Daniel Spratt: Thank you so much, Leslie. It's great to be here. At the AUA this year, we had a great discussion on the role of different treatment modalities for the management of patients with metastatic hormone-sensitive prostate cancer, specifically what's called M1a or the presence of non-regional lymph node metastatic disease. These are my conflicts of interest, and so what's the data for how we treat this? Well, there's been multiple Phase III randomized trials that have tested the role of radiation therapy to treatment of the primary that have been pooled together in what's called the STOPCAP analysis. There's also been a small trial that didn't fully complete accrual called the RAMPP trial we'll touch a little bit on that used surgery in this setting. Clearly most of the data and mature data is with the role of radiation therapy. Now, the STOPCAP analysis included three trials.
There was actually four randomized cohorts, and you can see these trials here. When you pool them all together with individual patient data, what you actually find is including both low-volume and high-volume disease, you have a near statistically significant improvement in overall survival. You have a definite improvement in progression-free survival that's statistically significant. You could say across all patients with hormone-sensitive prostate cancer, the use of radiation to the primary improves progression-free survival, which is the endpoint used by most drug companies today for FDA approval. But when we look at volume of disease, what we really see is the signal is much stronger for low-volume or less than five bone metastasis by conventional imaging. This doesn't seem to really be impacted by systemic therapy use, whether they had chemotherapy or not, a very similar treatment effect.
Really, I think the take-home message is that the randomized data supports radiation to the primary potentially in all patients, but really the strongest evidence is in lower-volume disease. The question is, "Well, Dan, you talked about bone metastasis. What about this M1a subset?" Well, actually in the STAMPEDE trial, they reported out the non-regional lymph node cohort, which is the M1a subset and there's 181 patients. In that, what you find is while of course it's a small sample size, it actually has a very similar benefit with radiation to the primary, whether it's low-volume by bone mets or M1a for both overall survival and failure-free survival with very large absolute improvements and outcome. Now, in modern days, we use PET imaging, and so a lot of these patients with M1a are by PET. The question is, well, what about the treatment of the primary in patients who have just high-risk localized by conventional imaging that may have PET-positive disease?
I scoured the data for Phase III trials with the role of surgery, and what you'll see here is there's been one trial that people might debate as positive. It didn't have almost any high-risk patients, but it showed sort of a margin positive improvement rate with the use of hormone therapy. But most of the trials that enrolled the high-risk patients closed early or were negative for the primary endpoint or were exceedingly small studies. I sort of ran out of steam looking at all the Phase III randomized trials that included variable amounts of high-risk patients with radiation, which is why the ongoing randomized trials and high-risk that usually the standard of care is radiation to the primary. How do the guidelines of multidisciplinary experts weigh in? Well, the EAU gives strong recommendation for treatment of the primary with radiation.
The NCCN guidelines gives recommendations for the use of radiation specifically in low-volume disease. Most of the data like from PEACE-1 is with abiraterone, but the other ARPIs are included. Bringing it back to the patient is we want to be able to tell patients that treatment of their disease is going to help them, and so when we look at... I'm sort of trying to ignore the small sample size of this surgical trial. What you see here is there's no difference to even delay progression of these patients, kind of we'll call it one of the earliest endpoints you might reach of doing surgery to the primary. In fact, the red curve, which is the surgery curve, sits above, which is not good, the blue curve. When you look at the STAMPEDE trial, again, ignoring the sample sizes, you can see the red curve is clearly, in this case... This is the control arm, and this is the radiation arm. The radiation had better outcomes.
Again, you could tell your patients, "We can delay progression." When you put this onto a forest plot, again, surgery actually at the point estimate was technically worse outcome, of course not significant. But again, in the STOPCAP analysis, progression-free survival was significantly improved with radiotherapy. We of course want to first do no harm. Again, in this RAMPP trial, there was significant increases in severe adverse events and Grade 3 surgical complications. Amazingly in STAMPEDE, there was actually a 1% numerical increase in Grade 3 side effects from radiation. That's it, but it's not even statistically increased. You can see a hazard ratio of just 1.01. Finally, I think for patients in the real world is the median household income today in the US for a 60-year-old man is about $82,000.
When you factor in taxes and other basic household needs, many Americans are barely meeting... They may even be running in a deficit. When you throw in the extra five, 10, $15,000 you often get hit with when you have a new diagnosis of cancer, you're looking at definitely going into your retirement or savings account. The just practicality is that if you're doing radiation to the primary, you can also treat those metastatic sites at the same time. If you're going to do surgery, you're going to have to follow that with radiation. That'd be about two to three times more expensive. There's many ways to do this now with modern radiation. This is just one example to where with five treatments, you could treat the prostate, the elective nodes, common iliac and even [inaudible 00:07:18] in one treatment course in just five treatments, for example.
I think the treatment of the primary with radiation, our goal at the end of the day is to help the patients. This is above and beyond just promoting one specialty or modality or society or our bank accounts. We really should encourage treatments be investigated on clinical trials to ensure we understand if we're actually helping the patients more than harming them. We've got a lot of treatments, we'll call them, out there that are promoted by different physicians, different societies. Some of these are even published, and I think patients are very confused. I want to use this to make sure our patients and all of the providers know we really need to enroll on clinical trials because we can do a lot of things to patients, but we need to make sure that we have evidence that it's helping them more than harming them.
We often talk about a very important trial called SWOG 1802 that's testing treatment of the primary, and surgery is allowed as one of the treatment options. But one of the things because enrollment from urology has been quite limited, right now it's projected to be the majority of patients are actually not going to have surgery. They'll have radiation. This is just hypothetical, but if half the patients getting surgery are low-volume, you're left with only 200 patients actually answering this question. I encourage people out there, especially in urology, to continue, the trial's not fully enrolled, there's about, I think, two or 300 slots left, to please enroll in this trial so we can learn more. Thank you so much. Appreciate you having me today.
Leslie Ballas: Thank you so much, Dan. That was really wonderful review of the data, and I agree SWOG 1802 is an open trial to address this question. It would be wonderful to get more patients undergoing radical prostatectomy on that trial. One thing that you mentioned is that the sort of benefit of radiation in treating the primary is treatment of either regional lymph nodes, non-regional lymph nodes, and/or metastatic disease at the same time, the convenience of all of that. I find a question that I get asked a lot is when you have a patient that has metastatic disease, let's say oligometastatic disease, and you're have great data to support treating the primary, you have reasonably good data to support treating the metastatic disease, what are you doing about the regional nodes? Less data there.
Daniel Spratt: Yeah. It's a good question. I think, as you said, so treatment of the primary to me is we have very strong evidence. It's not really, and I think the AUA discussion came out. It's not really a debate about doing radiation to the primary. It still actually, yeah, it's even treatment, we'll say, of those metastatic sites, some would say especially in the de novo setting, the data's not that great. Most of it's in the metachronous or recurrent setting where we've got STOMP and ORIOLE and these different analyses, and so I would say we need and there's numerous ongoing trials to treat the metastatic sites. We actually don't have that answer yet. Part of that to me is that sort of step one is if we can prove there's a benefit of that, then I think the question is, do you treat the elective nodes in between?
Because if we can't even show a benefit of treating those metastatic sites, you know and the audience knows that elective nodal radiation, we've had a lot of difficulty consistently showing we can improve outcomes. If you're already metastatic, it's probably even harder, one might hypothesize. But again, if there's potential benefit of treating those metastatic sites, then maybe fully we'll call it consolidative therapy, right? You're really trying to treat all the areas that might have growths and microscopic disease may be of benefit. In reality, what we do is if we were to treat those two nodal sites, we typically do treat the elective nodes kind of comprehensively up because it's very rare when you treat one node that there's not microscopic disease and adjacent nodes, but lots of unanswered questions.
Leslie Ballas: Tell me, the data for treating the primary in the setting of M1a or metastatic disease, if I'm not mistaken, relies a lot on conventional imaging. How do we integrate PET, PSMA and that new definition of either microscopic nodal disease into this paradigm?
Daniel Spratt: It's one of the biggest challenges that I think we almost... I don't want to say ignored it with MRI. I mean, MRI definitely had major-stage migration, right? We feel by DRE very few T3 patients. On MRI we may see many, and so there's been sort of a major-stage migration. I think PET though really just jumps out at you because it's not just going from localized to maybe locally advanced. It's going from localized to metastatic often. We really don't know how do we apply all the wealth of this data we have, especially with the different systemic therapy trials in this setting. I think we're left at we're going to have to almost... Do I think we're going to repeat all these trials with PET? I don't. I think that's just not a reality and a practical reality given, especially for drugs that are approved and they're not necessarily by definition of how they were scanned.
But I do think we need to appreciate, and I think a lot of clinical trial groups have done a good job, that now a low-volume by PET has a much, much, much more favorable prognosis, and this has been published, than people that are low-volume by conventional imaging. As we think about how we manage these ongoing and future trials, we're probably looking for more either intermittent approaches. Whether it's MDT thrown into the mix, metastasis-directed therapy, or even some de-escalation paradigms is necessary than treatment of patients with conventional imaging positivity. I don't by any means have all the answers, but I think we do need to be cognizant of that stage migration that's occurred.
Leslie Ballas: Yeah. Thank you. One last question. In accruing to SWOG 1802, I think we really do want to get patients on the surgical arm. How do you think we should approach that given the recent Phase II data that showed no progression-free survival in a surgical population using a somewhat similar paradigm?
Daniel Spratt: Yeah. It's definitely... It depends how you want to interpret that RAMPP trial. We could say it's just too small to give us really meaningful conclusions. Remember the STAMPEDE trial was a 2000-person trial, so maybe it's just too small to really see the signals we want to see. We need more data to sort of, I guess, be confident that there really is no potential benefit. But yeah, I mean, I think people accruing or not accruing, it does speak loudly, right? This trial's been open I think for about eight years plus or minus, and so clearly it's either something that people are either just doing this off trial and that they think this is the right thing to do, or it could be that they don't think it's the right thing to do based on other feelings and they don't have equipoise.
Clearly there's been 700 or however many patients enrolled to date, and so hopefully those centers that do have equipoise can continue to enroll patients because we don't know what we don't know. We can all think we have the answer, but we've been proven wrong over and over and over again. There's many examples we have of treatment of the primary where surgery does not clearly improve outcomes. There's the CARMENA trial in kidney cancer, and now there's other ongoing trials trying to further... Is radiation going to help to the primary and kidney? Maybe. Maybe not. Will surgery? There's the PROBE trial. It's just important for the field and for our patients.
Leslie Ballas: Thank you. Again, we could not be more excited to have had you here to discuss this topic, to learn from you. Thank you so much, Dan, for being with us at UroToday.
Daniel Spratt: It's my pleasure. It was great seeing you, and thanks everyone for watching.