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Ray McDermott: Thanks so much for having me, Silke and Aurelius. I emailed Silke last weekend. I was looking at a blank sheet, and I was wondering what to put down for my presentation. So I briefly thought of a text to Declan, saying, could I swap with him and do rectal exams? But I stuck with this one anyway, so we'll see what we come up with. So these are my disclosures.

And I think the things that we need to think about in these patients: So we're presuming that they've had surgery, salvage radiation, they're having a biochemical relapse, or as in the question, they may have had metastasis-directed therapy. So I think the first question, especially these days, is the patient still castrate? A lot of salvage treatments now will include hormones, whether it's for a long period or a short.

And so I think it becomes a very relevant question, especially when we look at the eligibility criteria for EMBARK, where a testosterone level over 150 was part of the eligibility. The PSA doubling time we've heard a lot about already, we'll talk a little further, extent of prior therapy. PSA level, I think, is important. The time since prior therapy, I think comorbidities—we've heard a little bit already. I mean, I think that we should approach these patients very differently depending on what else they have going on in their lives.

If they've got multiple comorbidities, does a rising PSA really matter all that much, and should we be intervening very aggressively? And then, of course, the final thing, as David said earlier on, is the patient expectations. This really has to be a shared decision because realistically, we're not talking about patients that we can cure anymore at this point, for the most part, I would have thought. So quality of life becomes very important. And I think the quality of life tools that are out there are very imperfect.

So we know from ASCO last year and also from this study that people who've been treated with ADT, many of them take a long time to recover, and some don't, from castrate levels of testosterone. And only a small percentage will get back to normal gonadal levels. The duration of the hormone treatment and the age at cessation are predictive factors, so that's important.

Obviously, when we're thinking about this population, is it the same to treat as in the EMBARK population? If your testosterone is still low, it's probably not because you're actually developing a type of castrate-resistant disease. 150 has to pick up. I was asking Neil there, why did they pick 150 as the cutoff? If you look at testosterone, 150 is where you see anything below 150 predicts for hypogonadism; above that, not so much. So maybe that was the reason, but it certainly is an important thing to do.

If we look at the NCCN guidelines, they say in this scenario where we have recurrent disease with nothing on PSMA scan, consider if you haven't had full pelvic radiation therapy to consider that. I mean, obviously, in the absence of anything on PSMA, it'd be interesting what the radiation oncologist would feel about that. I think perhaps in patients with slow-rising PSA and a long doubling time, that might be very relevant.

So I suppose then if we go to—now we have level 1 evidence to show that if you're in this scenario for PSA doubling time less than nine months, then 50% of the patient population in the EMBARK study were exactly that population, and the median PSA in those patients was 5. And as we—I won't get into the details—but intermediate therapy is appropriate for those patients. And I suppose I was specifically asked to talk about patients who don't have metastatic disease.

I think we all know that if the EMBARK study was being done now, the majority of patients on that study would have had findings on PSMA PET. So in my scenario, this patient who doesn't have anything on PSA, they're probably going to do even better than the patients who were on the EMBARK study because they don't have metastatic disease. Just to remember that.

And I'm grateful to Thomas, who's sitting there, for his slides. This is just to show you where the thought is going for these patients for the future. So this is a study that's going to be launched through the EORTC, Silke is involved and Bertrand also, and it's a randomized study looking at ARPI alone for nine months versus ARPI plus metastasis-directed therapy and/or whole pelvic radiation. And the important point there is that if you hadn't had pelvic radiation as part of your original salvage treatment, you get it as part of the study. So I think that probably is still a live question.

OK, so what if your PSA doubling time is over nine months? Well, then I think it comes down to your PSA level, again the extent of the therapy, and the time since prior therapy as well. This is the Australian study, the TOAD study, which showed that it's very reasonable to delay insertion of androgen deprivation therapy in patients. You don't see any difference for the first five years in terms of overall survival. So I think that's a very reasonable strategy, especially in these patients with slow-growing disease.

And if you look at the prospective study of PET scans in patients with recurrent localized cancer, we can see that the level of PSA at the time you do the PET scan is important. So if you do the PET scan when the PSA is less than 0.5, you can see that the probability of seeing something on the scan is less than 50%. On the other hand, if you wait until the PSA is between 2 and 5, it goes over 80%. And if it goes over 5, as we heard earlier, you're probably going to see something in the majority of patients.

In this study, it didn't seem to matter whether the PSA doubling time was less or greater than six months, but I think that we probably, in this scenario where I'm thinking of patients with a longer PSA doubling time, might be more willing to wait to pick up where you might be able to do metastasis-directed therapy rather than instituting androgen deprivation or even an ARPI and the associated toxicity.

There's one study that I found that looked prospectively at patients with biochemical recurrence in whom they repeated the PET scan. And in those patients, there were 33 patients, but four of them went on to hormones. It changed management. The PET scan showed something after it was repeated in 40% of the patients, and it changed their management in 20%. So I think it certainly comes back to the discussion about what does your patient want?

Some patients that I deal with at very low PSA are starting to get very nervous. Other patients are more, “It's whatever you want yourself, doctor.” So it really depends on what the patient wants and what they need for their individual circumstances to keep them satisfied. But I think doing nothing and repeating the PET scan is a very valid strategy.

This is a meta-analysis that was published earlier this year of metastasis-directed therapy. This is from one of the supplementary figures. I think it's important. It's the estimates for delaying ADT in patients who get metastasis-directed therapy. There aren't that many studies, and the numbers, as you can see, are quite small. But in 50% of patients, we were able to delay ADT for up to two years, which is a very significant proportion of patients.

So for a PSA doubling time of over nine months, I would favor a lot of patients' masterly inactivity, or as Cowper, who was an English poet, said, "Do nothing with a degree of skill."

So obviously, doing nothing is not something that is easy to— that involves a longer discussion probably with the patient, but I still think it's the right thing to do. Repeat the PSMA scan, try and find the target. Look at the extent of the prior therapy. There was one study that said maybe do a PET scan in these patients with negative PSA scans. There was a pickup rate of 10% on PET scans. I'd say that's probably in the patients with the lower PSA doubling times rather than the higher ones. And then I suppose if you have to treat, it's intermittent treatment, I would have thought, and it's ADT at the moment. But will it in the future be an ARPI?

So to finish up, the PSA doubling time: I think we now have level 1 evidence for treating systemically. Whatever your choice is, that's another talk. And then over nine months, let's be patient. Don't do the PSMA when the PSA is too low, or if you do, maybe think about repeating it. Has their whole pelvis been treated? Metastasis-directed therapy may significantly delay, in certain cases, the need for hormone treatment. And then intermittent hormone treatment is the most appropriate.

Thank you. I'm delighted to represent Ireland here. I know we had Declan here, he's defected to Australia, so I am delighted to represent Ireland here on stage. Thank you very much.