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Christopher Sweeney: And first of all, just to get the disclosures out of the way relating to advising and research, as well as being the PI of the CHAARTED and ENZAMET studies with Ian Davis, which may influence some of my thinking.

My assignmet: how to manage patients who have early progression after six to 12 months of combination therapy. And by that, testosterone suppression with ADT plus abiraterone and enza, apa, darolutamide, may have had docetaxel, may have had radiation to the prostate. How do we deal with this patient?

So first of all, how do these patients fare? The frank answer is we don't have enough data yet because we don't have all the individual patient data from all the clinical trials saying, how do the patients progress after they had a PSA that went down, then came up six months later.

We don't have that data for abiraterone and the amides yet. So it's a plea for us to be able to do individual patient data meta-analysis to really get good granular data through the StopCaP. We've done it with the ADT, with the docetaxel. Now we need to do it with the advanced hormones.

We've got it for all the cooperative groups: PEACE-1, SWOG, ENZAMET, and CHAARTED and STAMPEDE, but a plea for pharma to be able to help us access the data into that StopCaP repository.

But this is what I can say from ENZAMET, if you don't have a PSA progression during the follow-up, we've got 92% of patients alive at five years, and 8% of patients are dying of something else. And it's about 392 at this stage, with some still in follow-up who had not reached the five-year mark.

Black are patients who have PSA progression, and then radiographic progression with a 42% five-year survival. And 34%, 10% of the patients, purple, who had radiographic progression without a confirmed prior PSA progression. Some of them neuroendocrine, some of them anaplastic, but they do the poorest, as we can see here.

Early enzalutamide decreased the rate of all types of progression. And the hypothesis is that the five-year survival would be even worse for the patients who had early progression with enzalutamide because they didn't have the salvage opportunity with an amide for castration-resistant disease after ADT alone.

We would look into that for the publication. But this, I think, does make an argument for some degree of surveillance following on from Michael Morris's talk yesterday. And it would be great to also get this data from ARCHES. And we can actually see when and how often these patients were progressing, what were their features, and define a surveillance strategy with imaging in addition to PSA, even if their PSA is low.

So it is imperative to define the best first-line therapy option for each individual patient. There is no single therapy that is best for all patients. Patient and tumor profiling is key. So we can precisely deploy precision-targeted, personalized medicine, whatever term you want to use, we need to actually find the right therapy for the patient.

And our goal is to use as many life-prolonging therapies as possible, but we need to use the best one up front. Many patients are not able to go from first to second to third line. We just look at the PSMAfore study, 15% of patients didn't get to crossover to the early lutetium PSMA after their hormone switch. And that was a highly selected patient population in a clinical trial who were thought suitable for a hormone switch. So we need to get the best first-line therapy.

So how do we do this? And I say it is imperative we do proper profiling. Patient characteristics: Have they had docetaxel, have they had radiation to the prostate, are they suitable for docetaxel or cabazitaxel in the castration-resistant setting?

If cabazitaxel being—if they have had docetaxel for hormone-sensitive. And what access do you have in a given region? Lutetium PSMA is not available throughout the world, for example. And what are the tumor characteristics?

I would say we're in this APCC world where we get access to all therapies. We PSMA-PET-CT profile patients, tumor exome profiling, focusing on BRCA1 and BRCA2 and MSI, and the tumor suppressor gene mutations P53, RB1, and PTEN for the reasons that we saw in the talks yesterday from Matthew Smith and what Mary-Ellen presented.

And what's the extent of their progression? Is it oligo or diffuse progression? And here is our patient who's been on hormonal therapy for a while. He's not the fit Superman in his '50s like Karim Fizazi—oh, you're in your '40s. Sorry, Karim. Sorry, I aged you.

But look, he's a little older. He's a little frail. He's happy to see you because most of our patients are charming. But we want to do the best. This is a picture from Google, but I thought it matched. He's been on hormonal therapy. He's got the central obesity. So he's not super fit.

Has he got oligoprogression? Can we possibly think about external beam radiation? PSMA-PET high. What is the optimal high? SUV greater than 10. We've got some data for that. I'll talk about it. No discordance. Maybe the lutetium PSMA is an option for him.

Germline BRCA or somatic BRCA1-2 mutation, a PARP inhibitor. Loss of two or more suppressor genes, carboplatin and taxane. There's data for that. And none of the above. This old drug called docetaxel or cabazitaxel, it has a survival benefit.

If you resort to it, it's not that they are getting an inferior therapy. It's just older and it's not talked about as much, but it's still a therapy that we should be considering. And for the immune therapy, the one data set that I think is very strong that we should think about is if MSI high, consider a PD-L1 inhibitor, although the data is very limited.

So first of all, what's the data for oligoprogression and stereotactic radiation? Here we have a multi-institutional study, small numbers. And what you can see is if you can do complete ablation, black curve, you've got 40% of patients who are still on therapy and didn't need an escalation with SBRT alone by 18 months.

That's an option for these patients. This could also possibly include, as Mary-Ellen alluded to, irradiating the prostate if they're having some growth of their prostate and no other progression on scans. And again, I think this makes a case for surveillance imaging to see oligoprogression.

Well, what's the optimal patient profile for lutetium PSMA? Well, we know that lutetium versus cabazitaxel further therapy study, no real survival benefit. They're both good therapies. But when you drill into the data, the patients who had a high PSMA SUV mean greater than 10 did better than the cabazitaxel by radiographic progression and PSA progression. So maybe if there was a more biomarker-selected, we'd actually see a survival benefit with lutetium PSMA versus cabazitaxel.

In the VISION study, where lutetium PSMA was compared with non-life-prolonging therapies for castration-resistant, there was a clear survival benefit. And again, the outcomes were best for those who had a PSMA-PET SUV mean greater than 10.

So I would direct a patient with high PSMA-PET imaging to lutetium PSMA. However, if they have a BRCA mutation, a low PSMA-PET, with the PROfound trial and the long-term follow-up that was just published in the JCO shows that there's a clear survival benefit for a PARP inhibitor single agent in this setting. Biological, targeted precision medicine at its best.

But if they are biomarker negative, no indicative biomarker, let's look at history here. Greater than 90% of the patients on the TAX327 had two or more hormone manipulations for castration-resistant disease.

And we know mitoxantrone prednisone was better than prednisone alone in quality of life, and docetaxel prednisone was greater than mitoxantrone and prednisone for quality of life. And there was a survival benefit.

Let's not forget about docetaxel. We're not giving these patients inferior therapy because we don't have the new fancy therapy. It is a therapy we should not forget about. And cabazitaxel after docetaxel. Again, compared with mitoxantrone, there's a survival benefit.

I can't say that for a PARP inhibitor for a patient with the non-BRCA HDDRs as clearly as we can see here for cabazitaxel. And because we didn't believe it the first time, we did the study with a hormone switch and we again see a survival benefit.

So what about the patients who have this terrible prognostic disease, anaplastic variant? Sometimes small cell, sometimes neuroendocrine. And they tend to have two or more mutations in P53, RB, and PTEN. Do we have a therapeutic option for them?

And the MD Anderson team, representing the team here today, published this really well-done study that read, you had a survival benefit if you got a platinum with the taxane versus just the taxane alone.

Randomized phase II, but it's the best we have. And "trila" is a misspelling of "trial." That's not my Italian of trial, "trila." It should be trial, so apologies for the typo there.

So Memorial Sloan Kettering has a great project of profiling their patients with their IMPACT exome next-generation sequencing panel. 2% of patients have MSI high, so it's worth checking, but it's very rare when you're also checking for BRCA and the tumor suppressor genes. 11 of the patients actually had PD1. And notably, five of the 11 had meaningful responses, with some lasting more than 89 weeks.

So the profiling imperative for maximal patient benefit. Oligoprogression, think about external beam. PSMA-PET, lutetium PSMA, germline BRCA, somatic BRCA, PARP, loss of two or more carboplatin and taxane. None of the above, docetaxel and cabazitaxel. MSI high, maybe a PD(L)1 inhibitor in the future. Thank you very much. We can do this.