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Leslie Ballas: Hi there. My name is Leslie Ballas. I'm a Radiation Oncologist at Cedars-Sinai Medical Center in Los Angeles. And it is my pleasure to get a chance to discuss with Hoda Abdel-Aty, who is a clinical research fellow and STAMPEDE research fellow at the Clinical Trials Unit at University College London. She is joining us today to discuss her ESMO poster and the ongoing STAMPEDE research project or research protocol looking at SABR for oligometastatic prostate cancer. Thank you so much for joining us.

Hoda Abdel-Aty: Great. Thank you so much for having me. It's a pleasure to be on, and thank you for the opportunity to talk about STAMPEDE2. So, thank you for having me on and for the wonderful introduction. I'm going to talk you through the STAMPEDE2 SABR trial, or stereotactic ablative body radiotherapy trial, which is one of the three new trials in the STAMPEDE2 platform protocol. The SABR trial is a Phase III randomized open-label, multicenter trial that will be testing SABR in patients with newly diagnosed oligometastatic prostate cancer who are starting androgen deprivation therapy.

So just to give you a little bit of background, we know that oligometastatic disease is an intermediary metastatic state, as initially reported in the 1990s. We know from the two Phase II trials, the ORIOLE and STOMP trials, that SABR or even metastasis-directed therapy with surgery showed that there was an improvement in progression-free survival and deferred the use of systemic therapies with ADT. But there's very limited evidence for the role of SABR in synchronous oligometastatic prostate cancer. And that's why we're conducting the STAMPEDE2 SABR trial.

For patients to take part in the trial, they need to fulfill the SABR-eligible disease definition, which we've defined as one to five metastases in the bone and/or in non-regional (so extra-pelvic) lymph nodes. They need to have their metastatic disease confirmed on conventional imaging with a CT/MRI and an isotope bone scan. All the metastatic lesions need to be technically suitable for SABR, and patients should not have any evidence of visceral metastases on imaging.

So, going through the trial schema. Once the patients are deemed eligible, they will be randomized with a one-to-one allocation to either standard-of-care treatment in Arm A or standard-of-care treatment in addition to SABR to metastases in Arm S. The standard-of-care treatment will include androgen deprivation therapy plus an androgen receptor pathway inhibitor, or an ARPI, and this can include things such as abiraterone, enzalutamide, apalutamide, or darolutamide.

We also integrated docetaxel, only as part of triplet therapy. The decision to treat with docetaxel will be up to the clinician's discretion, and we will be stratifying for its use in this setting. Patients will also get prostate radiotherapy plus/minus pelvic lymph node radiotherapy, again at clinician discretion and also a stratification factor.

Within prostate radiotherapy, we have adopted radical doses including the PACE-C fractionation schedule, which is the 36.25 Gy in five fractions for prostate only, and the 60 Gy in 20 fractions for prostate and pelvic lymph nodes. The rationale is that we're trying to treat those patients radically, so we've chosen radical doses of radiotherapy, as compared to the standard that you would give for these patients based on the STAMPEDE M1RT data. Then for patients randomized in Arm S, which is the trial arm, they get standard of care in addition to SABR to metastases. The fractionation schedule here is 30 Gy in three to five fractions.

We also have an opportunity for patients that if they haven't started their ARPI or ARSI, they have the opportunity to have biomarker testing. We anticipate about 10 to 15% of the population to test positive for biomarker status. These patients will have the opportunity for a second randomization into Comparison N or the abiraterone plus niraparib trial.

So in terms of endpoints, we have a dual primary endpoint, and this is radiographic progression-free survival and overall survival. We also have key secondary outcomes including failure-free survival, prostate cancer–specific survival, toxicity from treatment, and quality of life using EuroQol. In terms of our statistical plan, we have a target recruitment of just over 2,400 patients. We have opened to recruitment and we've actually randomized up to five patients in the last couple of months. We anticipate recruitment to take approximately 55 months. We have a target hazard ratio of 0.7 for rPFS and 0.75 for OS.

We understand from the ongoing data that's produced, with the proPSMA being the landmark trial, that PSMA PET/CT has improved diagnostic accuracy. When we designed the trial, we ran a STAMPEDE2 site survey, which is two years old now. This was to finalize the trial design for the STAMPEDE2 trial. We found that although people or clinicians had access to PSMA PET imaging, there was still heterogeneity in when they were requesting them. And there was heterogeneity in terms of access and its utility across the UK.

So bearing those two points in mind, we have integrated a next-generation imaging substudy. If the clinician requests a PSMA PET or even a whole-body MRI, either to complete their diagnostic workup of the patient or as part of the radiotherapy planning, we know that those imaging modalities may either show more metastases or the same number of metastases or even fewer metastases compared to conventional imaging findings. It will be up to the clinician's discretion to treat based on either imaging modality, and we will be stratifying for the use of next-generation imaging in this trial. Thank you for listening.

Leslie Ballas: Thank you. This is such an exciting trial, and I'm excited to talk to you a little bit about it. I think you laid out really nicely how this trial differs from ORIOLE and STOMP. Are you finding that in the UK people are extrapolating from those trials and just using SABR in the synchronous setting?

Hoda Abdel-Aty: Yes, Leslie. I think that's a very good question. It's a very important point to raise as well because there is certainly extrapolation from the ORIOLE and STOMP trials for the use of SABR in oligometastatic disease. But if we actually look at a meta-analysis to look at those two different groups, so we've got the low-volume metachronous and we've got the low-volume synchronous, and they actually are different prognostic groups in terms of their survival. So the fact of the matter is, we actually don't know whether SABR is beneficial at all for the group of patients with synchronous oligometastatic disease. And I think that really just kind of gives us a bit of equipoise for running this trial. I would also say that there are several other trials running in this setting. Again, there's a lot of heterogeneity with the trials, but I am hoping that the STAMPEDE trial will be able to answer this question.

Leslie Ballas: I also noticed that you defined oligometastatic disease as one to five metastases. In SABR trials, there's been a variation in definition. How did you guys decide on one to five metastases?

Hoda Abdel-Aty: Yeah, so that's a very good question. So I would say there are two points for this question. The first answer is that from the STAMPEDE2 Arm H trial, which is the M1RT that looked at prostate radiotherapy, we know that in the low-burden metastatic disease—so those patients were using the CHAARTED criteria of three or fewer bone metastases on bone scan—they were the group of patients that had most benefit from prostate radiotherapy. But in a post-hoc analysis from this trial, we found that there was a continuum of benefit from prostate radiotherapy for overall survival extending up to eight metastases. And it even went beyond 10 metastases for a failure-free survival benefit. So this was kind of the background as to why we set up the trial as is.

And I think also from a practical point of view for centers taking part, we kind of don't want to overburden centers for treating more than five metastases. And we thought that was a pragmatic cutoff. The other point I would say is that there are recent consensus guidelines from the EORTC, from ESTRO/ASTRO, and they've actually defined oligometastatic disease as up to five metastases. And I think that aligns quite nicely with STAMPEDE2.

Leslie Ballas: Yeah, I agree. The other question that I have is that as a radiation oncologist faced with this scenario that arises where you have a pelvic bone metastasis, and you need to treat the prostate and that pelvic bone, it's hard sometimes to create composite plans with a SABR dosing as well as your sort of standard hypofractionated dosing. And so, what are you doing in those situations?

Hoda Abdel-Aty: Yeah, absolutely. So as you know, that is a very common scenario with these patients. So within the trial, we've actually permitted that you can incorporate this pelvic bone metastasis within your pelvic field, so that would be the 60 Gy in 20 fractions daily schedule. And you also have the option to boost the bone metastasis to up to 51 Gy in 20 fractions. So, we've definitely taken that into account.

Leslie Ballas: Good. Okay. I was intrigued by the idea that you're going to have as a stratification factor, the inclusion of lymph nodes or not, and not dictating how those treatment fields are being done. What do you think is the percentage of patients in the UK that would get a lymph node? I mean, do you think it's going to be 50/50? What is the common practice?

Hoda Abdel-Aty: Yeah, again, that's a really good question. And I think that would actually go back to the imaging modality that they've used to look at nodal metastasis. So it's not quite common that you see nodal metastasis. I mean, they need to be quite chunky to be picked up on a CT scan. And I think that kind of makes it easier for a clinician to say, "Well, that's definitely an involved node, therefore I will include." But I think it is quite hard to know the exact percentage of who's doing what. But obviously, in terms of the standard treatment currently, that doesn't include pelvic lymph nodes. But our rationale is that we are hypothesizing that we are treating those patients radically; then potentially we want to address all macroscopic disease. So if you have seen a pelvic lymph node, again on either imaging modality, then you have the option to treat the pelvic lymph nodes within your radiation treatment.

Leslie Ballas: And then lastly, I do want to ask you—the imaging substudy is very interesting and obviously very much aligns with sort of modern-day treatment. Because especially in the U.S., we're getting PSMA PET on almost all of these patients. Your primary outcome, however, is radiographic—one of them is radiographic progression-free survival with conventional imaging. Correct?

Hoda Abdel-Aty: Yes, that's correct. So we are not using PSMA PET or whole-body MRI to either assess response or progression. We are basing our rPFS on Prostate Cancer Working Group 3 and RECIST criteria. But the PSMA PET is more—I think it's more relevant for the baseline imaging, because that's going to influence what you do to your patient who's sat in front of you in clinic. And I think as the trial goes on—I mean, it's a very dynamic field with imaging. And that's sort of one of the things that I'm hoping to do, is to actually incorporate more next-generation imaging modalities at various time points within the trial. But that's currently not the current status quo.

Leslie Ballas: And what are you going to do for patients who qualify for STAMPEDE2 based on five oligomets on traditional conventional imaging? Then they get a PSMA PET as part of the substudy and are found to have six oligomets? Do they come off study, or how are they handled?

Hoda Abdel-Aty: Sure. So I think that it depends on the timing of the scan. So if the scan is done pre-randomization—which actually the patients that we've randomized so far are exactly that same scenario—then if it's pre-randomization, then yes, there is the option to say, "Well, hold on. You can actually take part in the PSMA lutetium comparison," which includes patients that have PSMA-avid disease and any volume of disease on conventional imaging. But if the scan were to happen post-randomization, and let's say that they have been randomized to the SABR arm or Arm S, then it really is up to the treating clinician to decide which five metastases they want to treat.

Leslie Ballas: Oh, so they are limited truly in only treating five.

Hoda Abdel-Aty: Yes.

Leslie Ballas: Interesting. Hoda, this is such an exciting study, and I am going to be anxiously awaiting you recruiting 2,500 patients and seeing what your results are. But congratulations to you on this trial, and thank you for being willing to discuss it with us today.

Hoda Abdel-Aty: Thank you so much. It's been a great pleasure, and thank you for having me again.