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Oliver Sartor: Hi, I'm Dr. Oliver Sartor with UroToday. And really have a very special guest, Ana Aparicio, a professor at the M.D. Anderson Cancer Center in the GU Medical Oncology Group. Been there a long time. Welcome, Ana.

Ana Aparicio: Thank you for having me.

Oliver Sartor: Yeah. So you presented a very provocative series of data with an overall survival benefit in a pretty small trial at ASCO 2025. And it was a little bit interesting, a little bit surprising. And I'd love for you to take us through who were these patients, what was the treatment, what were the results, and help our listeners appreciate what you've done here.

Ana Aparicio: I would be delighted. I'm going to share some slides just to illustrate some of these points if that works. So I'm going to talk about this trial. This is what I presented at ASCO. And basically, this builds on this notion that prostate cancer is heterogeneous. And we all see it in the clinic. I mean, we all agree. There are these people that do so, so well with hormone therapy and then those that just progress very rapidly through it.

And so we had done a previous clinical trial a while back that we had called the DynAMo clinical trial where we treated patients with early castrate-resistant disease. So at the time, abi (abiraterone) and apa (apalutamide), and all of these had not been approved in the firstline setting. So these were people that were just coming off of ADT. And so we treated them with eight weeks of abiraterone and apalutamide. And after eight weeks, based on their percent PSA decline and circulating tumor cell count, we allocated them to a satisfactory group and an unsatisfactory group.

But depending on what group they went into, they got different treatments. But the treatments didn't make that much of a difference. I just want to focus on the fact that, if you can see in the waterfall plot on the bottom, about 2/3 of the people ended up allocated to this satisfactory group, satisfactory decline, meaning they were hormone responsive, and about a 1/3 were allocated to this unsatisfactory group. So it was a very-- so there was this dichotomy. And that's kind of a split that we're seeing in other earlier disease settings as well. So it's maintained throughout.

And what was quite, I thought, dramatic was the fact that just the fact of separating the groups showed a difference in overall survival, meaning that those that had this good response or satisfactory decline in their tumor markers had a median overall survival that was more than double that of those that didn't. And so we were interested in figuring out who these people were and how we could develop therapies for them because obviously, they weren't doing very well.

Oliver Sartor: Great idea. And nice stratification. Leave the good ones and let them run and take the bad ones and say, oh my goodness, let's do something else.

Ana Aparicio: Right. And so what we had done to try to address these here is we, again, tried to identify them with clinical-pathological criteria because we didn't really have any robust biomarkers at the time to look for them and be able to select them for clinical trials that were dedicated to them. And that's where this whole aggressive variant criteria came from.

We just use clinical-pathological criteria that are typically associated with the small cell or poorly differentiated neuroendocrine carcinomas because we know from long-term experience that those patients with small cell prostate cancers tend to do very poorly and not respond to hormone therapies and if anything, benefit from platinum-based chemotherapy. And so this was just an attempt at grouping, selecting for bad diseases, if you will.

And so we've done a long series of clinical trials, and C3NIRA is the last of them, where we've been trying to build first showing that indeed, if you had one of these criteria, you seem to benefit from the addition of platinum-based chemotherapy. But the progression-free survival were still very short, even with progression with platinum-based chemotherapy. So that's where we started to add to the backbone of those platinum-based chemotherapy to the cabazitaxel and the carboplatin.

And again, in a trial that I'm not going to go over right now, we had shown that maybe there was some benefit from adding PARP inhibitor maintenance. So here in C3NIRA, what we asked was what if we add an anti-PD-1. And basically, this was based on the immunomodulatory effects of the chemotherapy, on experience in other tumor types that are pretty similar to aggressive variants, like small cell lung cancer or triple negative breast cancer. And we wanted to ask would the addition of chemotherapy improve the outcome of people treated with this backbone of chemotherapy and a PARP inhibitor maintenance.

And so we also got tumor biopsies along the way. And what we found was that the addition of anti-PD-1 did not overcome the chemotherapy resistance in men with aggressive variant. And we know that because in a previous trial without the anti-PD-1, we had the same exact percentage of patients progressing during the chemotherapy. It was 36%.

So with or without the anti-PD-1, 36% of people will progress prior to reaching-- or completing six cycles of cabazitaxel chemotherapy. However, for those that were randomized, we did see a significant improvement in median progression-free survival and overall survival. Go ahead.

Oliver Sartor: Let me get a little clarification, if you don't mind. So in order to be randomized, you actually had to complete the cycles and still be responding? So you've not yet developed resistance?

Ana Aparicio: Correct.

Oliver Sartor: Got it. So the patients-- and I'm sorry, how many cycles of the cabazitaxel-carbo?

Ana Aparicio: Six cycles. Up to six cycles.

Oliver Sartor: --cycles without progression. Then randomized to the PARP inhibitor, niraparib, or the niraparib plus the PD-1?

Ana Aparicio: Yeah.

Oliver Sartor: Got it.

Ana Aparicio: And so unfortunately, as you can see, half of the patients did not make it to randomization, 36% due to progression and then 15% or almost 14% due to toxicity or other, but mostly toxicity. So one thing that is not included in these slides but that we have talked about, is this regimen, unfortunately, did not really come without toxicity. So not only was there the chemotherapy toxicity and what you might expect with cabazitaxel-carboplatin, but also the addition of the IO toxicity was significant. So it's certainly a regimen that has to be used very carefully.

Oliver Sartor: Yeah. And These results are quite striking. Obviously, the RPFS, nice. Very good hazard ratio, 0.5. But it's really the OS that got my attention. And when you go from 24.3 median to 10.2. Now, admittedly, these are gigantic confidence intervals. This is a small group of patients. Only 30 in each arm. But nevertheless, when you have a hazard ratio of 0.51 and a more than doubling of the OS, I think it's very provocative. And so I'm a little bit curious where do we go from here?

And I'm going to drill down a little bit because I think our readers will be interested as well. So the niraparib in this particular setting without identifying HRR defect would be a little bit controversial. That's not the typical use of a PARP inhibitor in an unselected population. So that's point number 1.

And then this interaction that you see between the inhibitor and the PD-1, that's just, like I said, really striking. Is there precedent? So maybe one question at a time. Let's talk about the PARP. And then let's talk about the combo and understand how you got to here and where you might be going.

Ana Aparicio: We got to the PARP inhibitor maintenance with the previous clinical trial called the C-COLA. And on that trial, we treated the same population, same eligibility criteria with, again, six cycles of cabazitaxel-carboplatin. And then we randomized them in a 2 to 1 fashion to observation versus olaparib maintenance. In that trial, again, we were underpowered because we registered 96 patients and we expected to randomize 72 patients. But instead, we were only able to randomize 54. And yet, numerically--

So we did not meet the primary endpoint of improvement in progression-free survival with olaparib maintenance. But there was a trend. So the median progression-free survival with olaparib was in the order from the time of randomization, remember the chemo takes four and a half months, was 4.9 months versus 2.3 with the observation.

And more than anything, what we found was that there was a tail of a subset of patients who seem to have a prolonged response to the PARP inhibitor-- to the chemo induction PARP inhibitor maintenance. And when we looked at their molecular features, even though it was not complete, because we didn't have all of the molecular profiling for all 96 patients.

But what was fairly clear was that the long-term responders were not more enriched for genomic alterations in DNA damage repair than the early progressors. So genomic alterations in these DNA damage repair genes did not explain these early progressors and prolonged responders.

Oliver Sartor: Yeah. And so when you're looking at this, the niraparib was added after the six cycles among the responding patients. So you've got a selection. So that laid your backbone and you switched from olaparib to niraparib and created a new backbone and then put in the PD-1. But what about that prior trial, admittedly underpowered. Did you have any OS trends that were interesting or just on the RPFS?

Ana Aparicio: No, that one didn't have any OS trends that were interesting. So I think one of the questions that this raises, obviously, is how would an anti-PD-1 alone maintenance arm behave?

Oliver Sartor: If we go to-- and I'm no bladder maven, you know that. I don't really do bladder. But I do remember the avelumab trial, which used a similar approach in which the patients who responded to a platinum-based regimen, and that was cisplatin, if I recall correctly, or predominantly cisplatin, that adding in the avelumab had a dramatic effect. The curves were so far split apart, you could drive a big truck through them.

And I remember that because I was so struck. And I wonder if there's something about being able to eliminate some of those more rapid progressors than creating alterations in the microenvironment that are selective for these patients who are responders as opposed to the early progressors? That would be my hypothesis. And I know that you've got some biopsies. I don't know if you have enough time to mention that or is there anything provocative or too early?

Ana Aparicio: So it's a little early. And people ask, why did you add the anti-PD-1 after one cycle of chemo? And the answer to that question is because what we wanted to see, what we wanted to ask was what did the anti-PD-1 add to the chemotherapy effect.

So we have biopsies after one cycle of chemo alone. And then after two cycles with the addition of anti-PD-1. And then we have biopsies after three cycles of niraparib plus or minus cetrelimab. And so then the questions there are going to be-- we have some baseline biopsies also. But the questions there are going to be, OK, what is the differential effect after that one cycle of chemotherapy between those that ultimately progress and those that don't? And does anti-PD-1 change that?

And with very preliminary results, we do see that there appears to be an increase in the T cell effector cells in the responders and a decrease in the T regs. And the opposite appears to be true in the progressors, which goes along with this. So we're digging. Single-cell RNA sequencing takes a lot of time to analyze. So hopefully, we'll have that by the end of the summer and we'll have more hints there. So you asked where do we go from here.

Oliver Sartor: That's an important question. And I think your clinicians will say, gosh, I don't have the ability to give niraparib, nor the PD-1 inhibitor in this context. So how do you make a practice-changing study that will allow others to participate should it be positive?

Ana Aparicio: So there are various choices. I think that one possibility is to design a study similar to, and I'm just going to go back to this one, to this trial but with a cycle of chemotherapy and get an early sense of the response perhaps with circulating tumor DNA content and then allocate patients that can move forward with that particular cabazi-carbo-anti-PD-1. And then at the end of that, actually randomize to anti-PD-1 plus or minus a PARP inhibitor to understand what the effect of the PARP inhibitor might be. And then I think the other set, we need some novel agents because cabazi-carbo is clearly not doing it. They do very, very poorly.

Oliver Sartor: Yeah. But they do better than if they have the alternative. And just to let you know, having been involved in some of the platinum data myself and yours absolutely demonstrating that the addition of platinum can make a difference for these patients, these poor responders are ideal to receive some form of platin. And carboplatin is certainly very reasonable.

And then the question is, what can we do more? And so I think you're helping to shift the paradigm about how we think. There clearly is a need for more study because unfortunately, all the patients continue to die. But to me, that overall survival really caught my attention. And I was saying, gosh, I wonder what Ana has to say about that?

Ana Aparicio: I have to confess, this was funded by DOD. So I followed these very, very carefully. And so I obviously didn't look at progression-free survival or overall survival. But when the data came in from the statistician, I was so shocked that my first impression was, is this real?

Oliver Sartor: Oh, of course.

Ana Aparicio: And then I looked back at my notes and as I had been capturing every three months with the progress reports and everything. And I was like, no, it is. I've been following this so closely. So that's one advantage, I guess, of the frequent progress reports from the DOD. 

Oliver Sartor: Yeah, no, that's good. I do remember and I think it was James Gulley that had presented some initial data combining PARP and a PD-1 inhibitor based on a STING pathway hypothesis, if I remember it correctly. And unfortunately, it didn't seem to do very much. But that is a different population than what you've done.

And I'm almost a little curious about whether or not this sort of avelumab concept in which you treat the patients and eliminate the poor responders and then create a second subset, that that may be the ones that benefit? So anyway, I think it's very provocative.

You've got a lot more work to do. But the good news is that some of the patients are living longer. And that's, of course, what we achieve to do. So congratulations. I appreciate the hard work that you've put in over many years. The field appreciates the hard work you've put in over many years. And we're going to look forward to learning more.

Ana Aparicio: Thank you.

Oliver Sartor: All right. Thanks for being with us on UroToday. And thanks for going over the data you presented at ASCO 2025.

Ana Aparicio: My pleasure.