Read the Full Video Transcript

Piet Ost: I'm a radiation oncologist based in Belgium. These are my disclosures, but one of my biggest disclosures is actually I will only be discussing randomized trials because that is what we do. I won't mention the series. I will mention one—that's the one of surgery.

So if we look at setting the scene, and I'm actually summarizing a bit what everybody does, there are three disease variables. We look at PSA, we look at the microscope, and we look at our TNM. And then what we do is we try to combine all these variables, and as you can imagine and as already mentioned, a patient with only one risk factor does better than a patient with three risk factors.

But also in between the risk factors, there's a difference. You're better off with a PSA of 21 and a Gleason 3+4 than having a Gleason 10 with a low PSA.

But nevertheless, one risk factor is enough to treat the patient in the same way. And I think there is where the future will change, where we'll adapt more.

So looking at the treatment variables, we actually categorize our patients or our treatments according to castrate-sensitive or hormone-sensitive and resistant. We look at organ-confined versus metastatic. Then we again subdivide: low, intermediate, to very high risk.

If you look at the treatment, it's pretty easy. The more you move to the right-hand side, the more the patient actually benefits from systemic therapy. The more you move to the left-hand side, you mostly benefit from a good local treatment or maybe even no treatment at all.

Of course, high to very high risk is a difficult one. How much local treatment do you need? How much systemic treatment do you need? And that's the big puzzle we are trying to lay out in the upcoming years.

So what is this multimodal thing that we're all talking about? Well, there are three treatment variables. There's surgery, there's radiation, and there's systemic therapy.

So let's start with what I would call the doublet therapy. That's a good local therapy with systemic therapy. What is the evidence? And I will summarize a bit what has already been said.

We know that there is an interplay between our dose and our systemic therapy. We can play with that dose. We can give a low dose, we can give a high dose. We can play with the duration of our systemic therapy—shorter duration, longer duration. And this is just one figure, but behind this figure, there are several randomized trials. And as you can see, the line in the middle is our reference. That's low-dose radiotherapy. If you move up, you go to high-dose radiotherapy. And as you can see, as compared to low dose, the difference isn't that big.

Where's the big benefit? It's adding systemic therapy, and you move up all the way to the left-hand side where you increase that duration, you derive a bigger benefit on hard endpoints.

So this is what we mostly do. And for patients with one risk factor, we now have contemporary trials where you give a high dose, as compared to a low dose with a long duration of radiotherapy. And I just want to highlight one of the recent ones. This is the [inaudible 00:03:18] effort. And the question is, if you end up with 96% OS at up to 10 years, what is there to improve on our doublet therapy? Do we need an alternative therapy if you have this?

So, of course, what happens when you have two or more high-risk factors? Well, the narrative changes. This is your OS. This is worse. Why? Because these patients had more aggressive features. But these patients are not dying because radiotherapy has poor local control. No, these patients die because of metastatic disease.

And you can increase the dose, you can do more surgery, you can do whatever. Nevertheless, a lot of these patients already have distant metastasis. Sometimes we pick them up with fancy scans, sometimes we don't. But these patients still have that issue.

So how do we change this? Well, beautiful work being done, already said. Instead of giving ADT only, you add something—you add an ARTA, and you actually improve your OS. But still, you can still see that a proportion of patients is still dying from their disease, so more effort needs to be done.

So what are the lessons learned from three decades of trials only? Well, local control is no longer the issue. We can boost with brachytherapy. We can do focal boost. We can increase the entire dose to the prostate. That's not the problem. Distant recurrences—and that is biology—is the problem.

So do we need to combine it all for all patients? That is the question. And there are three beautiful trials that we'll actually hopefully be reading out in the next years where we escalate our treatment.

I do think that not all patients do need escalation, and that's why I think we need to look at subcategorization here.

And the future will probably be that we add more, and adding more—this is the THUNDER Trial—we are going to add PSMA PET. So I stepped on the train that I was not on two years ago. I stepped on the PSMA train. I was waiting for that. Thank you, Ken.

But we also stepped on the Decipher train, and the same is being done in the U.S. So if you want to have Decipher in Europe, send me an email and you can participate in our trial. And this will be for APCC2030, I hope.

So what about variables in the multimodal therapy? What happens when we look at quality of life? And that's important. I'm going to show you four figures. This is sexual function, this is bowel function, this is incontinence, this is urinary irritation.

And if you ask me what curve do you want to be on, I'm not telling you which is red or which is blue, but you know which curve you want to be. You want to be on the blue curve. The blue curve is radiotherapy, and this is one versus the other in a prospective cohort. It's not randomized, but that's all we have for now.

So if we look at the monotherapy surgery only, and you look at your preoperative variables, so if you have a biopsy score of Gleason 8 to 10 and one of these other variables, what is the risk that you require multimodal therapy? Well, this risk is very high. So why would you go for surgery if you need all the rest? And I do agree. If we can better select our patients, that will be great. But as of today, these tools are not really available.

So often surgery ends up with a triple therapy, and we do have good data, but why do we need two local therapies if we can already do it with one? So these outcomes of these triplet therapies, oncologically, they're not bad. So if you combine everything, it's not bad.

This is from the RADICALS trial. So if you add radiotherapy, if you add long duration, it improves, just as we've seen with radiotherapy only. So what's the point of doing that surgical part?

If you look at node-positive—this work by Derya Tilki—indeed adding radiotherapy does help, adding hormones does help. But what's the added value of the surgery?

So if we look at the quality of life of these triplets, well, actually, if you add radiotherapy on top of surgery, you will have what I would call double trouble. You add toxicity, but do we improve outcomes? That's something we don't know. We only know that, at this time point, we are adding something, and what we are adding is toxicity. And is this good enough? If you know beforehand that your patient will have 90% chance of requiring multimodal therapy, why would you go for it? That's my question.

So some concluding slides. If you have more risk factors, you probably need more systemic treatment. You probably don't need more intensified local treatment. We figured out how to do that, so that part is figured. We need to tackle the distant disease.

Second conclusion, I think the doublet therapy offers excellent outcomes for these patients. So why would we need a triple?

So for me, the triplet therapy actually increases morbidity over the doublet without really a proven benefit. So why as of today would we want to do this?

I'm happy to take any questions afterwards, and I hope to make it out alive out of this session room. Thank you.