Evan Yu: Good day. We're here again at UroToday at ASCO 2025. And I'm here with Atish Choudhury. He's a physician at the Dana-Farber Cancer Institute. A senior physician is his title, and also an assistant professor at Harvard Medical School. And today, we're going to be talking about a wonderful abstract that you are going to present that's looking at EZH2 inhibition as well as PARP inhibition combination. So I'm super excited to hear more about this.

But before we get started, can you just give us a little bit of background. I mean, we've all heard lots about how work about how PARP works and DNA repair, but EZH2, we've known about that for many, many years from, I believe, rule Chennai and had a Nature paper ages ago, and I thought it was going to change the world. But here we are in 2025 and we're still doing clinical trials, and it hasn't made it into the mainstream market yet. Tell us a little bit about the biology of EZH2 and the promise for use for metastatic castration-resistant prostate cancer?

Atish Choudhury: Yeah, so EZH2 is an epigenetic modulator and it's upregulated in metastatic prostate cancer. And it seems to go up in expression the more advanced the disease. And it also seems to be associated with lineage plasticity. So it seems to be associated with the transition from an adenocarcinoma phenotype to a neuroendocrine phenotype as well. And so it is a component of the PRC2 complex, which is an epigenetic modifying complex. But it also has some activities outside of that complex that's associated with AR signaling as swell.

So what the true dependencies are to EZH2 and how best to then use it to target advanced prostate cancers isn't really known whether it would work well as a single agent, or whether it works best in combinations is really important for us to know. And also in what disease settings is it more critical. Is it more important for the neuroendocrine prostate cancers or the adenocarcinomas? And then are the appropriate combination partners different in the different disease states? These are all things that we're trying to learn about EZH2.

Evan Yu: There have been some agents that have been developed targeting towards EZH2, and I know in other cancers as well, not just prostate cancer. I believe lung cancer, there's a whole host of other tumor types. Do you mind just sharing what's been done a little bit with EZH2 inhibitors in prostate cancer as a background before we jump into your work?

Atish Choudhury: Absolutely. So there is an approved drug that's an EZH2 inhibitor, that's tazemetostat, and that's the drug that's been used in this particular study. And tazemetostat is approved in lymphomas and seems to have good activity when there's EZH2 mutation that's activating. And that makes sense in our paradigm of precision oncology. And also does seem to have some activity when EZH2 is overexpressed as well.

So tazemetostat has been tested in prostate cancer as a single agent and also in combination with AR pathway inhibitors, though the activity has been modest to date. And so what we're really testing in this particular study is that does it create additional vulnerabilities within the cancer cells that can be exploited by a second class of drug?

Evan Yu: So tell us how that might happen. Is there really strong biology there to tie the DNA repair pathways, single-strand break repair with PARP and EZH2?

Atish Choudhury: Absolutely. So what the laboratory of Miles Brown has demonstrated and other labs at other institutions as well, is that EZH2 is actually directly involved in regulation of the expression of DNA damage genes. And so when cancer cells are exposed to EZH2 inhibitors, it actually downregulates some genes that are involved in DNA damage repair. So APEX1, MUTYH, POL. And then another lab suggested it was involved in regulation of expression of MAD2L2. And that one sensitized to DNA damage in general, like from ionizing radiation, but also seemed to sensitize to PARP inhibition. And so that was where the idea of this particular trial came.

Evan Yu: I see. OK. Well, let's jump into the specifics here of your trial. You want to tell me a little bit about the design and the combination of drugs that you use?

Atish Choudhury: Yeah. So this is a first in human trial. And as far as we know, this is the first combination of an EZH2 inhibitor and a PARP inhibitor. And the idea here is that just like we've heard about synergy between different sorts of agents, that if EZH2 inhibition sensitizes to PARP inhibition independent of the DNA damage-- any mutations in the DNA damage repair response, we elected to enroll an unselected population into this trial, partially just to understand the biology of how these two drugs work together when the DDR pathway is wild type and also when it's mutated.

And so it was designed as a two-part trial. The first part, the part 1A, was just a dose escalation, a 3 plus 3 design. And then it was followed once we established the recommended phase II dose with an expansion of an additional 20 patients to get some more information of the safety and efficacy, and also to do some biomarker testing to understand in whom it's working and how is it working when it does.

So in the dose escalation, we started at a 75% dose reduction of each of the two drugs compared to their monotherapy doses, with an idea of going up or down based on the dose limiting toxicities that were seen. And essentially, what we saw in that part one was that there was certainly myelosuppression, as is known to be side effects of EZH2 inhibitors' monotherapy and PARP inhibitors' monotherapy. There were 0 DLTs at the initial dose level, one of six DLTs at the next dose level, and then once we got to the two dose level, which was full doses of both drugs, then we started to run into problems with more limitations around thrombocytopenia and anemia. So it was that dose level plus 1, which was talazoparib at 0.75 daily and tazemetostat 800 milligrams BID that we decided to move forward into the part 1B which is an extra 20-patient expansion.

Evan Yu: OK. So just to summarize. So you're moving forward one dose level down basically from the standard dosing as monotherapy?

Atish Choudhury: Right. So the EZH2 inhibitor is at the full dose and the talazoparib is at a 25% dose reduction.

Evan Yu: 25% dose reduction. OK. Can I just ask, I'm sure that you didn't put every single patient on this study. But in your experience, if you get significant myelosuppression after you hold these drugs, just recover pretty quick, or were there patients that remained having problems afterwards?

Atish Choudhury: Yeah. So the myelosuppression was generally reversible, but it did take a long time, as we do see with PARP inhibitors clinically as well. So it could be weeks and weeks before there was recovery of counts even after a hold. So that was certainly the biggest limitation of this study.

Evan Yu: OK. And can you just review the early efficacy that you saw in the patients that were treated?

Atish Choudhury: Yeah. So to understand the efficacy, I think you have to understand the background of the patients who wound up enrolling. So this was a heavily pretreated-patient population. There were no limitations on prior treatments. So people can have had taxanes, they can have had even radiopharmaceuticals like Pluvicto that came on board. In the 27 patients that were followed for efficacy, the median number of lines of prior treatment was four. And again, this was a biomarker unselected population.

So understanding those limitations we did see some clinical activity. So among the 23 patients who were evaluable for PSA response, three had a PSA 50, four had a PSA 30. And in total, out of the 27 patients who were treated at this dose, six remained on treatment for 270 days, so nine months or more, which in this very heavily pretreated population, we thought was an encouraging signal for efficacy. And so what we're really trying to figure out now is who are the patients who really benefit? Because certainly, you wouldn't want to subject a patient to this degree of myelosuppression if it wasn't going to be an effective treatment. But understanding that even in biomarker unselected patients, there is some clinical activity, can we discover the biomarkers that would identify those patients?

Evan Yu: So if I heard you correctly, it wasn't just the homologous recombination repair-altered populations that responded. Some of the responses were in patients that don't have any known homologous recombination repair genes, is that-- mutations, is that correct?

Atish Choudhury: Yes. So that is not what's being presented in this particular abstract. But--

Evan Yu: I'm pushing you.

Atish Choudhury: Yeah. But I can tell you that we have clinical genomics on the patients who enrolled. And in a subsequent abstract, we'll report the outcomes based on the mutations that are seen. But certainly, I can say there was activity outside of the standard panel. That is the approved DNA damage repair altered panel that's used for talazoparib clinically in prostate cancer.

Evan Yu: OK. That's great. Well, we look forward to seeing that future data and presentation from you. Before we wrap up, I just want to know, it seems like this is a promising combination. Of course, you've got to worry about the toxicity issues, but you also made it really clear that these patients were pretty heavily pretreated. And many of these drugs cause myelosuppression, so it might be that you saw that myelosuppression just because of the patient population. If you test it a little bit earlier, you might not see that. My understanding is that there are some studies ongoing with EZH2 inhibition that are moving into randomized phase III with metformin. I think those are earlier populations. Is that correct?

Atish Choudhury: Yeah, that is earlier populations either first-line CRPC or just post-abiraterone. So not the same heavily pretreated population. And that is kind of an interesting concept because in this particular trial, there was no maintenance of AR inhibition. So AR was not particularly suppressed with the talazoparib and tazemetostat. And could AR inhibition actually be helpful in making this combination work better?

Evan Yu: I see where you're going with this potential triple therapy down the road there.

Atish Choudhury: Yeah. Important questions for down the line.

Evan Yu: OK. That's great. Well, looking forward to seeing more on this topic. Thanks so much for joining us today.

Atish Choudhury: Thanks so much, Evan. Thanks so much to UroToday for this opportunity.