Zachary Klaassen: Hi. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm on UroToday with Dr. Gerhardt Attard, who is a professor of medicine, medical oncologist at UCL in London. Gert, thanks very much for joining us on UroToday.

Gerhardt Attard: Thank you. Thanks for asking me.

Zachary Klaassen: So we have a huge topic that we're going to cover today, hopefully in about 10 to 12 minutes, looking at just advances in prostate cancer and how we implement that into our clinic and assessing real-world data. So just from a high level, in your opinion, whether it's over just ESMO we just had or over the last year, what's some of the exciting data that's really piqued your interest?

Gerhardt Attard: Yeah, wow, that's huge.

Zachary Klaassen: Yeah, we've got three hours to talk about it. Never mind.

Gerhardt Attard: Yeah. So ESMO is great for prostate cancer. So I got to give the summary, so I'll give some post-ESMO thoughts. And the focus was on optimizing upfront treatment for advanced patients, either metastatic or very high risk, non-metastatic on conventional imaging, but very high risk of having metastasis. So there's three messages. The first is in metastatic patients, everyone should receive ADT and an ARPI, if they're fit enough. We're still missing out.

Zachary Klaassen: Absolutely.

Gerhardt Attard: Some patients receiving an ARPI, it doesn't matter which ARPI for efficacy. There's differences in drug interaction, some differences in side effects. But every patient who's well enough should receive that backbone. That's one. Two is we need to be careful about over-treatment. When we add to that backbone, 30 to 40% are in remission at eight to 10 years. This is great, but we don't want to over-treat. So over-treatment now is coming to the fore. Three, still a significant proportion of our patients are dying and they're dying too soon. So we do need to intensify and we need to intensify in a rational way, either using molecular tests and we can talk about that and using imaging to stage patients and prognosticate. So those are the three messages.

Now we have new data from ESMO that really reinforces some of those. So the first is ENZARAD. ENZARAD is a trial that randomized high-risk by NCCN receiving ADT and radiotherapy to the primary plus or minus nodes. And were randomized to enzalutamide or no enzalutamide. Enzalutamide for two years. ADT I think was for three years. We reported the STAMPEDE trial about five years ago. And in STAMPEDE our inclusion criteria were very high-risk. So about 40% were node positive and the node negative had at least two very high-risk features. So ENZARAD goes to the left of that.

And what we saw with ENZARAD was there's no evidence of an improvement in MFS, no evidence of an improvement in survival, and the prostate cancer mortality was exceedingly low in the control arm. So what we now know is that the boundary for intensifying treatment in a high-risk patient, and I must add that includes PSMA-PET positive patients. So this is non-metastatic by conventional imaging. It's a group of PSMA-PET positive patients there. The boundary is to the left of that STAMPEDE population, but not as far left as NCCN high risk. I think that's a really important practice-informing trial. We need to be careful about over-treatment. Over the next few years, we have a whole range of biomarker analysis across multiple consortia planned to define that cutoff. So that's the high risk.

Now, metastatic disease, we had two positive trials and a positive trial presented at ASCO, which I had the honor of presenting. Really, we're now focusing on molecular analysis to define subgroups with poor outcomes that we could therapeutically target. So I'll start off with PARP inhibitors. So that's the AMPLITUDE trial actually published a few weeks ago in Nature Medicine, the intention to treat population where metastatic patients with an alteration and a gene involved in homologous recombination repair, just over half those patients had an alteration in BRCA2 or BRCA1 and the whole population, well the trial was positive, met its primary end point and the whole population, the HRR ITT, the hazard ratio 0.63 and the BRCA subgroup 0.52. So we have significant benefit for RPFS. Overall survival is immature. There's less just about half the number of events we will need for final analysis.

But here we're now seeing a subgroup of patients. There's a study also presented at ASCO and published in Annals of Oncology from Spain. The CAPTURE study, which reported BRCA mutants and HRR mutant patients have a shorter survival, shorter duration of benefit to standard treatments. So as a group they do badly, they should be treated with a PARP inhibitor. We will debate whether that should be at mHSPC or Line 1 mCRPC. Maybe you can talk about that next.

Two other trials at ESMO. The first was of capivasertib. So patients who had PTEN loss by IHC receiving ADT and abiraterone, all metastatic and randomized to capivasertib versus none. The study's positive, but the hazard ratio is 0.81 or 0.82 in the ITT. And then a post hoc exploratory analysis, there's evidence or suggestion of greater efficacy with higher thresholds for defining PTEN loss. There's a clear signal here. We have a population of patients who benefit from capivasertib, the test probably needs to be better. There's probably too many patients in that group.

Zachary Klaassen: For PTEN loss, there are not very many options for these patients as well.

Gerhardt Attard: There is. There's docetaxel.

Zachary Klaassen: Fair.

Gerhardt Attard: There's lutetium. There's radiotherapy to the primary. Those are three treatments. Of course, the patients in this trial, not of course, but of course for lutetium, they did not receive docetaxel was not allowed. I do think radiotherapy was included for the low volume. So there are other options. I think there's a group that is going to derive benefits. I think it's an important trial again, but needs a bit more understanding of selecting that group of patients.

Now, the third patient I mentioned, PSMA, lutetium. We've seen such important efficacy in mCRPC with RLTs and now we're seeing data in mHSPC. I think it's no surprise the trial is positive, met the primary endpoint for an improvement in RPFS. I think the challenge here relates to the second point I made, which is overtreatment. The event rate and the control arm is about 30%. That is a relatively small number of patients progressing or a large number of patients not progressing. Let's take that angle. A large number of patients not progressing. I said there'll be 40% of ADT+ARPI in remission at 10 years. We need to identify those in advance of treating them with lutetium.

But for poor prognosis patients, we now have several new treatments in our armamentarium niraparib for BRCA mutants, capivasertib for patients who have activation of that pathway. Lutetium for patients with poor prognosis. Docetaxel, highly effective for a subgroup and that's all on that backbone. And the last thing I'll say about docetaxel is many groups have been working to identify who benefits, and we published a large analysis from STAMPEDE that identifies the biomarker treatment interaction for the transcriptome classifier well known to the prostate cancer community Decipher. This is a prognostic test and localized disease widely available commercially in North America, not yet in Europe. I hope we'll get there. And patients who have a high Decipher score and that's a score or a cutoff bespoke for metastatic patients, which we pre-define, those are the patients who appear to derive benefit from docetaxel. It's again, introducing precision medicine for an old therapy. I think that's the future.

Zachary Klaassen: Phenomenal summary. I mean there are several jumping off points. You mentioned one, whether we move PARPs from the first line mCRPC to metastatic hormone sensitive, and really we're seeing the question of sequencing, what we give in mHSPC, how we translate that in mCRPC. What are your thoughts on how we should be using PARP? Should it be in the first line mHSPC or should we wait to mCRPC?

Gerhardt Attard: Yeah, so there remains equipoise. My bias is we should move testing upfront at diagnosis. There should be a reflex test by our pathology teams as soon as prostate cancer is diagnosed and I think we should use niraparib. I think there is a significant benefit in reduction of time to symptomatic progression. That's a reduction greater than 50%. The overall survival data is trending in the right direction. So the hazard ratio estimate is 0.75. As I said earlier, that is underpowered and not significant. 33% of patients at this cutoff in the placebo group when they progressed and received the next line of treatment, that treatment was a PARP inhibitor. We will not have a perfect experiment of early versus late. But the reality is patients become unwell. They can't go on to their second treatment.

I think giving them the option of a PARP inhibitor at mHSPC maximizes response, reduces the risk of missing out on that opportunity. I think we've shown an improvement in survival, but we need that data. The flip side there is toxicity because of course patients will receive PARP inhibitors for longer. There was one case of MDS we reported we need to continue to watch carefully for this. So I think this needs a discussion with patients, but I'm certainly keen to have that discussion. And as soon as niraparib is licensable, the label is extended, start using it.

Zachary Klaassen: So when we think about optimization for mHSPC, we just saw a PSMAddition readout that RPFS is above 0.7 hazard ratio waiting on final OS for that. But we have OS data in this disease space, whether it be doublet or triple therapy where the hazard ratio is less than 0.7. So how do we select in optimizing that first line of treatment for mHSPC for those patients?

Gerhardt Attard: Yeah, so I think we need prognostic tests. There's going to be two questions. The first is the effect of lutetium heterogeneous in this population, and they may not be. We do not see a heterogeneity of effect with ARPIs. We do not need a predictive test for ARPIs. We may not need for lutetium. We see widespread PSMA expression, or at least the patients who are recruited to PSMAddition all have PSMA positive disease. But we need a prognostic test. And in patients who are going to progress rapidly and die from their prostate cancer, I think there will be a clear survival advantage. Interpreting the data in a population here with event rates, although is going to be a bit more challenging and we'll need further follow-ups to fully understand that.

The other beautiful part of PSMAddition is that it allowed crossover. So in patients progressed on the control arm, because it was not placebo controlled, so that allowed crossover. When patients progressed, they were allowed or they were offered, given the options sponsored by the sponsoring company to receive lutetium. So we will have a very clean experiment of early versus late and the OS is trending in the right direction. Clearly too early to comment on that, and this is going to need longer follow-up.

Zachary Klaassen: Sure. Last question from me as we move into 2026, what trials are you excited about for GU ASCO, ASCO? What's coming down the pipeline that has your interest?

Gerhardt Attard: I think as these survival readouts, we're going to be anxiously awaiting, and there's two other PARP inhibitor trials in mHSPC. Those we'll report over the next couple of years. And the understanding the magnitude of survival benefit, that's clearly going to be needed A, for several jurisdictions where payers will require demonstration of a survival advantage and also for us to fully understand the true benefit for patients.

Zachary Klaassen: Yeah. Fantastic discussion. Very high level and breaking down ESMO and where all the data fits in. So thank you very much, Gert.

Gerhardt Attard: Thank you.