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Paul Nguyen: Hi, everybody. Thanks very much for coming back after lunch. I appreciate that. I know it's a tall order. I appreciate the opportunity to be here, Silke and Aurelius. So here are my disclosures.

So this is my topic, this question. Question number 49: In the majority of patients with a confirmed PSA rise after radical prostatectomy with prior salvage radiation to the prostate bed and PSA doubling time less than one year or pathological ISUP grade group four or five, and one to three positive lymph nodes in the pelvis alone on PSMA PET, what is your treatment recommendation regarding the radiation therapy? A) SBRT of positive nodes alone; B) whole pelvis RT plus or minus boost to positive nodes; or C. So really, A versus B.

I was very happy to get this question. But then I thought, there are 183 questions, and some people had big topics, like high-risk prostate cancer, and I got one question. So one question, it turns out, this equals 0.54% of the topics to be covered. And so maybe because it's my first time at APCCC, Silke wasn't sure how much I'd be able to handle, so I got 0.54% of the questions.

Now, to keep it fair, everyone gets 10 minutes for their topic. So if I had proportionally the same amount of time for my topic, 0.54%, it would be 2 minutes and 11 seconds. So you can actually ring the bell at 2 minutes and 11 seconds, and that'll be OK.

All right, let's jump into it. So first of all, we have to figure out, is any local radiation justified in this setting? And I think the answer is yes. If you have positive nodes on a PSMA PET in a recurrent patient, we can take a look at retrospective data that suggests that metastasis-directed therapy, including to the nodes, improves cancer-specific survival. There was a multi-institutional study: 659 matched men, 25% of them received metastasis-directed therapy. This was a mix of salvage pelvic lymph node dissection and SBRT for up to five lymph node metastases. And you can see, on the right, a significant improvement in cancer-specific survival. It's retrospective, but it's still good data.

Let's get to the debate. I actually don't have a debater. But to make it interesting, let me debate myself. But let me take on one position, which is I think that we should be starting from the position of whole pelvis. So what would justify just doing SBRT instead of whole pelvis? And look, I recognize there are differences of opinion here, but let's take a side. I think it would justify SBRT if we could show, number one, if the cancer control is comparable to whole pelvis and/or, number two, if the toxicity is less than whole pelvis radiation. So can we show this?

Is SBRT cancer control, going after a focal node, as good as whole pelvis? I think the answer is no. We can extrapolate from the surgical series here by Doctors Bravi and Briganti in European Urology. They're looking at salvage lymph node dissection for nodal recurrence after radical prostatectomy. Positive on PSMA PET, they found that 66% of the patients with a single node positive on imaging had more nodal metastases on final pathology. So if you just aimed for one node, you would still have more disease there.

How about another series? Is SBRT cancer control as good as whole pelvis? We would have to say no. This is a retrospective series by Dr. Bleser in European Urology. They found that there were fewer pelvic nodal failures after elective whole pelvis radiation, only 8% versus 42%. And there was improved metastasis-free survival to treat the whole pelvis instead of just treating one node. The hazard ratio on the left is 0.5. The p-value is 0.09.

So cancer control is not comparable with SBRT. But what about toxicity? Maybe it's a less toxic treatment. That would make sense. We could do it if it's less toxic. Is toxicity with SBRT less than whole pelvis? Here, I think we also have to say no. This is data from the STORM PEACE V trial. This is from Piet Ost, who you saw this morning. I thank him for his slides. This was presented at EAU just a couple of weeks ago. So this is fresh off the press.

This was a randomized trial—oligorecurrent PET-detected pelvic nodes, fewer than or equal to five nodes. They were randomized. Everybody got six months of hormones, and either you got SBRT to that single node or a lymph node dissection, or you got whole pelvis radiation with a focal boost or nodal dissection. And so what about the toxicity? If you look at the box at the bottom, there was no significant difference in toxicity between just going after the single node versus doing the whole pelvis radiation: 22% versus 26.5% on GU toxicities, and it was the exact same result for GI.

If you look at just the node versus the whole pelvis, the grade 2+ GI toxicity was 5.3% versus 6.6%. This was not statistically significant with a p-value of 0.94. This is randomized data that does not show worse toxicity with whole pelvis.

Now, we're all waiting for the oncological outcome. So it turns out that in two weeks in Glasgow, you can get the oncological outcomes from this study. And so this talk may be completely moot in two weeks, but at least between now and two weeks from now, we have to come up with what to do.

So what would justify SBRT instead of whole pelvis? Neither of these seems to apply. SBRT, at the moment, appears to have inferior cancer control, although we're waiting for PEACE V, and similar toxicity to whole pelvis. And so in my view, today at this moment, whole pelvis radiation should be preferred.

Silke also asked me to talk about should we use ADT with nodal radiation. I think the answer there is yes, I would use it. This is the data from the RTOG 8531 trial. This was started in 1985, when Back to the Future was the number one movie in the United States. But it's still relevant today. This was looking at radiation plus or minus lifelong hormones for node-positive patients. In the node-positive subgroup, there was a significant benefit to overall survival for using hormone therapy. And so I would continue to use it in this setting.

The question is, how long should the ADT be? In my view, I would say greater than or equal to six months. Here's the OLIGOPELVIS Trial. This was just in press. This is in press in European Urology. Phase II study, 67 patients, fewer than or equal to six nodes—they got all radiation and six months of hormones. They had five-year very good overall survival. Biochemical recurrence-free survival was 31%. Metastasis-free survival was 59%.

Of course, this wasn't compared to anything. But I think at the moment, we have to decide to do something. We can't have perfect data at the moment. We still have a patient in front of us. I would use at least six months of therapy.

There are important future randomized trials coming in this space. Of course, STORM PEACE V, next week in Glasgow. OLIGOPELVIS 2, which is similar to OLIGOPELVIS, but now this is going to be randomized: six months of ADT, plus or minus elective nodal radiation. I think that's going to be very interesting. PRIMORDIUM is looking at radiation and hormones with or without apalutamide. PEARLS: ADT plus pelvic radiation, plus or minus paraaortic radiation.

So the question is, OK, if you see the nodes and we're going to treat the whole pelvis, should we go up one chain higher and treat the paraaortic? Because that's where a lot of these patients will recur. That's the most common site of recurrence when you treat the pelvis with a patient who has nodal recurrence.

So just to summarize, because we have to do something today. We can't always wait for perfect data. What do I do for N1 recurrences? Number one, I treat whole pelvis radiation. I do boost that lymph node to extra dose. I do not treat the next echelon nodes. I do not do prophylactic paraaortic nodal radiation. I do use anywhere between 6 and 24 months of hormone therapy, and I tailor this based on age and clinical factors. And there may be some rationale to consider Abi, Apa, Enza, Daro, depending on age and clinical factors, today in the clinic—noting that we don't have the level one evidence yet. Thank you.