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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, Dr. Bertrand Tombal, who is a Professor of Urology and the Chair of Surgery at Catholic University in Brussels, Belgium. Thank you so much for being here with me today to talk about GU ASCO 2022.

Bertrand Tombal: My pleasure, first live meeting in a while.

Alicia Morgans: It is. It was the last for me before everything shut down, the first back.

Bertrand Tombal: Yeah.

Alicia Morgans: Today we're going to talk about your view on prostate cancer highlights. What are you thinking about?

Bertrand Tombal: If you allow, I'm going to give a European perspective to it because we have created distance because of the COVID. So let's first talk about an interesting question like, a trial I was [inaudible] which is ARASENS, it's kind of the era of the triplet. So now we should give docetaxel plus darolutamide and abiraterone, but actually, I followed a lot of discussion on this. Many people ask questions, and was also part of the PEACE-1 trial.

And actually, it's interesting because let's say that, when I'm going to go back Monday, what I'm going to keep from that is that we are now back 25 years before. At the time, as a urologist, we were doing an entire meeting on maximal androgen blockade. I know the company likes to create a new word like, drug treatment intensification, but it's back to maximal androgen blockade, just that we did not have the good drugs, with a few exceptions.

An interesting one like in Japan, they still use maximal androgen blockade with bicalutamide 80, which is kind of 150 for Caucasians. And they had shown overall survival benefit, and interestingly, if you look at the hazard ratio in low volume disease, it was low 0.65. So kind of similar to what we see now.

So now we are back to maximal androgen blockade, meaning that any patient that you would start on ADT that has metastatic disease and probably as we will know soon, also high risk localized disease, the reference treatment should not be ADT alone, but ADT plus one of the four agents.

That's already a big hurdle because looking at a poster, I see a few of our real-world data acquisitions from the US, and my gosh, I was shocked. Because today, I know companies speak a lot about darolutamide is better, and enzalutamide is better, but the problem is that I don't know. But people do not listen to us. The vast majority still give ADT alone. And I worry that is going to be the same in Europe.

So it means that we, as an academic community, should now educate on simple matters that maximal androgen blockade was there 20 years ago. It was very easy, now we're back to that. So we absolutely need it.

And my enthusiasm about the ARASENS data was kind of diminished by this real-world evidence. So I don't know, do people not believe in guidelines? They do not believe in the paper. I don't know, but we have hard work.

Then on top of that, there is a second more important question, is that if you look at the EAU guidelines, I'm European, so they say, "ADT plus docetaxel is the standard of care." I think that I'm going to write to the guidelines and say, "Can we still say that today?"

I think that to me, the first message of ARASENS and PEACE-1 is that ADT plus docetaxel alone is not an option if you've got access to one of the three other drugs. And I think that's very important because there are still many countries that actually do not have a reimbursement of the AR pathway inhibitors, because it's more expensive and because they consider docetaxel as equivalent and cheaper. But as for today, that's done.

So to me, that's the first important message, that ADT plus docetaxel alone is not enough. So then comes the question about, when do we give the triplet? So I think that once we have sorted out that everybody receives maximal androgen blockade, then we are going to need probably even more data to really convince people that docetaxel has probably a much broader role than what we see in real-world evidence. Because if you look at certain countries in Europe like mine, ADT plus docetaxel was very popular. I must say that we would treat high volume and many low volumes with aggressive features. So that was very, very common. Then suddenly, I wouldn't say it disappeared, but it has been mostly replaced by Abi, by Abi [inaudible] and enza.

So now we are going to have to go back and say, maybe that was a mistake. Maybe we should keep our ADT plus docetaxel and compliment. So I think that these two trials are very important, PEACE-1 and ARASENS. But something I like to call the know-do-gap, meaning the gap between what we know after a meeting, and what we do in real life, is now getting very difficult to fill. And we are going to need a lot of effort from the academic world to try to do something.

So that is for the first observation. The second one is for PARP inhibitors. So for the two trials that were shown yesterday, PROpel and MAGNITUDE, I think that first of all, it makes sense. Second, it's a natural [inaudible], but with a huge caveat. Is that because of the discussion we had before and the nonmetastatic CRPC? 85 to 95% of the patients will progress on androgen deprivation therapy in my country and many European countries today.  I've already received an AR pathway inhibitor.

And in that setting, if you make the exception of docetaxel, and we are going to discuss that because that is another one we should question. If you are progressing like on enzalutamide, we have been doing a lot of work to give abi to these patients, and it is not a good idea. You should rather give docetaxel, cabazitaxel, PSMA Lutetium, olaparib. So what do we do with abi plus Olaparib? Do we mean should we be going, are we going to kind of go back to a back-to-back [inaudible]? Are we going to give Olaparib alone?

So that is a very interesting question. So what do we do with this combination? Considering that the proportion of patients who may be actually progressing is very limited. I'm the PI of the enzalutamide radium trial, which is called PEACE-3 [inaudible] trial. And we had extreme difficulty recruiting patients because the initial design was first-line metastatic CRPC, enza plus/minus radium. And with time, we saw these patients totally change.

First, it was docetaxel, which was very easy to adapt. But in a country like France, we did the PEACE-1 trial, many of these patients are actually receiving abiaterone and more and more enzalutamide. So once again, these are beautiful trials, very relevant trials, but we should realize that they are not within context everywhere on the planet.

So I do not know what it's going to be in the US, but I know that in Europe, we are going to have to resing what do we do with these data now.

About the question of, should we test DNA repair mutation or not? I mean, that's a very interesting discussion. I mean that for the physician, it makes sense, that if you look at the PROpel results, you can go like this. There is non-DDR activity of PARP inhibitors as well. So it may eventually explain the fact that there is some activity in DDR negative.

My worry, at least in Europe, is that payers and regulators are going to sing otherwise. They are going to look at the other trials and say, "No, no, no. You need to be DDR mutated." And so that's going to send us back to the conundrum of the first line. What do you do when you progress on Enza? So very, very interesting.

And then in that kind of third line segment, which is the one we have the most development, assuming now we've done a lot of work from the metastatic HNPC, and for the non-metastatic CRPC. This has become very easy to treat. I still do not realize why people have so much difficulty starting Apa, Enza, or Daro in one of these patients. These drugs are very easy to handle.

So once you assume that is done, you will end up with all these patients that will progress on this drug. And then if you look at the guidelines, if you look everywhere, we are both participating in APCCC's meeting, and everybody says, "Oh, next line is docetaxel."

And a few months ago, I was asked by my local authority to look at that. Because docetaxel was never tested in that setting. And yesterday we had a very important trial, but not necessarily for the message they want to carry on, but for actually the activity of docetaxel in patients that are progressing on enzalutamide. My God, that is very little. I'm not sure it would never be positive in a phase three randomized trial.

So we have to sit down and we have to really, I think, have the discussion, what is the remaining role of second-line docetaxel? I'm not speaking about the triplet. I'm speaking about docetaxel in a patient who has already received AR targeted therapy. The fact that you keep enzalutamide, improves the results. It's normal because there is too much [inaudible].  But the overall response rate to docetaxel, the overall duration of response, knowing that back to that, we are going to get PARP inhibitors, all forms of precision medicine like PSMA Lutetium.

I consider knowing that countries will still impose to give docetaxel. I think that may be kind of a problem. And we have to think about what is the role we believe is remaining to docetaxel.

So that PRESIDE study, which actually everybody looks at continuing enzalutamide, that's a very nice study. But I have a totally different view on this. And I tweet and I was asking myself, why do I still give docetaxel?

So we are going to get trials with all forms of PSMA. So maybe that is to be a very important message.

So one of the problems, and Matthew Smith alluded to very well, when we planned ARASENS, it was not yesterday, it was like five years ago, and the context has changed. So now, there are questions about docetaxel, there are questions about docetaxel in the first-line setting where I think there is a benefit. But we need to be prudent that with all these beautiful results with AR pathway inhibitors because they are easy and safe, we actually pray for the triplet, but it's not going to come. Especially in a world when the number one treatment is still ADT alone. So we have a lot of work to do in the next months to come back and say, "These are patients that benefit from a triplet therapy."

And as a disregard, I really anticipate seeing what people will say at the APCCC meeting. Because I remember Karim's presentation at ASCO. There was in Europe, a lot of people promoting the triplet. In the US, a lot of people say, "Why? Why is there this triplet?" So that's going to be an interesting discussion.

And then a very important discussion we have to have, about what is remaining of docetaxel in the metastatic CRPC setting, now that we have all these trials. As for the PARPinhibitor, I believe that the question is not, should you add abiraterone to olaparib? Should you add olaparib to abiraterone in a patient who is progressing on enzalutamide? But should you do it the other way around? Today it would start with olaparib and we usually start to screen patients when they are on the AR pathway inhibitor.

And I think that it has become, everywhere it is available, the gold standard to go with the PARP inhibitor. The question is, are we going to have to switch also the AR pathway inhibitor? So these are very interesting questions.

My worry though is that we are never going to get the answers, which is a good thing because we can have more discussions like this. But in the end, I think there is a lot of work to do in terms of educating physicians everywhere. Because there is, I believe, and that is probably my most worrying observation from the meeting, is to go to this real-world evidence. We've been doing a lot of work with EORTC, looking at the added value of real-world evidence.

And I must say that if I was today, working in a big guidelines organization, like EAU or NCCN, I would look at this real-world evidence with a lot of attention. And then I will ask myself, do people really follow my guidelines? And I think that is the number one challenge we have in the next two, three years.

Alicia Morgans:  So I love that your approach to the huge amount of data that we have gotten from GU ASCO 2022, is to really give us as a community some key points to focus on and some key points to investigate. And for all of us to remember that sometimes the simplest message is the most powerful because that message needs to be heard. Not just among academics, not just among those who want to read some extra literature, it has to be heard by the clinicians and the patients, and all of us who treat these individuals.

So I love your take on all of this and want to really emphasize for all listening that maximal androgen blockade is a very clear and key message that is coming out of GU ASCO. And if nothing else, we need to take that home, that the backbone of therapy, it is no longer ADT alone.

Bertrand Tombal: No.

Alicia Morgans: It is maximal androgen blockade, and we as a community need to think about who might also benefit from docetaxel, who might also benefit from olaparib, from all of these treatments, telazoparib? These are the treatments that are going to help our patients, niraparib, these PARP inhibitor approaches, these combinations. Who needs more, but the backbone at least needs to change.

So lots for us to think about, lots of data. And I really look forward to talking with you over time.

Bertrand Tombal: Thank you.

Alicia Morgans: And hearing about how you and the team and the group at EORTC, as well as the investigational teams you work with, try to answer some of the questions you laid down. Because you have set forth quite a roadmap for us as we think about the future. Thank you so much.

Bertrand Tombal: Thank you so much.