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Alicia Morgans: Hi, I'm so excited to be here today with Professor Ian Davis, who's a professor of medicine at Monash University. Thank you so much for being here with me today, and thank you so much for sharing time with me at APCCC 2024 in Lugano, Switzerland, where you gave a wonderful talk to help us think through the challenges of sequencing. Thank you so much, Ian.

Ian Davis: Thanks, Alicia. Always a pleasure to talk to you.

Alicia Morgans: Wonderful. Well, why don't you give us a little overview of your talk and we'll have a chat after you're through.

Ian Davis: Thank you, Alicia. It was great to be back at APCCC 2024 in beautiful Lugano. What a wonderful meeting that was. I was asked to give some guidance on what the ideal sequence of treatment might be for patients who have progressed after combination treatment for metastatic hormone-sensitive prostate cancer, who now have metastatic castrate-resistant disease. And really, the spoiler for this is that there is no ideal sequence. So I'm not going to try to convince anybody of what that should be, but I think I managed to identify a few less-than-ideal sequences, and I'm going to run through some of those for you today. So the key principle here is that we only ever give one treatment for metastatic hormone-sensitive prostate cancer, unless of course we change for toxicity because every subsequent treatment is for metastatic castrate-resistant disease. And we know, as I'll show in a later slide, that the benefit we get from later lines of therapy continues to diminish. So we get the best benefit for the first line of therapy.

The overall goal is to achieve the maximum benefit over the entirety of the patient's life, not just for this next treatment, but for every treatment that they might get. And we need to consider as part of this, the windows of opportunity that we have for treatment. In other words, will we be able to give an effective treatment later on down the track? And secondly, what is the probability of a benefit now, given that somebody has already had prior effective therapy? And as we're thinking of this, of course, we need to understand what we actually mean by maximum benefit. Are we looking at delay in cancer progression? Are we looking at survival outcomes? Are we looking at quality of life improvement? All of these things are important endpoints for our patients. So the principles are to use the most effective treatments and to use them in the most effective sequence.

I've shown this slide at a previous APCCC meeting, but it bears repeating. And that is that when we're considering the selection of initial treatments and subsequent treatments, the order of treatments sometimes matters. If we have two treatments that are not interdependent, then it probably doesn't matter what order you give them in, A to B or B to A, you're going to get the same benefit. But if you have treatments that are interdependent in terms of their mechanisms of action, then it matters very much which treatment goes first because if you choose the wrong one, then you may miss out on the opportunity for benefit from the other treatment. And I've listed some examples at the bottom left of treatments that do share some interdependent mechanisms of action where the sequence of treatment might be important. So here are options. I'm not going to go through these in detail. These are well known to most people in the audience. But I've listed some of the key life-prolonging therapies that have been demonstrated for castrate-resistant disease here and some of the key studies.

And of course, if you look at the dates of publication for those five at the top, these were all performed in the era where the standard of care for metastatic hormone-sensitive disease was ADT alone without any double or triplet intensification. So we are now in an era where we are using this intensification. The type of information that we have here needs to be considered in that light. I've listed some other studies at the bottom part of this slide here where some, perhaps not a majority, but some patients did receive intensification of treatment for hormone-sensitive disease. And we need to take that into consideration as well.

Now, this is a complicated slide. I'm not going to go through it in detail. The point of this slide is to show that the benefits that we see from these agents are really qualitatively and quantitatively different depending on the clinical state. If you look at the areas that I've highlighted in magenta here, you can see for Docetaxel, for example, that the magnitude of clinical benefit we see in terms of improvement of median survival is much, much greater in the hormone-sensitive setting than it is in the castrate-resistant setting. We also see that for Abiraterone, for Enzalutamide, and I've included Apalutamide and Darolutamide here as well, although the data is more limited for those. So we really are seeing fundamental differences here depending on whether there has been prior selection in terms of the effective therapies received for the hormone-sensitive state. So when we're interpreting the literature, there are various challenges. Firstly, the various protocols for metastatic hormone-sensitive disease that are now well-known do not control the sequencing of subsequent therapies.

We know that there are regional and temporal variabilities in access to subsequent life-prolonging therapies, either not available or not available in those regions. And there were very diverse patient populations, which I'll show you in a moment, which means that we cannot assume that the trials are directly comparable. We cannot assume that they are directly representative of the broader population because of selection. And I've listed this here. These trials are the key clinical trials for metastatic hormone-sensitive prostate cancer listed in order of the end of recruitment. So you can see the first six there going down to 2017. And then ARCHES, the overall survival data was presented a little bit later. We have ARASENS and PEACE-1 with triplet therapies there. And the points that I want to make here, if you look at the third column there, is that the populations are quite different in terms of risk.

The proportions of participants with synchronous M1 disease, in other words, metastatic disease at the time of initial diagnosis, and the proportions of patients with high or low burdens of disease depending, and that was classified in different ways, really vary quite considerably across studies. So these were different patient populations. Some consolation in terms of access to any life-prolonging therapy, particularly for the control group, which was greater across the board than the active group. But you can see there, there was substantial variability in access to those therapies. So again, as I said previously, the older castrate-resistant studies did not include patients with intensified treatment for hormone-sensitive disease, although we know still sadly today, probably over half of patients still only receive ADT alone for metastatic hormone-sensitive prostate cancer. Although we heard at APCCC that that might be changing. But can we learn anything from the older sequencing data?

I won't go through those in detail, but what we do know is that Docetaxel is less effective if it is used after an androgen receptor pathway inhibitor, although Cabazitaxel does retain activity in that setting. And we also know that it is really illogical to go from a drug like Enzalutamide to Abiraterone, because the probability of benefit there is very much lower. There is some logic in going from Abiraterone to a next-generation AR antagonist such as Enzalutamide. But again, activity there in ARPI switching is known to be much less. We know from real-world data that prior treatment does affect the probability of response to later treatment. And the real-world outcomes are very dependent on patient factors. And I mentioned before about the probability of benefit, you can see in the last line of this slide, the probability of improved survival diminishes as we go on.

I won't spend any time on this slide. It is really just to demonstrate that as we go through first, second, and third line treatment, Docetaxel, for example, is not used commonly. We don't really see that happening in this series from the US until third line treatment. So what are some specific situations? Well, if we have a patient without errors in DNA repair, mismatch repair, or high tumor mutation burden, then PARP inhibitors or combinations are less likely to be helpful. And there's little evidence yet for immunotherapy, although this might change. A patient who has early or rapid progression after initiation of treatment probably has a cancer where the androgen receptor targeting strategies are less likely to be effective, where we may perhaps need to consider other mechanisms of action such as taxanes, platinum monotherapy or combination, radioligand therapy, or perhaps some other targeted approaches.

Radioligand therapies, as again, we heard at the meeting, are moving earlier in the treatment course. These are logical and evidence-based choices for later lines of therapy. We've got some evidence for activity now in earlier settings in castrate-resistant disease, but caveats do apply to that. But some of these combination approaches may help us address tumor heterogeneity, and of course, clinical trials remain important and valuable options for these patients. So my last slide, what are some of the less-than-ideal approaches? Really anything that means you remove a later effective option, and this might not be obvious, such as, for example, missing a narrow window of opportunity to give a treatment that might be more toxic. Chemotherapy is an example. If you don't give it in the first-line setting, the patient might not be well enough to get it in a later setting. Use of a less effective treatment option before a more effective one. We know that Lutetium-PSMA is superior to Cabazitaxel, not in overall survival, but in many other endpoints.

And it really makes no sense to use an AR pathway inhibitor before Cabazitaxel based on the CARD data. We shouldn't be using new things just because they're new or just because we can. And really now, why should Docetaxel not be first-line treatment for metastatic castrate-resistant prostate cancer in a patient who's had intensification with an AR pathway inhibitor in the first line? And my final call to the meeting was really that we should, as a group, stand up against the use of clinical trials using ineffective or what I call toxic placebo comparators, such as AR pathway inhibitor switching. And I'll close with that. Thank you for the opportunity to present this information.

Alicia Morgans: Ian, thank you so much. That was really a wonderful tour de force through a lot of information, some lack of data. And then to your point, at the very end, there are some things we absolutely should not do. And one of those things I think I'll just echo is that we should not be using a second AR-targeted agent for the majority of our patients after progression of disease on a first AR-targeted agent. One area where I want to push back and just make sure, I think, not that we're all on the same page, because I think we can all be on different pages and different patients are going to have different answers. It was interesting, the TheraP trial, a phase two trial, which ended up not showing a survival benefit, did show probably some superiority in terms of quality of life, but also was a selected population that really compared lutetium PSMA-617 to patients receiving Cabazitaxel, again selected by PSMA and FDG PET for eligibility.

And I wonder, do you feel like we really have the firm evidence that we need to say that we should always be using lutetium before Cabazitaxel in this setting?

Ian Davis: That's a difficult question to answer, Alicia, and very insightful. I think we probably do. The TheraP study was designed to include patients for whom the next treatment was going to be Cabazitaxel. So there was selection there for patients who were fit enough to receive it, and there was additional selection based on imaging criteria. So in that patient population, if you had the choice, TheraP showed that lutetium PSMA was superior in terms of PSA progression-free survival, and also quality of life and patient satisfaction, patient-reported outcome measures as you say. The study was not designed to show an improvement in overall survival, and there was a lot of crossover. So patients did get lutetium down the track, which contaminated that endpoint. So we weren't trying to show that. I guess it was really not surprising against an effective comparator that overall survival was not substantially different in this very heavily pretreated patient population.

Alicia Morgans: I really could not agree more. I think it was a really nicely done trial, and I would emphasize the quality of life superiority as being a major driver there as well, just because PSA response rates and progression are important sometimes, but not necessarily tied always to clinically meaningful outcomes. Although, of course, it's always nice to see a PSA go down, and patients appreciate that just as much as the doctors. But I do think it was a really interesting comparison and certainly useful in my clinic for those patients who are eligible for treatment with lutetium PSMA-617. So the only other question I wanted to ask and pick your brain about, and we probably have different access availability for PARP inhibitors, but how do you see them fitting in, given especially the new data in first-line mCRPC with combinations? Do you have the opportunity to use them frequently in combination after you see a patient progress into first-line mCRPC, or is that a challenging combination to give, assuming patients may have had prior exposure to an AR pathway inhibitor?

Ian Davis: It really comes down to what's available in the region. And in Australia, PARP inhibitors are approved and reimbursed, which is the important part of it, only for patients with a BRCA1 or BRCA2 mutation. And I think that actually fits well with the evidence. We're seeing a lot of clinical trials looking at the BRCA-like genes, but most of the activity does seem to be restricted, particularly to BRCA2 and BRCA1. So that's the restriction in Australia. We do use it. We don't yet have access to the combinations. Some of the newer regimens, which have been recently approved by the FDA, I think those will come soon.

Alicia Morgans: Great. So final message to the audience. What would it be when it comes to sequencing and all the knowns and the unknowns that you talked about today?

Ian Davis: I think that the final message is be aware of your own biases and preconceptions. Just because you're unfamiliar or a little bit nervous about using an agent doesn't necessarily mean that you shouldn't. I know nobody gets up in the morning and says, "I really wish I could have chemotherapy today." But sometimes it is a good choice for these patients. These drugs still work. And so I'm a bit of an advocate for using drugs like Docetaxel and Cabazitaxel probably earlier in the treatment sequence than we have been up until now.

Alicia Morgans: Well, that's a wonderful message. And I also remain an advocate for chemotherapy. Having every tool available in our tool chest I think is always going to be important when it comes to the chess game that is metastatic CRPC. So thank you so much for your time, your expertise, and sharing all of it with us today.

Ian Davis: Thank you, Alicia. It's been a pleasure.