Vidit Sharma: Thank you so much for having me.
Neeraj Agarwal: So, you're doing this very innovative trial on how to tailor radiation therapy for patients who have biochemically recurrent disease after prior radical prostatectomy. Before we go into the trial and trial design with it, first of all, congratulations for taking on these initiatives, which I hopefully will change standard of care for these patients down the line.
Vidit Sharma: Thank you.
Neeraj Agarwal: Would you please tell us the need for this strategy? Why we should be looking at these patients? Why shouldn't we just give radiation therapy to all of these patients?
Vidit Sharma: Yeah. I think that's a great question. First of all, I think radiation therapy is the standard of care for biochemical recurrence after radical prostatectomy, but with the rise of modern imaging, PSMA PET-CTs, combined with pelvic MRIs, have a really high lesion detection rate after biochemical recurrence for radical prostatectomy, and so a lot of our data is independent of imaging findings. A lot of the guidelines are independent of imaging findings. Currently, the guidelines will, I think, rightfully recommend salvage radiation for patients with biochemical recurrence, regardless of whether or not there's a lesion in the prostate fossa, but as imaging gets better and better, I think we have to see, "Okay. Do those statements still make sense? Do they still hold?"
And so, as imaging gets better, we can identify recurrences that are smaller and that are in various locations, so that then begs the question, can we tailor who gets what kind of treatment for the recurrence? And so, this trial is aiming to randomize patients who have negative imaging, and so we don't know, with the best imaging that we can get, where the recurrence is. In that situation, there's a conundrum because the disease can be local or distant, and oftentimes it's a combination of local, regional, and distant. What we're aiming to do is randomize patients between salvage radiation to the prostate fossa, or observation with repeat PSAs and repeat imaging every time the PSA doubles, and then tailor the radiation once we see the lesion.
Neeraj Agarwal: So, when you repeat the imaging studies, when PSA doubles in these patients, what kind of imaging studies we are talking about?
Vidit Sharma: Currently, the best imaging that we have is a combination of PSMA PET-CT, plus multi-parametric pelvic MRI with a good, enhanced MRI sequence. Those images at multiple institutions have looked at these imaging modalities, and they have about a 50% lesion detection rate individually for patients with biochemical recurrence, who have a PSA between 0.2 and 0.5, so that early salvage range of BCR after radical prostatectomy, and so they're really pretty good at identifying lesions. When the PSA gets to over 0.5 to one, the lesion detection rate goes even higher, but those are the imaging modalities that we're using.
Neeraj Agarwal: So, in the trial, if you see local lesion, say on the pelvic MRI and the PSMA PET, but no distant metastasis, how do you approach these patients?
Vidit Sharma: So, these are the patients that essentially are fantastic candidates for local prostate fossa radiation, and these are the patients that we've done studies to show that, if you have an isolated local recurrence on imaging in the pelvis, those patients have a really, really good control, in terms of distant control after salvage radiation, and so they would get standard of care salvage radiation based on the radiation oncologist's discretion in terms of the dosage in the fields.
Neeraj Agarwal: And how about those patients where you don't see local recurrence?
Vidit Sharma: So, in patients who continue to be negative, who are randomized to the observation arm, they continue to just be observed with serial PSAs. The patients who initially got randomized to radiation and continue to be free just stay on surveillance with PSAs.
Neeraj Agarwal: Potentially, these patients who do not have local recurrence, and they're unfortunate to develop distant recurrence, they may potentially avoid radiation therapy to the pelvis.
Vidit Sharma: Correct, so there's a subset of patients who have biochemical recurrence and have, let's say, a bone lesion somewhere distant that would have gotten salvage radiation per the standard of care currently, but there would be harboring or distant metastasis and may not have benefited as much from the initial radiation, but received some of the toxicity. Those patients, I think, would be benefited from knowing that they have distant disease and then treated.
Neeraj Agarwal: So, moving forward, assuming the multicenter trial, as I understand, is positive, and if you decide to do a bigger trial and you replicate the results, what would be the implications on practice?
Vidit Sharma: The trial is a three-center trial at all three Mayo Clinic sites, and it's designed and powered to detect an essentially 9%, 5-year metastasis-free survival difference after a 12-month landmark period. Our hypothesis actually is that radiation still prevents some metastases, even when the imaging is negative, and that's because there's probably still some local burden that these images, that our best of care imaging is still not appreciating. If that is the case, then I think now we have data to guide patients with negative imaging to say, "Okay. Salvage radiation to the prostate fossa still makes sense, even though the imaging is negative."
If that is not the case, it is not a non-inferiority study. To power that, we would need over 1,200 patients, and it would be a much more logistically complicated trial. The other arm or other piece of this is looking at secondary outcomes of maybe which subsets of patients benefited more from the radiation, and I think those are more hypothesis-generating questions that can lead to perhaps more targeted studies in those cohorts, that these are the patients that actually are okay to watch with BCR or these are the patients that we should treat, even if the imaging is negative.
Neeraj Agarwal: Very nice. Any plans to include metastasis-directed radiation therapy in this protocol?
Vidit Sharma: This protocol is actually part of the Divine Deviate Framework, which is a trial led by Dr. Jake Ormi at Mayo Clinic. That trial, ARMS AMD is actually looking at metastasis-directed therapy with SBRT, with or without systemic therapy. And so, patients on this trial who are found to have metastatic disease are then encouraged to enroll in the metastasis-directed therapy arm, and so it's a very complementary framework, because a lot of these biochemically recurrent patients will harbor oligometastatic disease that's just occult, and then when that emerges, they have access to that as well.
Neeraj Agarwal: This is great protocol overall, I think, allowing our patients hopefully in future, in the very near future, a tailored radiation therapy and hopefully a tailored systemic therapy. Potentially, you can avoid systemic therapy or delay systemic therapy in those who want to do it with metastasis-directed therapy, but before that, in the immediate future, hopefully a more tailored radiation therapy approach for these patients. Well, congratulations with it for this trial and for your presentation.
Vidit Sharma: Oh, thank you so much.