Read the Full Video Transcript

Bertrand Tombal: My conflicts of interest have not changed. So as a preamble to that session, we have now established—and it was clear from today—that the current standard of care for treating metastatic HNPC is at least the minimum being a doublet in the vast majority of patients with docetaxel and/or prostate bed radiotherapy, and this being continued until progression.

We must recognize, however, that we have achieved great results in terms of making these patients live longer, but it comes with a price. This comes mostly from real-world evidence series, clearly demonstrating an increase in the risk of cardiovascular events, falls and fractures, cognitive toxic effects, and all of these will be addressed later on. And it has a huge financial toxicity, which in Europe and the US may not be an issue, but all over the world is growing as the number one limitation to prescribe this drug.

In Europe and abroad, there is now a big movement toward seeking treatment optimization. From the start, the EMA (European Medical Agency) has established the Cancer Medicine Forum with the academic group, including EORTC. And we had a very nice meeting on treatment optimization two weeks ago. It's on the website.

In Canada, there is the Optimal Cancer Care Alliance from Ian Tannock. And basically, we share the same goal, meaning maintain theoretically the overall survival that we have achieved, or at least understand that we may have a loss in overall survival, reduce toxicities, improve quality of life, and reduce cost. And as such, everybody starts speaking about de-escalation. And basically, interrupting ADT, ARTA, or both has become a very attractive concept. What I would like to do is to show a few examples, but also highlight some of the caveats in these strategies.

First thing you can do, and seems very popular, is say, OK, why don't we stop just the ADT and keep the patient on the ARPI? I took an example from studies that are broadly available. This would be the LIBERTAS study, where in patients with an undetectable PSA, you basically only stop the ADT, and you keep the patient on the AR pathway inhibitor.

Is it a de-escalation question? I like to call that more a number question. That does not really pertain to the intensity of the drug, but which drug we use. Is there a potential loss in overall survival? Actually, the only good data we have is EMBARK. And although there was no comparison, everybody seems to pinpoint the fact that there was close to a 20% difference in the hazard ratio for the MFS.

When it comes to toxicity, if you look by the numbers, there is no difference. In EMBARK, the rate of grade 3 or more is the same in the monotherapy and the combined. And if you look at the toxicity, basically what you're doing is you trade off toxicities like hot flashes for gynecomastia. And finally, if you look at quality of life, it is not clear, but there is a limitation that I believe that the quality of life questionnaires, I said that yesterday, are not adapted to that kind of question.

So what I try to do for each of the strategies is say, considering the goal—OS, adverse events, quality of life, and cost—what is the likelihood we're going to… what is the OS risk? There is a risk; EMBARK points at that risk. Is there potential gain in adverse events? By the number, certainly not.

Is there a potential advantage in quality of life? We don't know. And is there a cost saving? No. And I'm going to pick a little bit, but I like to see this as the de-escalation seen by the former company where basically you don't save a lot of money.

The second one is to stop the ARTA and keep the patient on the ADT. This is the Dutch approach. This is a very nice study by DUOS in the Netherlands. It's called the APA/Enza-short study, where actually they stop the ARTA after a certain period of time. And they look at PSA progression, time to CRPC, and quality of life.

Is there a risk, a potential risk on OS? Yes, clearly, because that's where ARTA has been so good—it's increasing OS. Is there a potential gain in adverse events? Yes, probably, because the adverse events of the ARTA are significant. For quality of life, is there? We don't know. And for the cost, clearly that saves cost.

And then there is the extreme European approach, which is part of the P6 program. This is revisiting intermittent androgen deprivation therapy exactly like it was done already 15 years ago. This is the DE-ESCALATE study. It is sponsored by the European Union, who actually invests a lot of money into pragmatic and dose de-escalation trials.

Basically, we repeat Dr. [INAUDIBLE]'s trial, and we do intermittent androgen deprivation therapy. The concept has evolved over time. There are the statistical endpoints like, is it feasible? Meaning, what is the proportion of patients without ADT at a certain period of time? Because if everybody comes back on ADT, your arms are similar. But whatever, the study should start during summer.

Is there a potential overall survival loss? That's the never-ending story of the SWOG trial. It's all in how you read the data. And the bottom line is that if you look at Dr. [INAUDIBLE] herself, she said, OK, it's inconclusive. But you cannot say there is no loss. So yes, there is a potential OS loss.

What about quality of life? There have been other studies—this is the Finnish study—that showed that actually during the off period, there was clearly a benefit in quality of life for these patients. So this has yet to be confirmed.

So is there OS risk when you revisit intermittent androgen deprivation therapy? Clearly. Is there a benefit on adverse events and quality of life? Probably, and this is the highest cost-saving you can imagine.

I think that, can we do that? I would say no. I think that because of that potential OS loss and absolutely unavailability of gain in quality of life, we must do trials on this. There are many trials, as I showed you. So we have to test it. However, I would like to point out something which has been evolving in the DE-ESCALATE trial. One of the characteristics of the trial is that it was, from its inception, designed with the patient. So Europa Uomo, the European patient organization, has been part of the development of the trial.

Because I personally believe there is something that is very strange, which is that when we do trials like this, the physicians decide what is an acceptable loss for the patient and what is an acceptable gain in quality of life. And many of us are not patients. So we don't speak for them, we speak for us.

So what we have started in collaboration with the IMI—it's another European product—and a pharmacoeconomic group in the University of Leuven is a discrete choice experiment to better understand what patients expect from this, what they would rate as an acceptable loss in OS, and what gain they do expect in quality of life and side effects. This is fascinating because it's extremely complex. But the idea is basically that we would redesign the endpoint and especially the confidence interval on the non-inferiority study based on patient feedback.

Finally, we still have a problem with quality of life. I highlighted that already. Many people use PR25 and QLQ-C30 from EORTC. It's fascinating because actually, if you had read the seminal paper by Aaronson, you would have read that it's not good when you use hormonal treatment. PR25 was designed to measure incontinence, digestive complications, sexual function, but not hormonal treatment. So what we did is the same.

We don't work with fixed questionnaires anymore. We use item lists. And we took patients who had or had not experienced hormone therapy, and we asked them to select the topics that were missing in C30 and PR25, and they actually came up with that new item list that's going to be tested in that study. So I think that if we do that, it is the patient who has to decide.

Finally, this has been addressed today. I will conclude with this. Is there a role for incorporating modern imaging technology today in deciding who should go to the de-escalation? I think that the answer was clear from yesterday: it is no. We don't have, neither for PSMA nor whole-body MRI, a good prognostic signature. So this should be incorporated in the trial but not used in the clinic.

So I think that de-escalation is promising. It is attractive, but we need to test it before we broadly embrace it. Thank you very much for your attention.