Thomas Zilli: Thank you so much for your kind invitation. Great pleasure to be here to UroToday and to talk about the role of SBRT for oligometastatic CRPC. So when we talk about oligometastatic CRPC and the role of metastasis-directed in the setting, we have different open questions. So the first one is what is the optimal role of modern imaging, namely PSMA PET-CT? The second one is what could be the primary clinical objectives that we can achieve with MDT? And finally, which is the evidence that support the role of SBRT for this setting of oligoprogressive prostate cancer patients?
So when we talk about the evolving spectrum of the CRPC disease, we have two main scenarios. One, the M0 CRPC and the M1, both based on conventional imaging, CT scan and bone scan. But of course, when we are using PSMA PET-CT, we're identifying many patients harboring a limited number of metastases, these so-called oligoprogressive CRPC patients.
This is important because we have data suggesting that when we restage a patient with non-metastatic CRPC based on conventional imaging, we can identify in almost the majority of the patients a disease and we need to consider that approximately 30% of these patients have between one to three lesions. So it means that patients that are recommended for systemic therapy can consider to have a window of opportunity to treat these patients with MDT.
I think we have strong data supporting the role of metastatic-directed therapy in the prostate cancer setting. So we have the data from the meta-analysis from WOLVERINE, including five prospective trials, SABR-COMET, EXTEND, ORIOLE, STOMP, and ARTO, and we see that metastatic-directed therapy compared to standard of care systemic therapy or just observation can improve PFS, radiographic PFS, and CRPC-free survival. So I think that this is an important strong rationale to support MDT also in the setting of oligoprogressive prostate cancer patients.
What we can expect from MDT, it depends on the setting. Certainly in the metachronous oligoprogression, we can use MDT before the first-line systemic therapy to postpone the first line. together with the first line, we can use MDT to postpone the second line and also when you're using it in the next line, and probably, altogether, we can aim to improve PFS and overall survival.
I think that postponing the next line of treatment is an important and meaningful endpoint. We have data from this review and Delphi consensus on behalf of EORTC and ESTRO for the OligoCare consortium. And for trial testing MDT in combination with systemic therapy versus systemic therapy, you see that, of course, overall survival is one important endpoint, but also the start or the switch of next systemic therapy and the polymetastatic progression-free survival are both important endpoints, supported also by the patient representatives.
Which are the settings for the CRPC? We have the metachronous oligoprogression, patients treated on the primary on their active systemic therapy and then with oligometastatic progression. We have the induced oligo progression, so patients that are polymetastatic beginning and then they have a few spots progression. And then of course we have the repeat oligoprogression, so patients that are already being treated with MDT for an oligometastatic setting and we retreat again with MDT in the next lines.
Which are the data that support MDT in the setting of the CRPC in the early oligoprogressive patients, so patient that are before the first-line systemic therapy? Patients that have a PSA of less than 2 nanograms per milliliters in a castration-resistant phase. When these patients are restaged using a dual PET using the PSMA and FDG, then the patients in this prospective Chinese trial have been selected to receive for an oligometastatic or recurrence SABR, SBRT to all disease spots, or just observe, and the patients without any evidence of disease, these patients continued just ADT alone.
As you can observe from the Kaplan-Meier curves, in terms of metastasis-free survival but also PSA response, when we treat these patients with an early oligoprogressive disease containing also ADT, we can improve metastasis-free survival compared to patients that are just treated with ADT alone. And the final results are quite comparable to the patients that don't have any disease spot visible on the dual PET. So this suggests that before the start of first-line CRPC systemic therapy, we can use MDT to prolong and improve metastasis-free sur, we can use MDT to prolong and improve metastasis-free survival and postpone also the first-line systemic therapy in the CRPC setting.
What about the role of metastatic-directed therapy when we decide to start the first-line CRPC systemic therapy? We have the data from the ARTO Italian trial. This is a phase II randomized clinical trial randomizing patients between one to three non-visceral lesion, mostly identified on next-generation imaging, to receive a standard of care, Abi plus ADT, versus Abi, the same systemic therapy, plus SABR. And where we see the result in terms of progression-free survival, you see the impact that the addition of metastatic therapy can have improving progression-free survival. Of course, there was a benefit in PFS, but this time when the data had been published in 2023, there was, not yet, overall survival benefit observe.
The same concept has been validated by the Canadian PCS 9 trial. Again, patients with up to five lesions, on conventional imaging this time, randomized to receive enzalutamide versus the same treatment plus SBRT. Primary endpoint radiographic PFS. And the data, you can see from the Kaplan-Meier curves, you have a huge benefit that you had SBRT, and this translated an improved radiographic progression-free survival from 2 years to up 4.6 years and of course you delay also the time to subsequent therapy from 3 to 5 years. That's an important and meaningful endpoint.
Coming back to the ARTO, we have now the updated results with a longer follow-up. And what we observe initially, so this benefit in terms of PFS translated also an overall survival benefit. You see here a hazard ratio of 0.55 in favor of the patient treated with Abi plus SBRT. So we have not only the PFS benefit time to next line of therapy, but this translates a finding also on overall survival benefit.
What about toxicity? Side effects were comparable in the two trials. So what we can conclude is that addition of SBRT to first-line ARPI is not associated with an increase of adverse events. That's an important endpoint and message for the community.
Concerning the further lines, we have data also from the TRAP trial. This is a UK study with patients having one to two lesions and conventional imaging with a very high median PSA, more than 40. They were oligoprogressive during ARPI. They had a minimum 6 months with evidence of response and these patients were treated with all disease spots. PFS was improved, so the goal was to improve PFS for more than 4 months, and finally the results were 6.4 months. And what is important also is that you can prolong the time to the next therapy up to 27 months. This is a huge benefit so you can postpone for more than 2 years the benefit of the treatment. And another important point of this trial is the implemented translational part, and when we see the role of ctDNA, we can observe that patients with a ctDNA-positive had a lower PFS compared to patients having ctDNA-negative. So this could be, of course, hypothesis-generating, but we can probably use these new biomarkers to select patients for MDT in the oligoprogressive setting.
We have ongoing trials, so we needed to confirm that with phase III randomized clinical trials. So we have the GETUG PEACE-8, randomizing patient in the first line between darolutamide versus the same concept plus SBRT. And we have also the MEDCARE trial in Belgium testing the same concept in the different lines of CRPC before the first line, or even the further lines, always randomizing between standard of care plus MDT.
Many other ongoing trials, mostly phase II, trying to give other inputs on the role of SABR for patients with oligorecurrent, oligoprogressive disease. And last but not least, we have some consortiums, like the CO-IMPACT, trying to integrate the role of PSMA PET-CT and SBRT for these patients with oligoprogressive disease.
I think, in conclusion, this is my take on messages, just to consider that the metachronous oligoprogressive CRPC, SBRT plus systemic therapy can improve PFS, OS, and delay the first systemic therapy, but of course we need a validation in phase III trials. You can use MDT in the first line, but also in the further lines for the repeat oligoprogression. And certainly what is important, you need to integrate moderate imaging, namely PSMA PET-CT, new biomarkers to select the right patients for this attitude. And what is important is just to discuss multidisciplinary setting, trying to put the patients inside clinical trials and prospective cohorts. Thank you so much and I'm open for the discussion.
Leslie Ballas: Thank you so much. Something that I'm curious about is how should we as practitioners define oligoprogression? Some of the trials have one or two sites of disease, some have less than three, some have less than five. What is your take on that?
Thomas Zilli: I think, as the oligorecurrent disease, we don't have a true cutoff. So I think that to five lesions makes sense to consider the role of SBRT for these patients to metastasis-directed therapy in combination with systemic therapy. Then I think what makes a difference, probably, is the role of modern imaging. Personally I'm a believer that if we recommend it, even the setting a metastasis-directed therapy approach, we need to use the best imaging we have, in this case a PSMA PET-CT to have a whole comprehensive vision of the disease burden.
We have data that we can translate also in the setting of CRPC coming from the ORIOLE trial, which, when we treat all the disease spots visible on PSMA PET-CT and we have a concordance between conventional imaging and PSMA, we can achieve a better outcome than when we use and we treat the patient only on conventional imaging and we are missing some disease spots that are visible on PSMA PET-CT. So I think that if you recommend this approach, of course you need to have the best way to see where disease is located, so namely you need to use PSMA PET-CT and try to target all the disease spots that are visible.
Leslie Ballas: And I guess we'll see as SABR-COMET-10 comes out if 10 is the new number of sites.
Thomas Zilli: Yeah. At this time, in the oligoprogressive setting, all the numbers are the cutoff of up to five. But yes, of course it remains an open question if we can enlarge the spectrum to a higher number of lesions.
Leslie Ballas: I was really intrigued by the consensus guideline that you showed in terms of endpoints for these trials, many of which have used progression-free survival. Obviously the update presented at GU ASCO for ARTO showed clearance of overall survival and prostate cancer-specific survival, but PFS has always struck me as a funny endpoint in this population, especially since that includes rise in PSA. For these future trials that you highlighted, what are their primary endpoints and do you think that progression-free survival is an appropriate endpoint at this time?
Thomas Zilli: Yeah. So in this Delphi consensus, inside the OligoCare community, we discuss which are the meaningful endpoints that we can consider when we are discussing about MDT. And of course what we can achieve with MDT is local control. So finally we're asking sometimes if you have a progression outside a spot that has not been treated, it could be something meaningful like when we are using, for example, systemic therapies.
And as more and more we are combining systemic therapy with MDT, the question was, which is the meaningful endpoint we can achieve? Of course OS is always the major endpoint that we can achieve, but clearly in a time in which we are trying to intensify and beginning all the systemic therapy that we have available for prostate cancer patient, the next-line treatment could be sometimes complicated. So I think if in this armamentarium, different systemic therapy and strategies, we can include radiation has a further weapon to improve the outcome to postpone the next-line therapy. That makes sense. And that is the reason why these new endpoints like the next line systemic therapy-free survival or the polymetastatic progression does emerge as new important endpoints for the future trial that we like to implement in the setting of MDT.
Leslie Ballas: And I guess my last question for you is how do you envision incorporating radioligand therapy in with these patients given the results of RAVENS and LUNAR? And those were in the oligometastatic or sort of limited number of sites of disease setting.
Thomas Zilli: Yeah, that's a very important question. So I think there is a huge potential to combine both strategies, especially in this setting in which RLT has a quite well-defined role. I think we can manage to combine not only for oligometastatic patients, but also for induced oligoprogression. So you can imagine, I don't know, in the first line, a patient treated with RLT with a polymetastatic setting and after two or three cycles of lutetium-PSMA, you have just a few spots that are persisting. In this case, I think you can combine MDT with a focal treatment with SBRT in combination with the lutetium to improve these disease sites in which we are able to achieve a complete response with lutetium.
Of course, it's hypothesis-generating. The data that we have up to now are mostly based on the oligorecurrent setting. We have data from LUNAR. There are other trials that are ongoing. It remains an open question, because even the combination from a dosimetric point of view, we don't know so much when we needed to combine, if we need to put SBRT before RLT as a sandwich procedure or even after.
Leslie Ballas: Or how many cycles of RLT?
Thomas Zilli: Exactly.
Leslie Ballas: I mean, there's a lot of questions, obviously.
Thomas Zilli: I think a completely new field, really appealing, and personally I see many huge potentials in this setting of CRPC patients.
Leslie Ballas: Professor Zilli, thank you so much for joining us today. We really appreciate your expertise and for sharing with us your presentation.
Thomas Zilli: Thank you so much for your attention and it's my pleasure. Cheers.