Alicia Morgans: Hi, and welcome to APCCC 2022, where I am so thrilled to be talking to Dr. Bertrand Tombal, who is the head of the Department of Surgery at the Cliniques Universitaires Saint-Luc in Brussels, Belgium. Thank you so much for being here with me today.

Bertrand Tombal: My pleasure.

Alicia Morgans:  Wonderful. So, Bertrand, you gave a wonderful presentation on treatment de-intensification in metastatic hormone-sensitive prostate cancer. Can you share with us a little bit about what the overarching theme was so we can dig into it?

Bertrand Tombal: The overarching theme actually dates back before all of this started. So, basically, let's get back in 2010, 2013, where we realized that many metastatic patient, especially those with a profound PSA response, we could actually suspend the treatment for a while. Usually in medical oncology world, this is called drug holidays. What is the benefit of drug holidays? I think primary for the patient to get out of ADT, out of any other drug, improve their quality of life. That has been well documented. We've done many, many trial on this. We know that you can interrupt for sometime quite long period that span over two, three years de-ADT, wait, that the disease is coming back.

So the theme is, can we revisit this intermittent androgen deprivation therapy now that we have all these escalation trial. So, we have managed to demonstrate that the patient should receive [inaudible 00:01:34] in almost every situation. And we have this observation that the proportion of patient will reach a very low PSA, less than 0.2, quite stringent criteria. That's one-third of the patient, so it means that in one-third of the patient, maybe we are over-treating. Maybe we could pose the treatment, give them the opportunity to brace a little bit, to recover some good quality of life, and in some country, we must admit, also save a lot of resource because it would make the treatment more affordable. I don't think that affordability should be the ultimate goal. The ultimate goal is to still maintain everything we have achieved.

So this bring the concept of treatment optimization, which is very high in the agenda everywhere, which is how can we define the minimal dose or duration of a treatment to achieve similar efficacy while preserving quality of life, decreasing side effect and decreasing resource utilization. In the case of AR pathway inhibitor, it will be mostly treatment duration. So I think that this is an important inflection point where now we have all these treatment and we realize there is a group of patient who need more than that probably, because we still fail, and there is a large group that should be tested for the possibility of stopping. So I think that these are very important trial we have to do, and I'm sure that's going to save a lot of side effect to the patient.

Let's say your patient is on ADT and enzalutamide, and you could say, okay, I can stop both of them. I could stop only the enzalutamide, but then I would say that would be mostly an affordability question. Or I could stop the ADT only and keep the patient on ENZA monotherapy. So these are different scenario we must envision. But I still believe that the number one to be studied is we stop everything. You go on drug holiday. I like that term actually much more than de-intensification because de-intensification would mean more, who doesn't need APA, ENZA, DARA. I think that's not a good way to go. The good way is early intensification and then drug holiday, and everybody likes to go on holiday.

Alicia Morgans: Everyone does like to go on holiday. But I really appreciate that you're describing this in terms of a trial that needs to be done, Because sometimes I think there are conversations in clinic or amongst colleagues where individuals will say, "Well, I really believe in treatment de-intensification. I believe in trying to protect the patient. And so when my patient has a really good PSA response within the first few months, I'm not going to use that second AR-targeted agent." What are your thoughts about that?

Bertrand Tombal: I think it's an education bias is that with the people I work, mostly through my career with EORTC, I value equipoise for every other treatment as one of the highest value. We should not offer something which has not been tested. And I must say, I feel nervous many time regarding concept, and that goes from PET PSMA, metastatic-targeted therapy, deescalation, where we just believe that we can adopt because we believe it's good. We have so many history showing that it's not good. So it's a hypothesis, It need to be tested. It need to be tested in a simple way, but it need to be tested because it's very easy to harm patient. We not here to please patient. We are here to help patient that, and sometime, to help them is to spend time imposing things that don't please them.

It's very attracting for patient to say, "Okay, why don't we stop?" That's so easy. And indeed, many people say, "Oh, yeah, you're not going to be able to randomize." I mean, that's our job. We are living in the academic glass house and that's our responsibility. So, to me, the concept is extremely attractive, but it has to be done in a framework where actually we collect the data. Does it absolutely have to be a randomized control trial? I believe so, but we are now discussing much more attractive methodology, such as, TWiCS Trial Cohorts or things like that, where actually we can get quick information, but still we need to do the trial. That's very important.

Alicia Morgans:  I would agree, but that's going to be a large trial with long followup, if it's metastatic hormone sensitive disease, or would you do this in the mCRPC setting? That seems even more challenging.

Bertrand Tombal: No. There are many, many situations you can envision. You can envision that in non-metastatic, CRPC. You can envision that in metastatic. But I think the primary target today are the newly diagnosed metastatic patient, and this for two reason, because first, that group is [inaudible 00:07:13], in patient being diagnosed as metastatic with new imaging modality, meaning you expect a very, very long survival. Okay. That's the first thing. The second one is that these are the patient who actually are... they are the candidate for drug intensification today. So I think that they are the primary target. Now, is it going to be long study? Yes, I guess, but the point will still be valid in five years from now.

Alicia Morgans:  Absolutely.

Bertrand Tombal: As you mentioned, this will be built as non-inferiority trial. So if we believe in our hypothesis, we already going to help 50% of the patient. So I believe that's already an achievement. This trial will help a lot of these patients. So, hopefully, I think it's still manageable.

Alicia Morgans:  Well, this definitely sounds something that would be of interest to patients. As you said, a complete holiday sounds ideal. Even a holiday from the backbone of ADT to see if we could get a similar sort of response with our oral AR-targeted agents might be of interest to some.

Bertrand Tombal: Yeah. And that we missed just one piece of evidence, which is the EMBARK trial. EMBARK is ADT plus ENZA versus ADT versus ENZA alone. I'm a big fan of anti-androgen monotherapy. I use a lot of bicalutamide 150 myself in Europe [inaudible 00:08:45]. So we still need some reassurance, but I think that if tomorrow, the result of the EMBARK trial is that the enzalutamide fall within this non-inferiority boundary, then we going to have to discuss that third arm, which is going to be... I would call that deescalation for the riches, meaning for those who have the privilege to stay on antiandrogen monotherapy because... You were just in a very nice session on patient supportive care. I mean, the line is that actually the most toxic of all is ADT. We spend too much time speaking about the toxicity of all these drug. I mean, ADT is still, on the long term, very toxic. So if we could get rid of ADT and we had that patient giving experience about this cycle of intermittent treatment, that would be already a major goal. And I'm sure people would be feeling more secure that they still have a backbone treatment.

Alicia Morgans:  Yeah. Yeah. And I think through feedback loops and things, there may be actually elevated levels of testosterone, depending on the agent that you're using, which it would need to be studied, as you mentioned. But maybe there's some more muscle mass preservation or energy or something. I mean, obviously we're blocking the receptor, but perhaps there are other ways that it could be effective.

Bertrand Tombal: That we already have good data on this. We did a enzalutamide monotherapy trial. Some did apalutamide monotherapy PTRI. We have very long experience with bicalutamide monotherapy. That's not the same ballpark. I mean, that's absolutely different. This goes from preserve sexual function, to preserve bone mass, to preserve muscular mass. There's always been that kind of worry that estrogen would go to the top, but that's not what we observe. So I think that in term of tolerance at least, this is absolutely acceptable. So I always say that my dream as [inaudible 00:10:51] is that when I retire, we will use no ADT anymore. I still have 12 years to do that, so I'm confident I can do it.

Alicia Morgans:  Well. I think that there are many who would support you in that, including myself and so many patients. So I applaud you. I love your emphasis on clinical trials because I think we all feel like the data will be really important in guiding these recommendations, because our hearts say we want to try to not harm people and to do as little as they ask of us, but as you said, our job is to take care of people, even if it can be uncomfortable sometimes. But having the data to tell us that we can safely do something and maintain quality of life and help them be off therapy, would make everybody happy. So let's hope for that, and you have 12 years.

Bertrand Tombal: Thank you.

Alicia Morgans:  You are on the clock. So thank you for your time, your expertise-

Bertrand Tombal: Thank you.

Alicia Morgans: ... and your efforts.

Bertrand Tombal: Thank you so much.