Neeraj Agarwal: Welcome to another episode of UroToday Video. It's such an honor and a pleasure to welcome Professor Eleni Efstathiou to our program today to talk about the phase III AMPLITUDE data, both efficacy data and the quality-of-life data. So Eleni, first of all, thank you for being here today.

Eleni Efstathiou: Dr. Agarwal, or Professor Agarwal, I should say, it is such a great pleasure to share with you this meeting and to help introduce some of the data we recently presented together. You're obviously a co-author in this very important work. Thank you for that, thank you for having me.

We recently had the opportunity to share with our colleagues the patient-reported outcomes from what I think we all agree is a very important trial. The AMPLITUDE trial is the first randomized placebo-controlled phase III trial of a PARP inhibitor, in this case, niraparib, combined with abiraterone acetate plus prednisone in metastatic hormone-sensitive prostate cancer patients with homologous recombination repair mutations. Now, this is what I want to stress: this is the first in hormone-sensitive disease, and the data were originally shared during 2024 ASCO, but more recently were published in Nature Medicine, and you can all take your time to review them. But here, we want to share a few slides showcasing the importance of this trial.

Now, the background. We all agree by now, and we worked hard to get there, that doublets of androgen deprivation therapy plus ARPI, with or without docetaxel, are the standard of care for metastatic hormone-sensitive disease. We also agree, and we have really used a lot of data coming from important retrospective and prospective trials, that patients who harbor HRR mutations in their tumors have a worse prognosis and they really can't catch up. Niraparib, in this case, that is used for this trial, is a potent PARP1/2 inhibitor and is approved for the treatment of men with metastatic CRPC who have BRCA mutations in their tumors.

Now, the AMPLITUDE study took it a notch further and went earlier in the disease and investigated abiraterone acetate plus prednisone plus niraparib versus placebo plus abiraterone acetate plus prednisone in patients with metastatic hormone-sensitive prostate cancer whose tumors harbored HRR mutations, and the primary endpoint is radiographic progression-free survival. Now, we're all familiar with the fact that this primary endpoint was met, and I'm going to go over that in a minute, and we know that the triplet, in this case, androgen deprivation therapy, niraparib, plus abiraterone plus prednisone, significantly reduced the risk of radiographic progression or death by 37% across the board for these patients, and also halved the risk for time to symptomatic progression. Now, what we also know is that the combination of niraparib plus abiraterone plus prednisone, and we already have that information in the CRPC space, will incur some safety concerns, so we have to be cognizant of that. And this is where the patient-reported outcome work ties in very nicely together, because you want to look at the impact that this type of treatment will have on the quality of life of our patients.

So just as a reminder, this is a randomized double-blind placebo-controlled trial in these patients, and the key inclusion criteria were to have metastatic hormone-sensitive prostate cancer, have at least one alteration in key HRR-mutated genes, ECOG status 0 to 2. Key exclusion criteria: no prior treatment with a PARP inhibitor or an ARPI, other than abiraterone. Now, the randomization, one-to-one, about 700 patients. Imagine, we needed about 4,000 patients to be genomically tested in order to be considered for this trial, a very important task that, as the data showed, needs to be undertaken in every clinical practice, as you can change the outcomes for these men if they do harbor such mutations. The primary endpoint is rPFS, as we said, and the key secondary endpoints are time to symptomatic progression and overall survival. We're still waiting on that since the data are immature, as expected. Safety, obviously, and patient-reported outcomes, which we're going to focus a little more on today.

Very well-balanced trial, as expected, nothing unusual there. You see that you have a lot of high-volume disease, about 80%. It comes with the territory; we know well that these types of mutations incur more of a negative prognosis, more high disease volume. And importantly, great representation of BRCA alterations, over 50% of patients. Here's the data. Look on the left for BRCA—really high impact. As I like to say, you're essentially changing the phenotype of the disease, and that is not trivial. I have a patient four years out with no progression on such a combination, for instance, and he has a germline BRCA2 mutation and he's 44 years old. This is a game-changer. And also, you see the positivity across the board for HRR-mutated tumors.

Now, what we need to focus on: obviously, you want to look for that anemia, especially when it's grade 3, you want to be careful and cognizant of the need to check for it, some neutropenia, some thrombocytopenia, and then your usual, what you expect with ADT, your hypertension, your arrhythmia. Very little concern there with cardiac failure. I always say, still, check a priori, do your baseline testing. But nothing that a clinical practice cannot handle, as long as they are aware of it a priori.

Let's talk a little bit about this recent presentation of patient-reported outcomes. We used these questionnaires that can be a little bit taxing for the patients, and we used them every month for the first 24 months of patients being on trial, and then if the patients were on long-term follow-up, we went every four months. Well, believe it or not, these patients really helped and contributed, and more than 95% of patient questionnaires were completed, which is amazing and speaks to the dedication of, yes, the investigators, but more importantly, the patients.

So you can see here, we've got FACT-G, and FACT-G is more of that scoring that comes from the questionnaire that is across the board for cancer patients. You can see in the beginning, the first four months, there's a little bit of a dip there for the niraparib combination. It's expected; you're seeing the first adverse events that are a little bit more profound and different from those of ADT plus ARPI alone. But then, there's a bounce-back, because patients have adjusted, because now we have the right dose for the patient, because patients are getting a benefit from the treatment, for many reasons, but you see no difference, and that is very important.

The same thing with FACT-P, that is more dedicated to prostate cancer. And I'm not going to drill you with all the details here, but that is what is most important: that there is consistency. You lose it a little bit in the beginning, and then you gain a lot. If you recall, we've seen some similar data in the past with upfront use of chemotherapy; we gain a lot on the back end of things. And this is very important, because this is the answer of patients—were they bothered, were they not at all, were they a little bit, by the treatment side effects. And again, a lot of colors here, but you can see that this is comparable across the treatment arms.

So in conclusion, we know that for those men harboring such mutations in their tumors, the triplet combination, in this case, niraparib plus abiraterone plus prednisone on the backbone of ADT, significantly delays radiographic progression or death, and importantly, the baseline quality of life was maintained, following an initial but not significant reduction with the addition of niraparib. And of course, the key takeaway message here is that the addition of niraparib to a doublet maintained baseline health-related quality of life. Thank you very much.

Neeraj Agarwal: What an eloquent presentation, as always. You know I'm a fan of your talks and presentations, Eleni, and this is another fantastic delivery. Such a nice presentation of data for our colleagues across the country and across communities, so thank you for sharing those data with us today.

Eleni Efstathiou: Thank you very much for your kind words. We need to disclose, you always say such wonderful things about me. I appreciate you so much and you're such a leader in our field. Thank you.

Neeraj Agarwal: Of course, a pleasure. So tell me, Eleni, I would like to talk about some clear messages for our colleagues out there in the world, especially those who could not attend the ASCO or the ESMO meetings, or who probably may not have time to go through the full article which was published in Nature Medicine. So first thing, it looks like patients who have these DNA repair gene mutations, or homologous recombination repair mutations, seem to have clear benefit with addition of niraparib, a PARP inhibitor, in metastatic hormone-sensitive prostate cancer when they are already being treated with ADT plus abiraterone.

Eleni Efstathiou: Indeed. We are really hoping that, soon enough, the FDA will allow us to use such agents, in this case, niraparib, for patients, and we're waiting, of course, on that approval. But it is becoming evident, if you look across the development of PARP inhibitors in prostate cancer specifically, that we have come to the point that earlier treatment is warranted for these men who harbor such mutations. We can go on forever between us on the debate of which specific genes, but I think it is undoubted that if a man has a BRCA mutation in his tumor, or even more so, a germline event, then it becomes an urgent matter, because it's not... And I think it's very important for our community practitioners to realize that these men do not have your typical prostate cancer. You don't have that time to sit and think and just give the doublet and think about adding it later. Their disease is rapidly progressive; it is a different beast. It is not your more benign prostate cancer; it is inherently aggressive.

Neeraj Agarwal: Absolutely. I was struck by the number of patients or proportion of patients with de novo metastatic disease and high-volume disease, about 90% and 80% with de novo disease and high-volume disease. And then, you look at the progression-free survival on the abiraterone arm, it's much lower than what you would expect from an all-comer patient population.

Eleni Efstathiou: Yes, and I should comment on that, because I think that is what is more eye-catching. We cannot afford that luxury of saying, "Oh, I'm going to start on a doublet and I'll think about it." No. We can still discuss this and debate it over chemotherapy; we can't when it comes to these mutations, and it is important, and I'm passionate about it, that you introduce systematic genomic testing in the clinic from day one. Even when our guidelines allow it, they've allowed it since 2017, it's covered for the most part, you have to find the right vendor, the right provider to couple with, to partner with, that will allow you to get these results quickly, that will allow you to get these results comfortably, and then treat your patients accordingly.

Neeraj Agarwal: Very good point. I'm so glad you brought this up, to allow all our patients to have access to tumor NGS testing so that we know the status of the HRR alterations. How about germline testing?

Eleni Efstathiou: Well, that is a given. Now, you touched on a very good point. Since the time I joined—I'm going to give you this as an example—since the time I joined my more recent clinic, in the past four years, we've established across-the-board germline genetic testing, and I can tell you that the numbers we're getting in a population enriched for also Hispanic patients, that has not been studied very much, is about 16%, and this is south of the United States, Texas and other regions, 16% of germline events when you spread a wider net. This is not trivial. This is not just limited to HRR, obviously; it includes all potential alterations that are available.

But it's not just that you're trying to accommodate and help in planning the treatment of these men. When you identify germline events, you have a chance in your hands to save the lives of others. Even if it's one person, it doesn't matter. This is not a mean or median or average question; this is one person at a time and their families around them. And for me, I think we both learned the hard way back in the day when we didn't have access to this testing, when young children of these patients would show up with breast cancer—you could have prevented it from being such an advanced stage. So you can, and it's worth the time, it's worth the effort, for sure.

Neeraj Agarwal: Again, very pertinent message, that we need to be doing germline testing and somatic tumor testing, NGS testing, for all our patients. At least they should be given the access, an option. And some patients may refuse that, which is fine, but at least our job is to provide them the opportunity.

Eleni Efstathiou: I have not had one refuse, because if you talk to them, like we do, this is long-term, this is about the lives of them and their children—they're all on board, they're actually becoming very passionate about it.

Neeraj Agarwal: Very good point. So just to summarize, again, congratulations, Eleni, and the team—

Eleni Efstathiou: You too.

Neeraj Agarwal: —for conducting such a massive trial, screening 4,000 patients to get 700 patients with metastatic hormone-sensitive prostate cancer with HRR mutations, and significantly improving outcomes in patients who received niraparib in addition to ADT plus abiraterone, and the quality of life was not compromised while these patients were able to delay their disease progression for significantly longer. What a fantastic result from this massive undertaking, and thank you for sharing those data with us today.

Eleni Efstathiou: Thank you for having me.