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Alicia Morgans: Hi, I'm so excited to be speaking with Professor Silke Gillessen who gave a wonderful talk on the controversies and advances in advanced prostate cancer at GU ASCO 2023. Thank you so much for talking with me today.

Silke Gillessen: Thank you, Alicia. Yes, as you said, there was a lot of news in that, it actually was a educational session and mixed in some new data, so that was a quite interesting format. Gerhardt Attard, in reality, gave the talk before me in all the news in metastatic hormone-sensitive disease. And so I was for the part of metastatic castration resistant disease. It was interesting, because thinking about how I wanted to build up the talk, I realized that our decisions now are so much based on what the patients have received in this metastatic hormone-sensitive stage. So in reality, everything has changed. It's not ADT alone any longer in the hormone-sensitive stage. And then you have, actually, all the data that we have or a lot of the data that we have are really studies where patients were included with only ADT as treatment for metastatic hormone-sensitive disease. And now everything has changed.

So we have these four scenarios, because we still have patients or see patients with metastatic castration-resistant disease that have received only the ADT. I hope these will be less and less, but we still see them. Then, obviously, all the patients that have got ADT plus docetaxel. Also, these patients see less and less. And then the third scenario is the patients who got ADT plus a novel endocrine agent when we see them in metastatic castration-resistant disease. And more recently is the triplet therapy. I don't know how you use it, but now I'm already seeing patients who progress after having had the triplet, so ADT, docetaxel, and a novel endocrine agent.

In that sense, everything has changed and we have to think, probably, a bit in these four scenarios. As you can imagine, there was a lot of discussion because PROpel was discussed, the final overall survival results of PROpel were discussed in the same setting. At least for me, it was very important to see these overall survival results, because there is a lot of discussion. Now, in Gerhardt Attard's talk about metastatic hormone-sensitive disease, he mentioned a lot of times we need biomarkers, we need biomarkers. Now we have a biomarker, let's say BRCA mutation, and now we don't use it any longer. We try to give the PARP inhibitors to everyone.

For the people who are not aware of the PROpel trial, this is a trial in first-line mCRPC testing abiraterone plus placebo versus abiraterone plus olaparib. It was tested in not selected patients, so no biomarker. They were then measured, but it wasn't an inclusion criteria. The rPFS was positive and the OS was positive now in the final results, but for the all-comers and there was a quite large proportion of HRR-mutated patients or BRCA-mutated patients in there that may have driven a lot of the results.

And there it was a long discussion, Johann de Bono, Noel Clarke, and I think it was very interesting to hear what people think, because the benefit is obviously so much bigger in the BRCA-mutated patients. But, interestingly, there is a benefit in rPFS also for the biomarker-negative patients. We don't know exactly who are these patients who have the profit.

Now the big question arises, why should we really give that combination to everyone, also the biomarker negative patients? Because it's not non-toxic, as you know. So the PARP inhibitors have some toxicities, anemia, the patients needed a lot of pure blood transfusions. I'm personally also really a bit worried about MDS, the leukemias that maybe we haven't seen yet, but we have already seen that it exists. So we have seen that as a side effect, but maybe with more time we see more often. And also, these long embolize that are described, I think it's something serious for our patients.

Alicia Morgans: Absolutely, and I think it is such an area of discussion and controversy. What I find fascinating is that there was this rPFS benefit, certainly in the biomarker unselected population, where we would expect no benefit from a PARP inhibitor as a single agent if they're not being selected by these alterations. So it's very interesting. And then to know how to interpret it not just in the context of disease control, but then to know how to interpret it in the context of the complications and the number of pills and the other toxicities is a challenge, I think, especially if we're trying to make a blanket statement over an entire population, because there will be different people with different risk-benefit ideas and what they're willing to take. It's, to me, a very fascinating conversation with a lot of our colleagues coming out on different sides, leading to a lot of very robust conversation.

Silke Gillessen: That's true. We have to say in the ITT population, there were also the biomarker-positive patients, obviously.

Alicia Morgans: Yes, of course.

Silke Gillessen: If you mix enough biomarker-positive patients in that population, you will always have a positive result. But I have to really admit, yes, there is something in the biomarker-negative population. You see that in the fourth plot and in the Kaplan-Meier curves, I think we just don't understand who are really this subgroup of patients, biomarker-negative, that profit. But, if I may say, it's an ideal scenario to discuss at APCCC 2024 in April in Ticino.

Alicia Morgans: Yes.

Silke Gillessen: I hope to see you there and a lot of the other colleagues and we will have a debate about that question for sure.

Alicia Morgans: I am sure we will. I am sure we will. And among many more people than the few who were participating here at the meeting live, because I think that there are a lot of strong opinions and there might even be more data by then. It is 2024, so a lot more to discuss.

Anything else that you wanted to comment on in the mCRPC setting? We have radiopharmaceuticals coming more broadly available. Some things actually have been available, I think, in places like Germany and Australia for years and years, but I think expanding to new areas. Anything else that you wanted to comment on in mCRPC?

Silke Gillessen: No, I think, as you said, it's fantastic because we have all these new substances, including the radioligands, that have efficacy. I think the nice thing is they haven't kind of replaced another treatment, but they really have given us an additional opportunity, and I think that that is the beautiful thing.

Now the big question here in that setting, at least for me, is to understand who are the patients who may profit more from giving the chemotherapy earlier instead of the radioligand that, obviously, if you talk to patients, most patients would prefer to have the radioligand, but maybe there is also here a subgroup of patients who would profit if you would give the chemotherapy first. If that's cabazitaxel or maybe if ever the sequence is going to change, docetaxel and lutetium, also docetaxel. Also, here, I think we have to learn a lot. Who are really the individuals who profit from one or the other?

Alicia Morgans: Absolutely. One final question that I wanted to ask you, and I guess this does circle back onto the biomarkers theme, which all of this does, radioligands even are biomarker-selected. What about genetic testing? Where do you see that going in the future? What is your perspective on that now? Germline, somatic, I know that Gerhardt said we should do it and should be looking for new biomarkers. What are your thoughts? What are you thinking about in your practice, too?

Silke Gillessen: To be honest, the germline testing, I think, is something that is probably not done enough. So we are quite fortunate we can do it in the high-risk localized patients already or in patients with features like cribriform in the pathology and in all metastatic patients. And I think that's really something that's very helpful and probably a bit underused. That just was at the poster where I saw that about 50% of the patients who would, according to NCC guidelines, have to be tested, are really tested. And that was a poster from New Jersey. So I think it's quite interesting we've seen this.

We also saw, interestingly, that in our practice that a lot of men say no. My geneticist tells me that's much more frequent in men than in women. So maybe we have to try to, I don't know, also activate a bit the wives to see if that can be done more often. It's quite interesting. So it's not only us transferring, that's the first step to a geneticist, but then also obviously the patient has to agree to go there, to have the discussions to do the tree to discuss and maybe have then the testing. That's a quite easy blood test. So I think we have to work on the germline testing a lot.

For the somatic testing, yes, I can do it. I guess it's really a question of access. I see a lot of countries around Switzerland that don't have that access so easily in Europe. So in Switzerland, you have that access, but I guess not everywhere. Hopefully this gets a bit cheaper so it can be done for more patients.

Alicia Morgans: Absolutely as you said before, something that we'll need to continue to discuss at APCCC 2024, because it will continue to influence what we do, but we have to get the test in order to really have that influence. What would your message be to clinicians if they're thinking about the complexities of this landscape and how to really sort through everything that's been coming so fast and furious in terms of data and updates?

Silke Gillessen: Yeah, that's a good question. I think one thing we can say, if ever a study is open in that indication, treat the patient in a study, because I guess we have to learn so much. For me, always the best treatment for a patient is being treated in a study. So maybe this is, for me, a very important message. And then the other thing is the dynamics, as you say, are so fast that we have some scenarios where we don't have data, so we have to extrapolate. I guess that is a bit also the art of medicine, to try to extrapolate and do the right thing.

Alicia Morgans: That's right. And at the end of the day, that's what we need to do for our patients, the right thing. And to do the right thing in their eyes. To make sure that what they want to happen is ultimately what we do. Thank you so much for talking this through and really taking such an international and inclusive perspective in trying to help us sort it all through.