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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. I'm delighted to be joined today on UroToday by Dr. Giulia Marvaso, who's an assistant professor of radiation oncology at the University of Milan. Giulia, thanks so much for joining us today.

Giulia Marvaso: Thanks, Zach, for the introduction, and also for having me today and for the opportunity to share our work.

Zach Klaassen: Absolutely. So we're doing a series on highlighting some of the great work that came out of ESTRO 2024. And we're going to talk today about the RADIOSA trial, which you presented data on at that meeting. So maybe just walk us through some of the background of how this trial came to be.

Giulia Marvaso: Yes, because in the setting of metachronous hormone-sensitive oligometastatic prostate cancer, the management of these patients is still controversial. So this protocol was written in 2019 when the STOMP and ORIOLE trials came out, with the intent to prolong ADT-free survival and also to improve the progression-free survival of these patients.

So on one side, there is deintensification. But in the last few years, we've also observed deintensification and intensification with the use, for example, of therapy. And last year, the EXTEND trial was published, proving that the combination of metastasis-directed therapy with SBRT and a short course of ADT can improve progression-free survival. So the RADIOSA trial steps in the middle because it is in the middle between deintensification and intensification. And I will show you why.

Zach Klaassen: Perfect. That's great. So why don't you pull up your slides and walk us through the methodology and some of those key results.

Giulia Marvaso: So these are the results of a phase II randomized trial, the RADIOSA trial. The study design aimed to compare two different approaches to treating oligorecurrent prostate cancer patients: SBRT alone versus SBRT combined with a short course of hormonal therapy for six months.

The primary endpoint was clinical progression-free survival, defined as the absence of new metastatic lesions between the two arms. Here are the inclusion criteria. We included oligorecurrent patients with nodal relapse in the pelvis, extra-regional nodal relapse (M1a), and bone metastasis, defined with the use of choline PET or PSMA or also whole-body MRI, with a maximum of three lesions. So this is the design: it was a one-to-one randomization, arm one with SBRT alone, and arm two with SBRT plus six months of hormonal therapy. The criteria for randomization were stratified according to PSA doubling time, localization of metastasis, and imaging.

We enrolled 105 patients, but 102 were considered for the analysis. These are the results about the study population. We started enrolling in 2019 until April 2023, with 51 patients in each arm. As you can see, the population was well-balanced. These are the results about the primary tumor and how the primary tumor was treated. The median follow-up was 31 months, as you can see, but every patient reached a follow-up of at least six months to reach the primary endpoint. Going on through the results of the study population, here are details about the staging, the site of recurrence, the number of oligometastatic disease cases, and the PSA doubling time.

Just to note here in this box, we have the kind of lesions that we treated. Starting with the biochemical progression-free survival stratified by treatment arm, you can see there is an advantage in the combination. Biochemical progression was reported in 66 patients out of the total number, but for arm A, the median progression-free survival in months was 12.6, and in the arm with the combination, it was almost double.

The same thing applies to clinical progression-free survival, which was our primary endpoint. Clinical progression was reported in half of our patients, but the advantage was also in favor of the combination of SBRT plus ADT. As you can see in the arm, there is a median clinical progression-free survival of more than 30 months.

And also, we have to note that the pattern of relapse was polymetastatic more in arm A without SBRT. And the majority of the patients recovered with oligo-recurrent disease in the arm with the combination of ADT. Then we also performed survival analysis of clinical progression, dividing the patients according to the main variables. And what we noticed is that the additional advantage of the combination was evident for all the subgroups of patients except for these characteristics. For example, PSA at enrollment, so a low level of PSA, and also the time from the first treatment to the actual treatment and the enrollment of our protocol more than 40 months, for example, and the time from the last active treatment more than 36 months.

So in conclusion, the RADIOSA trial showed a significant improvement in terms of clinical progression rate in six months in the combination arms. But also, there is some population with favorable characteristics, such as a low PSA at the time from the first treatment of more than 40 months. And in these patients, we can still offer with better selection a treatment with just SBRT. Most of the relapses were oligo-recurrences in the arm with the combination. And there are many other analyses that we are writing up for papers. We added a series of other analyses, including testosterone recovery. At one year, in both arms, there was a recovery of testosterone for all our patients.

There will also be an upcoming analysis of patients' quality of life questionnaires, just to clarify the impact of both approaches in both arms, and a molecular analysis of biological samples that we collected over the years. I would like to thank the PI of this study, Professor Jereczek, my colleagues, especially our patients, and the Italian Association for Research Against Cancer that funded this study. Thanks again.

Zach Klaassen: Giulia, thanks so much. That's great data. I like how you have subsequent analyses coming up with the quality of life and some of the molecular data as well. The one thing I noticed, and it's probably during the time of the recruitment, is that there were 64 patients out of the 102 that had a PSMA PET. Other patients had MRIs or CT scans, bone scans. We know from some early phase II trials that if we treat and we identify all of these lesions and then treat them with SBRT, certainly those patients do better. Are there plans to look at an additional analysis just among the patients that received PSMA PET? And how did that work into the design of the trial?

Giulia Marvaso: Actually, the trial was designed when PSMA was not as available as it is now, especially in Italy. So that was not our main aim for this study. Moreover, we started recruiting at the beginning of the pandemic. So we were lucky that in our protocol, we had the possibility to stage with also whole-body MRI because, in this case, we had some trouble with patients outside our region, as you know. So at the end of the day, we are good with all this data on the imaging and with all these patients staged with PSMA, but that was not the main topic of this trial. For sure, we can perform a sub-group analysis maybe in the future. I think it's a great idea based also on the ORIOLE trial with the same intent.

Zach Klaassen: Right, exactly. Exactly. That's great. Thanks so much for your time. Maybe just a couple of take-home messages for our listeners today.

Giulia Marvaso: I think that the combination between metastasis-directed therapy with SBRT is the winner because most of our patients had oligo-recurrent relapse. And also, as you can see hopefully in the paper in the next couple of months, the time to castration resistance was better. So I think based also on the results of the EXTEND trial, we should prefer a combination, and we have to improve the selection of our patients. We are trying with this biological study on the RADIOSA trial, but I think that selection is the key. We can offer SBRT alone, but in very selected patients. So we have to be very careful in order to offer the best treatment and to understand when we have to intensify or not.

Zach Klaassen: Yeah, absolutely. Congrats again on a great trial, and thank you again for your time and expertise.

Giulia Marvaso: Thank you for having me.