADT. And I think it's fair to say that, at least biochemical progression has been improving for these patients. The question is, is that good enough? And we haven't seen all the data translating into really mature data like MFS or OS, except, of course, for the American data. But that was with 24 months of bicalutamide, which in practice, we very rarely use. So nowadays, if you look at the data in detail, we question, are there certain cutoffs we can use to add ADT, yes or no? And some argue that, a PSA below a certain threshold, like for example, 0.7, would be a good idea, or below 0.35, would be nice to abandon the ADT.

I'm not sure that is the case. Maybe we need bigger trials, maybe more information like a trial from RADICALS, to clearly indicate that. But for the patients with that, those low PSA values, I discuss it on a personal level, and I try to convince them what the pros are, but also what the cons are. Because you can't forget that, if we give testosterone depletion for six months, most often patients, it takes them up to another six months, or even a year or longer, to have their testosterone recuperate, and that can be quite bothersome. So for those patients, I discuss individually. For the patients who come in with a higher PSA, I try not to discuss it too much. I say, "Look, this is really standard of care. You will have a clear benefit." And they most often go for it.


Alicia Morgans: Yes. And it's not just bothersome, these long durations of low testosterone, especially in those settings where it takes so long for the testosterone to recover, have cardiovascular effects and have bone health effects. So it is truly a medical thing that we need to think about. So I appreciate that you do that.

I wonder what your thoughts are, in terms of using things beyond the PSA, to help understand that risk stratification. Do you do that, or are you waiting for maybe molecular studies to help characterize these patients better?

Piet Ost: Yeah. At this time point, I'm really looking forward to seeing more data from, for example, the molecular subset from DECIPHER, for example. These data were very, very interesting to see that, there indeed might be a subgroup where you can clearly indicate, look, these patients don't need the ADT. And that, I think, will probably be the future. That we can truly individualize, not only looking at PSA as a marker, which can be useful, but also, that molecular marker, that clearly states look, this is a patient that will have a local relapse only, you can cure this patient with one modality.

And so we, especially in Europe, it's very difficult to get your hands on a test like that.

Alicia Morgans: Ah.

Piet Ost: It's also quite expensive. There is no reimbursement. So we are always lurking a bit to what's happening in the US, and we are very jealous that, that is something you can offer to your patient in that specific setting. And I'm very happy to see, that in the US, all these trials, and are embarking, really randomizing. Using that test, versus not using that test, and see if it's truly impactful. And I think, that is where the future will be.

Alicia Morgans: Absolutely. And perhaps we should get that. To get the company to engage with you and the folks at the University of Ghent, and get-

Piet Ost: We're already doing that.

Alicia Morgans: Wonderful. So that you can get that for your patients-

Piet Ost: True.

Alicia Morgans: ... because access is always so complex and frustrating for patients.

Piet Ost: Yeah. Especially when, we had it differently. We had access to PSMA-

Alicia Morgans: Yes.

Piet Ost: ... everywhere, where we wanted, for all patients, we wanted it. And that was not the case in the US. So that's probably why the US really was investing more in the molecular. And we thought, yeah, we already have PSMA, but don't... So we saw that parallel, almost a parallel universe, and now what's happening in the US is access to both. So that will be very interesting to see, how complementary both tests are. And that is something which I'm also looking forward to. In how many instances does a PSMA PET completely conform to what we see on the DECIPHER. And Felix showed some very interesting data, that it does work for pelvic nodal recurrences, but the correlation with, for example, bone mets, appears to be a lot lower. So it might be that, they do have some benefit standing next to each other. And maybe we need both, for that perfect individual treatment.

Alicia Morgans: Well, I think there's always room for more investigation, and that certainly would be exciting. And thinking about the location of the metastatic disease, whether it's pelvic, whether it's bone, whether there's one, whether there's 15, identified on a PSMA PET, this is something that you've been thinking a lot about. In the context of metastasis-directed therapy, what are your thoughts about metastasis location? The number of metastases. Whether or not to combine with systemic therapy? Where do they stand there?

Piet Ost: Yeah. There have been enormous evolutions in our thoughts, especially on what we should be doing. And let me maybe start with the pelvic recurrences, because that is one of the most common failure patterns we see. And there, we know that, in patients with one to three nodal recurrences, you can do SBRT, you can do a whole pelvis, you can do a surgical resection. It appears to be, that the surgeons are saying, from their retrospective data, it's not that good. A lot of patients recur. So we've already, the retrospective data indicate it's not a good option, probably it's not a good option. We are still in doubt, whether SBRT or elective, we know what the best option there is. We just finished our trial. We'll be reporting acute toxicity next week at ESSO, SBRT versus elective nodal radiotherapy. So that will be the first indication if one is more toxic than the other. And in two years, we will be reporting the metastasis-free survival for these patients. So then, at least, we will know, for that subset, what the best option will be.

Do mind, that in actually both arms, we said that six months of ADT was mandatory. And we copied that a bit from what they did in the GETUG trial, what they did in the SPPORT trial, is that, the basis of six months of ADT, in that type of salvage setting, makes a lot of sense. So that's why we built that in.

Moving to the distant metastatic disease, that is even more difficult. Because the first trials we designed, designed in Hopkins, was observation versus SBRT, and just looking at, does it work? And if it's not better than observation, maybe this is where we should stop.


So that was for us, our first step, testing that hypothesis. But moving forward, I think we have to think beyond, SBRT only, and we have to start, at least, combining it with systemic therapy. And there are a lot of ways forward in that. What is the optimal systemic therapy to do so? What's the ideal duration? So there's a lot of open questions.


And we are starting to dive into the molecular assays, as well. We've been now doing targeted DNA of the primary, looking at high-risk mutations versus not having a high-risk mutation, and seeing which patient might actually benefit more than the other from SBRT. And what we see is that, probably the patients with the high-risk mutation benefit even more from SBRT, as compared to observation, but they still fail within the first year, indicating they need something more. And something more will be systemic therapy.


So I do think that, in the majority of patients, SBRT alone will not be the future. A lot of them relapse within the first two years. And if that's okay with the patient, it's okay with me, but I think we can do a lot better. And the future trials are all looking into that. That is adding something, which hopefully, still respects their quality of life. And there are different things we can do. There's even a trial with lutetium PSMA now. That we do one with darolutamide, there's one with apalutamide, there's one with classical ADT, there's even one with radium. So there will be an enormous amount of data that we will have in a couple of years, that hopefully, will help us decide.

Alicia Morgans: Yes. And as you said, hopefully, defining a discrete period and the right agent on the front end will be so important. And if it ends up that a non-castrating approach is possible, my goodness, patients would be excited. But even something that ends up blocking testosterone for a while, but still allows testosterone recovery and quality of life maintenance, I think, would be helpful. Just having the data will be helpful.

Piet Ost: Correct.

Alicia Morgans: So, thank you so much. I'd love to hear if you have a final message for viewers, who are thinking about this complex landscape.

Piet Ost: Yeah. I think, find a trial that you can recruit into, nearby. I think that is so important. Because the sooner we get the recruitment done, the sooner we will get the data, and we don't have to rely on expert opinion anymore. And that's the only way, I think, we can move forward. That is with the new tests, with PSMA, with molecular tests, but also, with new treatments, like SBRT and these combinations. If we don't do the trials, we will be thinking, or hypothesizing, what is best. But actually, in a few years, we should be able to tell us, this is best for that patient.

Alicia Morgans: It is so true. If we can identify the questions, we should be able to try to answer those questions. And the only way is through these trials. So thank you for reminding us of that, and for sharing your expertise today.

Piet Ost: Thank you.