Alicia Morgans: Hi, I'm so excited to be here at ESMO 2022, with Professor Noel Clarke. Thank you so much for speaking with me today.

Noel Clarke: It's a pleasure and it's a privilege to be able to talk about the PROpel and the updated analysis.

Alicia Morgans: Wonderful. Well, why don't you give us a little of a recap of the PROpel trial, the population that was investigated and the endpoints that were previously reported, and then we can launch into the updated analysis presented at ESMO.

Noel Clarke: Well, PROpel was born out of a Phase II study, known as Study 08, and the study was coordinated and sponsored by AstraZeneca, looking at Olaparib. And the prime philosophy was to see whether the combination of PARP inhibitor, Olaparib, with a novel hormone agent, abiraterone, was superior to abiraterone alone in the late stage setting. In other words, castrate resistant disease in pretreated patients. And the data prior to that had shown that Olaparib is monotherapy or PARP inhibitors of monotherapy, were only really effective if there was a homologous recombinant repair defect, an HRR defect. What Study 08 showed, and it was 142 patients, was that there seemed to be benefit across the board, whether or not the patients had got HRR mutations or not. Now clearly, that needed consolidating in a second trial and that was born out with PROpel, which was designed as an international multicenter Phase III trial.

And PROpel brought the therapy upstream, so at first line castrate resistance and patients were allowed to have Docetaxel in their primary setting, but they weren't allowed to have a novel hormone agent. So it was the first treatment effectively, on disease failure. And the study recruited just under 400 patients per arm in a randomization. And the active intervention was Olaparib at full dose, 300 milligrams, with abiraterone at standard dose, versus abiraterone and placebo. We presented and subsequently published the results of the first analysis of PROpel, and that's been published in New England Journal of Medicine Evidence. And what that showed was that, looking at radiological progression-free survival, there was a 34% improvement with the combination of the PARP inhibitor and abiraterone by comparison with abiraterone and placebo. And other end points, such as time to second treatment and further treatment failure, were also significantly improved.

However, the survival was immature. And so, whilst that wasn't significant, there was starting to be a separation in the actuarial survival curves at that first interim analysis. Now this was across the piece, yet again, it showed that there was a benefit, both in HRR mutated and non-mutated patients. The benefit was greater in the mutated patients, particularly BRCA and especially BRCA2, but there was still a hazard ratio of 0.76 for non-mutated patients. At ESMO, this time, what we're presenting is the second interim analysis, which has undertaken data lock in mid-April, sorry, mid-March 2022. And that has shown that there's been a consolidation of the effect in radiological progression-free survival. Again, we see that there's benefit, both to HRR mutated and non HRR mutated patients. The benefit's greater in those who've gotten HRR mutation, but the hazard ratio for non-mutated is still 0.76, with a significant improvement in terms of improved radiological progression-free survival.

Once again, what we see is that the TFS two and time to further treatments is also prolonged. The survival curve continues to separate. It's still immature. We now have 40% maturity on this. It's not significant at this stage, but the direction of travel is promising. So we're going to present that data. There are some toxicities associated with it, predominantly anemia, which is a class effect for PARP inhibitor drugs. And what we also found was that, there was a small but significant increase in the rate of radiological pulmonary emboli. We don't really understand the basis for that yet, but it does seem to be an effect. Now where we go from here is that, we're going to continue follow-up. There'll be a third interim analysis, we would hope to present that at GU ASCO. At this meeting here, in ESMO, we also have a detailed presentation to the biomarker analysis, looking at specific genes, and that will be presented on behalf of the team, again at the meeting, which will give further insights into our understanding of the importance of PARP inhibition in this disease.

Alicia Morgans: Well, it's so interesting I think, this, as you said, Study 08 building the groundwork for this story and then seeing this in PROpel. And I've only just recently started calling it Study 08. I used to call it the Noel Clarke study. So it is, I think, a study that made quite an impression and I'm glad to see it bear out in this Phase III. What I think is so fascinating is that, we not only seem to see this effect in those patients who have BRCA1, BRCA2, those HRR mutated patients, but really, we wouldn't expect Olaparib to have much of an effect at all other than causing perhaps some adverse events in a non-HRR mutated patient population. We saw this in the studies that led to the approval of PARP inhibitors in metastatic CRPC. And so, it seems that there must be something synergistic happening in this population. And I just wonder if you could comment on that, because as you said, the hazard ratio actually, now again, 0.76 in a non-mutated patient population.

Noel Clarke: Well, clearly there's a lot of the pathophysiology that we don't fully understand, and I probably would approach this from two angles. One is, what's the influence of the novel hormone agent in inducing, if you will, BRCA-ness in that population of patients and rendering them more susceptible to inhibition with a PARP agent. The second is the fact that there are many repair mutations which we don't fully understand, and those extend way beyond BRCA, BRCA1, BRCA2, ATM and so on. And there are elements of this, which I think we haven't yet worked out. So there's a black box approach to this, in a sense. So if we look at the basic science, looking at the way in which pioneer molecules are recruited to androgen related transcription, we know that there is an increased susceptibility to DNA repair and repair inhibition. And so that clearly is an effect, which broadens the spectrum of effect, if you will, of a drug like Olaparib.

What we haven't really worked out is, exactly what other HRR mutations it's affecting. And there are a whole range of those and you'll be able to see, or readers will be able to see through, under Armstrong's presentation, which is at this meeting with a more detailed range of HRR mutations that we can see. So I think this is a story which is going to develop. Now, the other element to this, as you'll be aware, that the parallel study which is presented at ASCO GU in 2022, which is the magnitude study, looking at Niraparib, that trial only demonstrated an effect in BRCA mutated. There was a futility analysis, I think it stopped early. That's my personal view, but there is an aspect to PARP inhibition which relates to dose. Now we know that PARP inhibitors are suppressors of the bone marrow, and anemia is a problem.

So a number of the drugs that are used with PARP inhibitors do have a marrow toxicity when used in combination. So that means that the PARP inhibitor dose has to be reduced. That's not the case with the Olaperib and abiraterone. We think that there's a bigger problem with the amide groups of novel hormone agents because of their enzyme induction effect. So there's a lot of work to do, I think, in working out exactly how good the drugs are in different groups of patients, whether dose level is as critical as we think it is. And further down the line, I think there are a number of drugs which are coming through, which are being more specific about targeting different parts, particularly, specific Part 1 inhibitors, which will enable, we hope, an increase in the PARP inhibitor dosage. And we know that these drugs are dose dependent.

Alicia Morgans: Absolutely. Well, very, very interesting and thank you for walking me through that, because I think a lot of our colleagues are wondering, how are these differences seen between PROpel and MAGNITUDE and why wouldn't this work anyway? So thank you for walking through that. So as you think about these data, and I know that you do not necessarily have access to use this combination in your clinical practice, and I acknowledge that, but if you did have access, would you use this combination in some patients in first-line mCRPC? Is the data compelling enough? Or is this something that you think is very attention getting, but might be best used in the future, maybe perhaps when we see the survival data?

Noel Clarke: Well, that's a very good question, and I think at this stage, I would still say that this approach is experimental. And we really need to see that third interim analysis. If, as I hope, those actuarial curves continue to separate and we see a longer term effect, particularly in overall survival. And if we see that across the piece, then yes, I think that's something which should be considered, because it clearly is beneficial at this stage, but it's too early to say and early readouts in trials are always a little bit skeptical about, we need to see what the mature data is. We only have 40% maturity on the survival at the minute, may be, and I hope at GU ASCO 2023, we'll be able to update this. I hope it'll be positive. We'll see.

Alicia Morgans: We will see. And when survival curves are not yet mature, I always lament a little bit for us, but I'm always a little happy for the patients, because of course we want them all to do well. And this is such interesting data and I hope that it does continue to bear out, and we'll have to just wait and see. But for now, thank you so much for your time and for your expertise, Professor Clarke.

Noel Clarke: It's a pleasure. Thank you.