Phillip Koo: Hello, my name is Phillip Koo and welcome to UroToday's exclusive coverage of the 13th International Uro-Oncology Congress, here in Sao Paolo, Brazil. We're very fortunate to have with us today, Dr. Bertand Tombal, who's Professor and Chair of Urology at the Université catholique de Louvain, in Belgium. Thank you very much for joining us.

Bertrand Tombal: My pleasure.

Phillip Koo: So first off, congratulations on ARASENS. As co-PI of that landmark study, I think it's amazing work. Can you give the audience an overview of the findings, and maybe, some specific messages you have for the Latin American countries?

Bertrand Tombal: Yeah. So when we planned that trial, keep in mind, it was six, seven years ago. And the debate was, should you give chemotherapy, or should you add a hormonal agent once you've got a guy, especially high volume metastatic cancer. And because of that kind of or, and the fact that if you look on paper, chemo may be better for many country, people have decided that they should not give access to the AR pathway inhibitor at this point in time.

So we wanted, basically, to demonstrate that, unfortunately for this patient, chemotherapy is not enough. And that actually it's not a or question, it's more like and question, and that's how we designed the trial. So that for everybody which believe, for whatever good or bad reason, that the standard of care was ADT plus docetaxel, we say, no, unfortunately it's not enough. You have to combine all the available agent. And I think that is very important, to convince states, insurance, and even patient, to invest in that triplet treatment, because this is really the best.

Very important, when we planned the trial, we have made sure that we had representation for really, a global group of urologists and medical oncologists. So it was not only US, not only Europe, it was everywhere. So we really believe that this result apply everywhere, whether you are in the US, in South America, in Europe, in China, in Japan. So this is, I believe, one of the first example of a very global trial, where we actually have cap very big country to have a broad representation.

So I think that everywhere, that's not a good argument for the patient, especially those with high volume metastatic disease. And we know that in country with a low level of PSA screening, these patient are very frequent. I think that if you've got access to the three drug, the best moment is to give all at the start of the treatment.

Phillip Koo: Wow. Kudos on doing that, and being very thoughtful about that global inclusion. Clearly, we know prostate cancer is a global disease, but there are definitely local nuances and differences in practice patterns that could impact some of the outcomes. So thank you very much for doing that.

So we're going to shift gears a little. You've been obviously, very involved in the nmCRPC space, and you're giving a plenary lecture on that. Can you give us some of the highlights from that lecture that you'll be speaking about?

Bertrand Tombal: Yeah. So basically, this is a topic we know. We've been doing a lot of studies, actually. It has always been as a holy grail, like when you are on hormone therapy, and your PSAs start rising, honestly we know, unfortunately, if you take time enough, that may be a little situation. And we know, that if by standard, or even modern technology, you have no metastasis, it's just a matter of time that metastasis will develop.

So we started working on the topic in 2005, but at that time, we were focusing only on bone metastasis. And we used drug, like denosumab, zoledronic acid, endothelin A inhibitor, and we could never succeed. Although, we learned something very important, is that in these patient, it's still a very heterogeneous disease. And that basically, the simplest test, which is PSA, is the one that helped you make the difference between indolent and aggressive disease.

So that's really, during these 15 years, almost, that we have developed the concept of high-risk non-metastatic CRPC done. When you are on androgen deprivation therapy, and your PSA start rising, just looking at the kinetic can help you identify who need further attention and who doesn't need further attention. And so, once we had that, and the conjunction of three new, extremely effective drug, the rest was easy. Because basically, once we had the good population, we could rapidly show that adding apalutamide, enzalutamide, or thalidomide, would actually, delay the onset of metastasis.

I must say, that as a urologist, I always believe that we would go, we should go, to overall survival. Company was a little bit, cold feet. They say, "We are not going to do that." So I was so happy that we made it, because explaining the concept of delaying metastasis-free survival is complicated.

What people don't see is that, behind that, you've got delaying all the suffering that come with metastasis, pain, deterioration in quality of life, including local symptom. So it's not just about delaying metastasis and overall survival. It's really about, maintaining a, I would say, optimal lifestyle, optimal social engagement, optimal lack of pain, which is all these domain that are measured by quality of life. So that's why it's so important to follow PSA. And once it start rising rapidly, engage with one of these agent, because really, it's a matter of living longer and better. And I know company, they like to speak a lot of about toxicity, side effect, to compare each other. Please, keep in mind, it's around 5% of the patient who will stop the treatment because it give them bothering side effect. So we are speaking about three, very good, extremely well tolerated drugs.

Phillip Koo: So that's a great point. I think this idea of PSA kinetics is what we should be focusing on more. I think, you alluded to this, PSMA PET-CT has kind of changed people's perspective on what is M1, what is M0? How should people navigate that? Especially in Latin America, where they have been using PSMA PET for a while now.

Bertrand Tombal: Yeah, I think that, it's diverting people from the main message. The main message is, once your PSA start rising rapidly, you're going to get a bad outcome, whether you are metastatic or not. Finally, if you think it has regulatory, it may have regulatory consequences, because a drug may be linked to a certain type of imaging. But if you take, for instance, take a drug like enzalutamide, which is approved for the whole spectrum, they don't have that problem. So why would it be a problem for the other drugs?

So, I mean, to me, you can use these new imaging technologies in two way. The bad way is to say, "Oh, I just see one or two metastases. I'm going to try to treat them locally.", and delay the start of these hormonal treatment. I think that's the wrong way. Because that's what we've been doing, blinded, but that's what we've been doing in the trial. And if you delay the treatment, it's no good.

And the good way, is to be informed, and may be, to design additional metastatic targeted therapy treatment, that needs to make their own proof. But I think, that to me, it's all about the whole philosophy of this trial, is really to demonstrate that it's not the fact that you have metastasis or not, that is making you at risk of dying. It's the speed at which your PSA start rising. So whether you have metastasis or not in that setting, the setting of a rapidly rising PSA, has no impact at all on the treatment. You should treat these patient. Now, I use PET PSMA a lot also. It's very rare that actually, I ask for a bone scan, or a CT scan. So it doesn't change the way we look at the treatment. We follow the patient. When the PSA start rising, we're going to start one of these drug, and PET PSMA come, actually, after that, to see what can we do more with that imaging information.

Phillip Koo: I think that's great advice, and it really gets people to think more about tumor biology. So any last thoughts you have for the audience, especially in Latin America, as they move forward, and they are increasing their involvement in trials?

Bertrand Tombal: I think that, first of all, that's an observation I want to make, so I'm the PI of enzalutamide trial, which is EORTC-1333. And really, if we are going to complete that trial, this is because of the engagement of Latin America through LACOG. So I think that, and that's really something investigator, like Matthew Smith and I, we really believe that Latin America has moved to that ability to be also, be part of this big trial, and being organized in research groups, such as LACOG, is giving even more opportunity. Because, like in my country, putting a patient in a clinical trial, the first benefit is giving him access to advanced technology and treatment. So that's a great opportunity.

Phillip Koo: That's wonderful. It's team science at its best. So thank you very much for joining us.

Bertrand Tombal: You're welcome.