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Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today for an ESMO discussion with Dr. Joaquín Mateo, who is a medical oncologist at Vall d'Hebron Institute of Oncology in Barcelona, Spain. Joaquín, thanks so much for joining us today.

Joaquín Mateo: Oh, please, thank you for having me.

Zach Klaassen: So we're going to discuss your exciting ESMO data you presented looking at ZZ-FIRST, which is really looking at a combination of enzalutamide plus talazoparib in metastatic hormone-naive prostate cancer. So why don't you give us a little background about how this trial came to be? Maybe some of the history of this combination in advanced prostate cancer.

Joaquín Mateo: Sure. Well, I'm sure this audience is aware of that, but in the last few years we have seen data from several clinical trials combining different AR-targeting drugs, abiraterone and enzalutamide, with different PARP inhibitors in the castration-resistant state.

So we had trial PROpel with abiraterone and olaparib combination. We saw data from TALAPRO-2 with enzalutamide and talazoparib. And there was also the MAGNITUDE trial with niraparib and abiraterone. All of them explore the concept of combining an AR-targeting agent with a PARP inhibitor in CRPC, right?

So both PROpel and TALAPRO-2 concluded that there was an improvement in rPFS in the overall trial population by combining these two drugs, right? And while clearly the magnitude of benefit was much greater in the BRCA-mutated prostate cancer population, there was also an improvement in rPFS in the non-mutated population. Or at least in those patients without an obvious mutation in the NGS assays that we currently use in clinical practice, right?

However, I think that the preclinical data, the laboratory data that tries to explain the biological synergy of these agents is at least complicated. I mean, there are some papers that suggest that there is an intersect between the AR pathway and the DNA repair pathways, but it's not really clear how these two drugs combined would be benefiting patients without those mutations. Whether it is just complementary because both drugs have some effect, or there is a true biological interaction. So that's one thing that motivated us to pursue further studies.

But on the other side, with the move of AR-targeting agents to the hormone-naive space, it was only logical to also test this combination. And I acknowledge that there are randomized Phase III trials ongoing for these combinations in the hormone-naive space right now, but we used this opportunity to run a smaller IIT with this combination. On the one side, to generate preliminary data of the activity of the combination in the hormone-naive space, but critically, to collect biospecimens, both tumor tissue and plasma, before, during, and after treatment. That can help us hopefully start these questions of, how are these drugs working together to increase the antitumor effect of either of them alone?

Zach Klaassen: Excellent. That's a great background. I thank you for that context. So maybe if you can share your slides and walk us through the trial design, and some of those exciting results presented at ESMO.

Joaquín Mateo: Yeah, that'd be great. So at ESMO we presented the preliminary, the first result, actually. This is the first time that we are reporting data, that includes the primary endpoint analysis and some preliminary analysis of rPFS as the key secondary endpoint. We did not present any of the translational work, because this is still ongoing, and we hope to present an updated report at some point next year.

So ZZ-FIRST is a randomized Phase II trial combining ADT plus enzalutamide versus ADT, enzalutamide, and talazoparib in patients with high-volume metastatic hormone-naive prostate cancer.

The inclusion criteria were pretty simple. So we were looking for patients with high-volume metastatic hormone-naive prostate cancer according to the CHAARTED population. There is no clear biological rationale to focus on high volume, but we wanted to focus on those patients who have worse prognosis, because they would be the ones where clearly further treatments are needed.

Patients should have had a PSA over four at diagnosis, and this is just because PSA complete response was the primary endpoint. And we were not selecting patients based on any molecular background, but we were pursuing retrospectively genomics to then be able to stratify the populations.

I said the primary endpoint was achieving a PSA complete response, defined as a PSA below 0.2, that is maintained after 12 months of therapy. So at cycle 13—it is actually not 12 months, it's week 48. So similar to the Lutetium PSMA trial in hormone-naive that was also presented at ESMO. And this is because there is some data that suggests that this time point, having a PSA complete response after 12 cycles, correlates with longer benefit. And of course, for a Phase II IIT, we wanted a clinical endpoint that we could address in a relatively short time. And then as a secondary endpoint, we used PFS—PSA PFS and radiographic PFS as the key secondary endpoints.

So all patients started ADT and enzalutamide as a standard of care. And then after two months of enzalutamide, they got a second biopsy, and were randomized to addition of the talazoparib, or continue with ADT and enza. And this randomization was stratified based on the presence of HRR mutations.

Patients received the treatment until progression, or before in case of toxicities. And then at progression, they were offered to have another biopsy before starting treatment for CRPC. And there was also a liquid biopsy component to the study. So we have collected longitudinally plasma samples at the beginning of the treatment, and then also at progression.

So this is the overall study population. We recruited 54 patients. Patients were randomized two to one favoring the interventional arm. So there were 37 patients receiving enza plus talazo, and 17 receiving only enzalutamide. This is our typical hormone-naive prostate cancer, high-volume population. You can see the rates of visceral disease were relatively low compared to studies that focus on patients with BRCA mutations, like the TALAPRO-2 study. And it was around 14% of patients who had mutations in HRR genes, primarily in BRCA2.

This is an overview of the genomics of the patients at baseline. So basically, you can see that there were four patients with BRCA2 mutations, two patients with BRCA1 mutations, one of them being concomitant with BRCA2. And then there was also a patient with a funky complete loss that was also considered HRR positive. But again, this was only used for stratifying the randomization.

So the primary endpoint was the maintenance of the PSA complete response in the enza/talazo arm. So it was not designed as a comparator, but just as an indirect comparison between the two arms. And the primary endpoint was fulfilled, because a significant proportion of patients in the combination arm achieved a complete response that lasted for at least 48 weeks. You can see here the rate was 73%.

Also, we acknowledge that in the enza-alone population, actually the proportion was also quite high, a bit higher than expected. And this was based on historical data from CHAARTED with docetaxel.

Probably the most interesting findings are the preliminary analysis of radiographic PFS, and of PSA-based progression-free survival. We are still early, with around 40% maturity for both analyses, but we start to see already how the curves are separating in both occasions. So we need to wait a few more months to get more events, but it is looking good, in terms of there may be some effect of the combination in this population.

It is also interesting to analyze the safety and tolerability data on this study. We have now a lot of data from TALAPRO-2, and from PROpel and from MAGNITUDE, in the CRPC space. One would expect that by moving this drug to earlier disease settings, you may be seeing a bit less of hematological toxicity, because these patients have not seen chemo. And the bone marrow probably would be less stressed by prior treatments. Although we are still seeing a third of grade three anemia, which is what has been seen in TALAPRO-2. So a significant amount of hematological toxicity with the talazoparib, but it is manageable with dose interruption and dose reductions—most patients can go on. We didn't have really many patients discontinuing because of hematological toxicity. Then non-hematological toxicity is what you would expect. But what was very interesting, I'm not going to say surprising, but at least it's something that should really catch our attention, is that in the talazo arm, patients were exposed for many years to PARP inhibitors. Differently to the CRPC population, where unfortunately we know these patients have a short survival expectation, right?

In hormone-naive prostate cancer, these patients are on treatment for three, four years, and we have seen two cases of patients developing acute leukemias. Again, we cannot say it is surprising, because there are reports in the breast cancer and ovarian cancer fields of a risk of 1% of leukemia with prolonged exposure to PARP inhibitors. But definitely, this is something we were not seeing in prostate cancer in the CRPC studies, and we need to look for these events in the hormone-naive setting. And see, this is a very small study, so I don't want to overcall this, but it's definitely a flag that we need to look for these events in the hormone-naive studies that are ongoing, to assess to what point this may be a limiting factor for delivering these drugs in metastatic hormone-naive prostate cancer.

So we are now working on one, getting more mature clinical data to be able to report the radiographic PFS and the PSA PFS later in 2025. Continue to follow these patients for other long-term toxicities. So after these two cases, we have implemented very stringent measures in terms of interrupting the treatment if there is hematological toxicity. Seeking consultations with hematologists and pursuing bone marrow biopsies if you face any patient with hematological toxicities.

And then also in the lab, we have started working with the biopsies collected. So we are doing transcriptomic analysis at baseline and after two months of enza, if we see signs of tumor adaptation that may explain why this combination would be beneficial for patients. And we have also collected these plasma samples that we now want to use for cell-free DNA analysis, with a challenge that in hormone-naive prostate cancer, normally cell-free DNA goes away very rapidly, right? So we are working in very sensitive assays that can help us use these samples for understanding the disease biology there.

This is pretty much what we presented at ESMO. There is lots of work to do. But we think that this could be a first data set in the hormone-naive study that will pave the way for all the studies that are coming, and that will help us understand if there is a role for these drugs in metastatic hormone-naive prostate cancer.

Zach Klaassen: Wonderful. That was a great presentation, and an honest presentation about some of these potential long-term toxicities. So I think your last slide was great, and I think you highlighted it in the beginning, that one of the reasons to do this trial was to get tissue, start doing genomics. You talked about ctDNA. In terms of particularly the molecular landscape, when we see patients go from hormone-naive to mCRPC, what do you anticipate to learn from some of these ancillary studies?

Joaquín Mateo: Well, there are two main objectives. One is to study what happens very early upon exposure to the enzalutamide. Because we think that may be the key to understand why the combination is successful. And then the other, as you mentioned, is the progression to CRPC.

Zach Klaassen: Right.

Joaquín Mateo: With implementation of ARPIs in the hormone-naive space, what we used to call CRPC 10 years ago is a different biological entity to what we use, what we call CRPC today. Because these CRPC patients have already been exposed to ARPIs and have become resistant to abiraterone/enzalutamide, apalutamide/darolutamide, right?

So we also want to understand if the molecular landscape of the 2024 CRPC population is the same or is different to the CRPC population we were treating until now, right? Because most of our trials, most of the studies are based on the map of the disease that we generated 10 years ago. So we want to understand what is the map of the disease today to help us plan for the successive treatments. And clearly, there are some things that we don't know. Like for example, if you have received an ARPI in the hormone-naive space, is there a point of re-challenging with another ARPI in the CRPC space?

Zach Klaassen: Right.

Joaquín Mateo: Data says that—I mean, we don't have data in that space, but data on sequencing ARPIs in CRPC says it is unlikely, right? But we need to generate the clinical data at the same time of generating data that help us better understand the biology behind this progression to CRPC.

Zach Klaassen: And I would say too, even with EMBARK now, we're going to see it moving up even further. What's happening to the tumor even in the high-risk biochemical recurrence setting, right? I mean, this could really change how we think about what does CRPC look like in 2016, 2024, 2028, 2030, et cetera. So very nice work.

The last question, you mentioned it earlier too. There's obviously big Phase III studies going on, but congratulations on getting a nicely recruit, getting some biological information from ZZ-FIRST. How would this trial potentially inform design for future Phase III trials? Maybe in this space, maybe tweaking some of the Phase III trials that are currently occurring?

Joaquín Mateo: Well, I think that something we are exploring in this trial that has not been explored in most of the prior studies or the ones that are ongoing is the fact that we are starting the enzalutamide two months ahead—

Zach Klaassen: Right.

Joaquín Mateo: ... of the talazoparib. Our main objective is to be able to study the biology upon exposure to enzalutamide, but it is true in terms of the clinical data, both safety and efficacy. It would be interesting to understand whether that makes any difference compared to using them together, right? In the CRPC space, both TALAPRO-2 and PROpel started the combinations together. But actually in the niraparib study, it was allowed for patients to start abiraterone while they were waiting for the NGS results. So there was a difference there in how you start the treatment. And because these hormone-naive patients usually are started on ADT upon diagnosis, and then there is some time while you are discussing with them therapeutic options, probably in real life we are going to be starting these combinations when the patient has been exposed to hormonal therapy already for a few weeks or a month. So I think it's important to understand from the biology perspective, what it changes because of having been on hormonal therapy before having the PARP inhibitor.

Zach Klaassen: Yeah, great point. Thanks so much for your time, but just a couple of quick take-home messages for our listeners today.

Joaquín Mateo: Well, I think that with this study we are generating preliminary data saying that PARP inhibitors may have a role in the hormone-naive space; but also acknowledge that we still need to understand who is the right population for this treatment. Both because of the biological rationale to use the drug, but also because this preliminary data suggests we are going to see new long-term toxicities that we were not seeing before. So we need to make sure that the population we are treating is the one that derives the most benefit. Because at the end of the day, we are not in a position to offer cure to patients with metastatic prostate cancer yet—hopefully we will, but we are not there yet. So at least we need to ponder benefit versus risk very carefully for this population.

Zach Klaassen: Wonderful. Congratulations on the ESMO presentation, and thanks again for your time and expertise, Joaquín.

Joaquín Mateo: Thank you very much.