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Declan Murphy: Thanks, Matt. I don't have any slides. So, Matt's asked me to talk a bit about Grade Group 1 in the MRI era in Australia. Australia's a very heavily screened country with a very high proportion of localized cancer, and since 2018, we've had widespread, fully funded access to MRIs for everyone. So there's no excuse—MRI is very heavily embedded in our diagnostic paradigm for five or six years. A couple of points I wanted to make: first, in the pre-MRI era, and we have great data from a supported registry to say this, back in 2009, 40% of all newly diagnosed patients were Grade Group 1, 40%. In the post-MRI era, it's dropped to less than 20%.

There are other factors, but I think predominantly what we've seen is, like in the UK, if you bring MRI into your paradigm across the whole country, you've greatly reduced the proportion of patients you find with Grade Group 1, just like the PRECISION trial has shown. So the patients are still out there, we're just not finding them because we used MR. Is that a good thing? Yes, I think that's a good thing.

The second point to make is, well, we're now in an era when there are patients out there like in the control arm of PRECISION who didn't get a biopsy, who have Grade Group 1 cancer, and maybe some of them have Grade Group 2 cancer. So what is going to be the outcome of not having biopsied those patients? Well, we're beginning to see it, and PRECISION is following those patients. So we will get some objective data. What I see is we still follow the patients, and they come back in for a further MR one, two, three, or four years later when there's a trigger, and we find them. My sense is that we're not disadvantaging those patients by not having done a biopsy back then.

So my comment is, if you have high-quality and community-based widespread access to MRI, you dramatically decrease the proportion of lower-risk patients you find, and I think that's a good thing. And on balance, as Laurie says, overtreatment is a bigger problem than undertreatment, and generally speaking, we find those patients.

The last point I want to talk about is, as we're finishing on, a question about uncertainty. And that's the question I have: how much uncertainty do you and your patients accept by not doing a biopsy in the first instance if your PSA is 6, but your MRI is normal, or by not acting on it, not doing further work based on biopsy? That's a theme I think we should explore as we try and deal with this issue of overtreatment. It's important to talk to your patients and your community about accepting uncertainty and to build in some triggers that you're going to find in the patient.

For example, PSA density is very important to us. The reason we still have 20% of low-risk treated is because the patients who are getting a biopsy with low-grade cancer have a red flag—they've got a high PSA density, are young, have a family history—and some Grade Group 1s will always need a biopsy and need treatment. But if you explore a theme of uncertainty and put in some safety measures so that you catch those patients eventually, I think that's a good way, and that's the way we practice in Australia.