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Alicia Morgans: Hi. I'm so excited to be here today with Dr. Jake Orme, who is a medical oncologist at the Mayo Clinic, and Dr. Emmanuel Antonarakis, who is also a medical oncologist at the University of Minnesota. Thank you both so much for being here with me today.

Emmanuel Antonarakis: Thanks, Alicia.

Jacob Orme: Thank you.

Alicia Morgans: Wonderful. So I wanted to talk with the two of you about a recently published paper looking into the use of PARP inhibitors in patients who have BRCA2 and SPOP mutations. And I wonder, as we're thinking about this concept, thinking about these alterations, Emmanuel, could you describe why it was important to even think about this kind of study?

Emmanuel Antonarakis: Some research starts from a clinical observation, and then you try to understand it and explain it better. When I was at Hopkins and then when I moved to Minnesota, I had accumulated a series of four patients who had exceptional responses to a PARP inhibitor, in my case, it was olaparib. And after three or four years when all four of these gentlemen were having complete and ongoing responses, I went back and I looked more carefully at their NGS reports and I wanted to see if there was any pattern or common theme. And they all had BRCA2 mutations, but the thing that caught my mind was in addition to the BRCA2 mutation, they had a second mutation in a gene called SPOP, also pronounced SPOP.

And at that point in time, I wondered whether that was an anecdote or whether there might be something to it. So we decided to use an existing consortium of 13 sites which we had created for another project, and those 13 sites are from the US, Brazil, and Europe, so international collaboration. And we asked our colleagues and friends to put together a panel of patients that had received a PARP inhibitor that had a BRCA2 mutation, and we subsequently looked to see whether those patients also had an SPOP mutation, so that was the genesis of the project.

Alicia Morgans: That makes a lot of sense, and I appreciate that and am really excited to see the clinical observation translating its way into a study like this. And I wondered, Jake, if you could really talk to us about SPOP mutations, what they do in prostate cancer. I think we've been batting them around for the last two years in our conversations, but are they good? Are they bad? And what's the function there?

Jacob Orme: Wonderful. When I think about how SPOP works, I don't know, you can pronounce it any which way you like, it's a very interesting protein. And I have a patient with an SPOP mutation who I think of every time I see this, and he followed that normal course where you see that you get some responses that are better in some situations and worse than others. So he's a utility trucker and a firefighter, and all he likes to do is hook up hoses. He told me that that's just basically what he wants to do for a living, so that's why he does those things. And it struck me that he is a lot like SPOP himself. So SPOP is a ubiquitin ligase component that helps recognize substrates to add on a hose, but in this case, the hose is ubiquitin. And when you get polyubiquitination of any given substrate, you can have two different things happen.

One is you can have that substrate get degraded, which is the most commonly known one which, of course, really affects how a cell behaves, but also you can have altered functionality in that cell. So in the context of prostate cancer, all of these mutations that we see in prostate cancer are in the MATH domain, meaning that recognition domain. And as a result of those mutations that by the way are dominant negative mutations, you get a failure to recognize the substrate. And so as a result, there are all of these proteins that would've been either altered or destroyed that are running around in the cell not altered and not destroyed. Why does that matter in prostate cancer? Could it lead to prostate cancer? Well, there's a lot of work that's been done over the last couple of decades that has shown that loss of ubiquitination by SPOP leads to a lot of problems.


So for instance, androgen receptor is ubiquitinated by SPOP for its degradation. It has other partners as well, TRIM24, SRC-3, BRD-4, all of which alter how androgen receptor activity behaves. And so that comes down to the why does it matter in prostate cancer? So upfront, it means that this subset of prostate cancers, which is about 12% of men with prostate cancer have this mutation as a driver, they're going to respond really well at first to androgen deprivation, to androgen receptor pathway inhibitors. The problem is, of course, that most of those men are still going to see that disease recur in the metastatic setting, and so that's why it matters. There's something else there that continues to drive resistance in these patients.

Alicia Morgans: Okay. Well, that makes a lot of sense and certainly explains our interest in this particular mutation. Now, Emmanuel, I wonder, can you tell us what were the findings in the work that you included in this paper?

Emmanuel Antonarakis: So we actually put together about 131 patients from these 13 sites, and they all had BRCA2 and had received a PARP inhibitor. Most of them were treated with olaparib. And of the 131 patients, we found 14 that also had the double mutant BRCA2 plus SPOP. And we looked at a variety of outcomes, and the bottom line is whether it was PFS, whether it was OS, whether it was time on therapy, the outcomes were, let's just say dramatically improved and statistically so in the combination that had the SPOP mutation and the BRCA2. So something about the combination of a cancer having both a BRCA2, a loss of function mutation, and one of these SPOP hotspot mutations, for some reason that I was not smart enough to understand, but my friend Jake figured it out, they were very, let's call them hypersensitive to PARP inhibition. So I teamed up with Jake so we can explore the underlying mechanisms of why this is happening.

Alicia Morgans: So before we get into those mechanisms and what some of the other novel biomarker highlights might be from this work, I wonder, Emmanuel, if I could just have a follow-up question here. We often think about SPOP mutations being potentially useful when we have an AR signaling inhibitor, and I wonder what your thoughts are for these patients. If we are using that combination strategy of an ARSI plus a PARP inhibitor, would you anticipate, perhaps, that they have an even more pronounced response?

Emmanuel Antonarakis: As Jake mentioned, the clinical hallmark of SPOP mutations is their exquisite sensitivity to androgen-directed therapies, and that has been known for two or three years. It doesn't apply to chemotherapies as far as we know, but it does bring up the question in the current era of PARP inhibitor-based combinations, either olaparib abiraterone or talazoparib enzalutamide, whether these patients might be the best opportunity to use the PARP inhibitor-based combinations upfront. We weren't able to address that in this study because all of these patients in our study were on monotherapy with a PARP inhibitor. But it does raise a very important question, and I would predict without having any data on this, that yes, those patients would probably be also hypersensitive to olaparib or talazoparib or enzalutamide.

Alicia Morgans: Thank you for humoring me because I feel like that's been something that certainly is in our mind with all those recent approvals and might be a population that really, really could benefit even as we recognize that they can certainly benefit from PARPs. I think this combination sounds like it may be a wonderful one for them. So back to you, Jake, wondering if you could talk about some of the novel biomarker work that you did within this and share some of those other highlights?

Jacob Orme: Sure. When you look at response to PARP inhibitors, you're thinking of synthetic lethality and you're thinking of all of these potential ways that we can measure proclivity for that synthetic lethality. So what we did is we went to the cosmic signatures and asked the question, well, if you just broadly take the available data that's public and ask the question, what combinations could predict? We found that in fact, although BRCA2 mutation alone can predict a higher cosmic SBS3 score, which is a homologous recombination defect score that we decided to use for the paper, you get that. If you have an SPOP mutation alone, it turns out you don't have a significantly elevated score. But if you have the BRCA2 and SPOP mutation together, you find that you have a significantly increased score broadly, and we were able to go back and validate that. And I think that goes back, if I can step back from the clinical data then into the lab data.

If we go back and look at a lot of work that's been done about SPOP and what it targets, it has effects on BRCA2 availability on RAD51, CHEK1 availability. There's a wonderful paper by Howard Truong's lab showing functionality matters that was published in 2021 in Nature Communications, and so there's all of these things that would lead you to believe that an SPOP mutation might help, but there is some indication to say that maybe the SPOP alone won't quite cut it. So I think that goes back to Emmanuel's point of maybe upfront in the combination that's where we should be doing this.

Alicia Morgans: Great. Well, Emmanuel, back to you in the clinic. What are the real-world clinical applications or ways that we might think about using this in our practice even today?

Emmanuel Antonarakis: Yeah. So as we were putting together the publication, we asked ourselves that question. And on the face of it, if you have a patient with a BRCA2 mutation, you're going to give that patient a PARP inhibitor anyway. So we were scratching our heads thinking, "Is this really a clinical advance or are these patients that are going to get the PARP anyway?" And I would say that it helps to confirm in your mind that this patient should get the PARP and as early as possible. So when you have the choice between two or three systemic agents, one of which is a PARP inhibitor, if I see a patient who has a BRCA2 mutation and an SPOP mutation, instead of saying, "Well, I might save the PARP inhibitor for a bit later," I might start thinking to myself, "Well, this patient might have a three-year progression-free survival, now is the time to include the PARP inhibitor," so that's number one.

The second thing is, again, we haven't tested this hypothesis, but as we alluded to earlier, this might be the exact type of patient where you would want to use the synergy of an AR inhibitor plus a PARP inhibitor. And again, we don't know which of the three FDA-approved PARP inhibitor combinations would be the best, but I think any of the three would be reasonable. We also know from other studies that there are other concurrent alterations that, despite the presence of a BRCA2 mutation, portend a worse prognosis to PARP inhibitors, so for example, a BRCA2 mutation in the presence of a concurrent P53 mutation, those patients do worse with the PARP inhibitor. BRCA2 mutation plus a concurrent PTEN or RB1 loss also do worse. So when we think about BRCA2, it's not just a single gene that we will consider in isolation of everything else. It's one of a constellation of genetic data that when considered together can help us to make a decision. And the SPOP is one piece of that broader genomic puzzle that we should consider when making these decisions.

Alicia Morgans: Well, certainly things are much more complex than one gene or even two. And I know that you, Jake, are working on future precision therapeutics for patients with SPOP mutations and thinking about ways that you can really harness synthetic lethality, particularly in this population. I wonder if you could share some of those future directions with us.

Jacob Orme: Certainly. Building off what Emmanuel's mentioned, I would say that there's also a suggestion that there's some underlying biology here. There's something to be found. And so even if we look to the future and had data showing that maybe on its own, an SPOP mutation doesn't necessarily make you do better with a PARP inhibitor, the question is what is it about the biology of SPOP that actually makes the BRCA2 a more problematic mutation for the cancer over time? And we're doing work on that in the lab, things that are already then in clinical development and clinical trials, then I mentioned our patient who's the firefighter who just loves hooking up hoses, and like most men with these mutations and widely metastatic disease, he had continued progression despite a whole host of treatments.

What we've found is, again, in that Nature Communications paper by the Hong Group, that an ATR inhibitor looks like it might be an exquisite new synthetic lethality that certainly worked out in the mouse models, and we have a clinical trial open here that I believe is the... Well, I shouldn't say it's the first, but it's the second clinical trial for patients with SPOP mutations. And we have the first as well, which is a separate trial looking at PARP inhibitors in precisely this setting to see if PARP inhibitors given in a prospective way can take advantage of those SPOP mutations. And we're very excited about both of those trials. They're accruing here at Mayo Clinic as well as the ATR inhibitor trial is open through CTEP at a number of locations around the country.

Alicia Morgans: Fantastic. So I guess, as we wrap this up, and congratulations to both of you on really leveraging this dataset to help us find some new understanding in an area that really is only scratching the surface, I would think. Emmanuel, I'd love to hear what is your main message from this work to the listeners who are trying to think about this in clinical practice?

Emmanuel Antonarakis: Yeah. My main message would be when you see a BRCA2 mutation, don't stop there. Of course, it is exciting because it's an opportunity for PARP inhibition, but look at the other molecular components of the report, look at the other clinical components of that patient, look at what other therapies he has or hasn't received yet, and discuss the pros and cons with the patient. And it's not just a monolithic BRCA2 equals olaparib. There are other things that can factor in, including in this case, the presence of an SPOP, which might make you a bit more likely to recommend the olaparib or other PARP inhibitors.

Alicia Morgans: Great. And Jake, your main message from a research perspective, what do we have to look forward to? Where do we go from here? Just your summary in that setting.

Jacob Orme: I'd say there's a lot of biology to be discovered. It's a rich area, and I think it's going to have an impact for patients who don't have the SPOP mutation as well. I think we're going to discover biology there that helps us make these therapeutics more effective for all men with prostate cancer, that's what we're most excited about. And I'd say that if anybody has someone with an SPOP mutation or has an SPOP mutation themselves, feel free to reach out because I think we've got a lot of opportunity for cutting-edge therapeutics that can significantly change outcomes.

Alicia Morgans: Wonderful. So from the clinic to the bench or to the research setting and back to the clinic, hopefully at some point with the therapies that we have and optimizing them and therapies to come in the future, this is all extremely exciting and just giving us one step closer to understanding what's driving this disease, at least in this patient population. So thank you both so much for your time, and congratulations on your publication.

Jacob Orme: Thank you.

Emmanuel Antonarakis: Thanks, Alicia.