Cancer Topics - Role of PARP Inhibitors in Prostate Cancer

Recent approvals of PARP inhibitors mark the beginning of precision medicine for prostate cancer. Through patient case scenarios, Drs. Lisa Holle (Oncology Pharmacist, University of Connecticut) and Pedro C. Barata (Medical Oncologist, Tulane University) dive in-depth into appropriate use of olaparib and rucaparib in clinical practice, including patient and disease factors to consider. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us

 

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ANNOUNCER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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LISA HOLLE: Welcome to the e-learning ASCO podcast on PARP inhibitors in prostate cancer. I'm Lisa Holle. I'm an associate clinical professor at the UConn School of Pharmacy, and I practice at UConn Health's Carroll and Ray Neag Comprehensive Cancer Center in Farmington, Connecticut. I'm joined today by Dr. Pedro Barata from Tulane University, New Orleans.

PEDRO BARATA: It's great to be here with you.

LISA HOLLE: Same here.

PEDRO BARATA: So, Lisa, I know we'll be talking today about PARP inhibitors in prostate cancer. And it's kind of a kickoff, you know. What do approvals of the different PARP inhibitors for patients with advanced prostate cancer mean to you?

LISA HOLLE: Yeah, this is a really exciting time in prostate cancer, because this is really the introduction of precision medicine in the treatment of metastatic castrate-resistant prostate cancer. So this is a group of patients, traditionally, who can benefit from PARP inhibitors that have not had good responses in the past to our traditional treatments. In fact, it really does allow these patients who would be eligible to receive PARP inhibitors to have an extended time on active therapy.

Now, as we know with metastatic castrate-resistant prostate cancer, we can't cure the patients, but we can extend that time that they're on active treatment. In fact, in the two studies that were conducted, the PROfound study evaluating olaparib, and the TRITON2 study evaluating rucaparib, the progression-free survival time on average was about eight months.

And in the PROfound study, which compared it to our new generation hormone therapies, that really doubled the progression-free survival time. And recent overall survival time was also improved by about five months. So this is really a significant advancement for these patients. And it really underscores the need that we have now for our metastatic patients to do germline and somatic mutation testing to see if they might be eligible for these treatments in the future. So Dr. Barata, who do you think could best benefit from the PARP inhibitors in prostate cancer?

PEDRO BARATA: Yeah, and also, it's a great question, by the way, great introduction to the topic. And you indeed touched on something very, very important. And I think it's a perfect segue way for your question, which has to do with can you identify the good actors or the patients who are likely to respond, right?

So when you think about how these drugs were developed, if we started by classifying this group of genes known as DNA repair genes, right, who have this job or function of repairing defects at time of cell replication. And so among these different genes, we start talking about BRCA, BRCA1, BRCA2, ATM, CDK, you know, RAD51, FANCA, et cetera.

And so it seems like patients who harbor a defect in one of these genes are actually more likely to respond to these therapies. And these therapies, by the way, they inhibit the PARP and the enzyme that helps with burying the DNA, if you will. And so, you harboring a defect in one of these enzymes actually helps you to kind of amplify the benefit of this therapy.

So what I'm really describing is a test who can find those defects, those gene differences. And we can do it in both ways. We can test the genes patients were born with. We call that germline testing. And we can also test a tumor for dose alterations. And that's also known as somatic testing, right?

And we now know that germline doesn't tell you all the story and somatic doesn't tell you the full story. And so getting both tests seems to be helpful because it's a way of not missing the biomarker positive patients, or in other words, patients with DNA repairs, who are, again, likely to respond to these therapies.

And so I would say, among these, definitely, patients with DNA repair defects. And we start learning a little bit more that not all the genes defects are the same, I mean the same in terms of efficacy signal. I guess we can talk about that a little bit later today. But I have to say, we expect somewhere 20% to 30% of patients who harbor dose genomic alterations. And so we are talking about a subset of patients within the group of advanced prostate cancer who really harbor those gene defects, and based on the data we have today, are destined to do better on these agents.

Now if we don't test, we don't find, right? And so that's something that I think the clinics overall across the country and really, around the world, are now adapting to develop an easy way to start offering germline and somatic testing to those patients. Because it does impact our decisions.

And so I kind of-- I just alluded briefly. And you did say, Lisa, you did talk about PROfound and TRITON that developed, respectively, olaparib and rucaparib, right? Do you have any thoughts about factors that makes you choose one versus the other? Is that something that you kind of use in clinic and to go through that thought process? Tell us a little bit how it goes when you get to pick one agent.

LISA HOLLE: Yeah, I think as we think about new agents that are available for each of our individual patients, we have to think about patient characteristics, I think is one big factor, such as comorbidities. For example, in the PROfound study, I think they had an instance of deep vein thrombosis and pulmonary embolism that was relatively small, but it was in the range of 4% to 7%.

And so I think in a patient who might have a history of a recent PE or a thromboembolic condition, you might shy away from using olaparib if they could receive rucaparib instead. I think the prior therapies that they have received too is also really important. So both of these trials looked at patients who had advanced after receiving either enzalutamide or abiraterone. And then the TRITON study evaluating rucaparib, they also had to receive at least one taxane therapy.

So I think you need to make sure that they've progressed on one of those therapies. You might try olaparib before a taxane in that patient population.

PEDRO BARATA: So basically, you're saying-- because I think it's a very important message-- is not that we believe agents might be different mechanistically, right? But the way we develop drugs in the oncology world is based in the setting they were developed, right? So you're basically describing different patient characteristics that were enrolled in PROfound and TRITON, and how that led to different approval specifically regarding chemotherapy. Is that it?

LISA HOLLE: Right, exactly. And so I think when you're trying to decide between two therapies that have similar outcomes, are used in a similar population, and trying to figure out which one might be better for that particular patient, I think these are some of the things that we think about. Certainly, insurance approval could be a possibility, although I would expect that insurance would cover both of these agents. They're FDA approved.

They do have some different indications that we can talk about a little bit more specifically as we talk about the specific testing that's done and what mutations were found to be most beneficial from these agents. But also, I think performance status is something to consider. So when we get to later lines in therapy, sometimes, our patients have poor performance status.

And as with all clinical trials, we enroll patients with good performance status. I think the PROfound trial enrolled ECOG 0 to 2, and TRITON2 enrolled 0 to 1 performance status on the ECOG scale. So again, well-performing patients. It doesn't mean that our performing patients can't receive these drugs, but they may not have the same outcomes and may have more toxicity.

PEDRO BARATA: Now it's interesting that you brought up access. I don't know your experience with that. I actually had a story, and I can share now or later.

LISA HOLLE: Yeah, absolutely.

PEDRO BARATA: So here in our clinics, we do test everyone. And we'll talk a little bit about that in a minute. And so this patient was a BRCA, a BRCA2 positive patient. And we tried at the time, we applied for olaparib for him. And unfortunately, we were not able to get it due to insurance restrictions at the time.

This was prior to the FDA approval. And so we got to be creative. And we went with a platinum-containing regiment as an alternative. And it turns out, it worked really well, as we know. I mean, there's significant data out there. But basically, demonstrating an increased activity of platinum-containing regimens for patients with DNA repair gene defects.

And so anyway, so that patient did respond well. And so I think he completed-- he got some carbo plus cabazitaxel at the time. And he completed six cycles, went on observation for while, on a chemo break, as we call them. And then he progressed a few months later. And at that time, we reapplied for a PARP inhibitor.

And it got approved that time, actually. So we got rid of the obstacle that we had the first time around, that we encountered the first time around. And so actually, that patient is still on olaparib and doing well. But I think that speaks a little bit to what you were saying or referring to, that sometimes, there are obstacles that we have to be aware of. And definitely, access to medication is one of them.

LISA HOLLE: Yeah, absolutely. And I think this highlights a good point that we're having in all of our patients with cancer right now, is as the studies come out-- so GU ASCO was just a month ago. Data comes out and the guidelines aren't updated right away. And during that period, when we know we have an effective therapy that could be used, that's the time, I think, and even a few months after that is when we have the most difficult time with insurance approvals. And then, of course, the FDA indication also can cause a lag in insurance approvals.

But certainly, I think that also shows that we can, as many of us have done, had a peer-to-peer with an insurance company to ensure that they understand the data and can approve these therapies. That's another way that we can go about that.

I think one other really important thing to think about these drugs are that they're dosed twice daily. So adherence could be a problem for some patients. Most of our patients have significant comorbidities. They're older adults, have multiple medications. So it's just an additional pill burden. And as we know with targeted therapies, adherence is really important to try to prevent the resistance that will ultimately develop, but try to prevent it from happening sooner.

PEDRO BARATA: Right.

LISA HOLLE: So I guess we probably should talk a little bit more about the testing that needs to be done and how we go about testing our patients. So could you share your experience with that, Dr. Barata?

PEDRO BARATA: Yeah, for sure. I mean, that's truly, truly important. And thank you for highlighting that again. So as I was referring to earlier today, there are two types of testing, right? Germline and somatic testing. So the germline can be done with, for example, a simple blood test. And there's a bunch of commercially available assays that can do that for us.

In regard to somatic testing, we can do it in the tissue. We can use a fresh biopsy or archival tissue, or we can do a liquid biopsy where we basically find circulating tumor DNA that's at the time of-- it's also a blood drawn, basically. So in prostate cancer world-- and I think that that's familiar to a lot of folks who treat prostate cancer-- they do know a lot of times, archival tissue is available from many, many, many years ago. And a lot of times, we cannot get fresh tissue or tissue that we feel represents the reality of the tumor today when we have the patient coming in to see us, for example, right?

So I guess access to tissue is often a problem. And as you were saying, Lisa, both PROfound and Triton and other really biomarker positive studies, they often start based on tissue, not based on liquid biopsy, right? So the question is, in the absence of tissue, what can we do? And there's an emergent number of studies have shown good concordance between liquid biopsy and tissue.

So I'll tell you what I do. We do favor tissue sequencing. And there's also a number of commercially available assays out there. And when I don't have tissue available and I really think we should do somatic testing, I use the liquid biopsy as a surrogate, if you will. It's not perfect, right? Because unless the tissue and liquid biopsy are kind of collected around the same time, and even though the panels are different-- so there are all these differences in there. But I think if we find, in this case, a gene defect with a good allele fraction, at least in my experience, I had that a few times. I did not encounter obstacles to access to a PARP inhibitor.

But I still favor tissue because that's where the data was developed. And so that's just my style, right? I try be data driven as much as possible in all germline, right? If I have a germline that more than likely is going to be the tumor, right? Because all the cells wouldn't have it, but not necessarily. But anyhow, if I have a germline test positive or tissue positive, I'll use it. If I don't have tissue and I have liquid biopsy, I would still try it. But that's kind of my go-to, right?

Now I do-- based on my conversations with my colleagues from the community, there's a little bit of concern about what to do with the results, meaning if you don't test, you don't know. But if you test and something positive comes back, you need to sit down with your patient or at least provide some kind of explanation and understanding. And some of us more than others are a little bit less familiar with some of the genomic alterations we can find.

And I don't know all of them, to be honest. And they can create a challenge. So sometimes, we don't test because concern about the results. I would like just to highlight the fact that these commercially available assays, they do a good job, even a better job now than before, in terms of providing genetic counseling sometimes online or over the phone. And actually, some of my patients have used that in addition to just kind of go through the results with me. So that's something to be aware and it's simple to do, right?

And we talked a little bit about reimbursement, especially before the approval. So approvals is based on the setting, right? So if I want to do, for example, rucaparib to patients who did not get chemotherapy, it can happen that insurance will, the payer will say, this patient needs to receive chemotherapy first. Because that's based on how TRITON was designed, right?

And so you have an alternative, which would be olaparib, that doesn't require prior chemotherapy. And that doesn't speak anything, as you said, regarding which agent is best. And I'll defer, you did a great job in terms of breaking down in terms of safety profiles and the differences. But my point is, knowing where the medication was developed helps when we ask for that therapy for our patients, right?

And then, the last point I would like to make is in addition to the therapeutic implications, especially germline testing, I think it's important to be aware of the familiar implications. And so, some way or the other, germline assays, test assays do provide support for family members to get tested. So here in clinic when we test them, basically, family members get tested for free if the patient is positive and as long as the patient agrees with it. Because he's actually the one who provides us the information to reach out to family members.

And so I'm just thinking an example where we found a patient who happened to be BRCA1. And then we were able to go after his family and test his family. And we found another two positive cases. And two females, one in the 40's, one in the 30's, I believe. And so I actually think we did change the future for those two individuals.

So the implications that go beyond the patient in front of us are actually huge. I have another case in kidney with a genomic operation, where we have, since this patient was diagnosed-- and it's not a kidney cancer conversation-- but since this patient was diagnosed, three others developed cancer. And we found another four patients who harbored that genomic alteration.

In that case, it was a path one. But I'm just sharing the potential implications for family, which I think is huge. Because our care goes beyond the patient in front of us, right? And sometimes, it can impact what we do with the family.

So that's-- so the bottom line, to me, is if we don't test, we don't find. It's OK not to know everything about the test results. And there's more resources out there that can help us with that. And the implications of testing are significant.

LISA HOLLE: You make an excellent point on those things. The other question I had for you is, you know, I think the guidance right now is that we do somatic testing at the time of development of metastatic castrate-resistant disease. But there is also some suggestion that we should repeat that somatic testing when somebody progresses after a treatment, right? So do you do that routinely?

PEDRO BARATA: Yeah, that's a great question. That's a great question. And obviously, I'm biased because we do research in addition to standard of care approach. So I have to say, what I do, and here at Tulane, we basically test everyone for germline at time they step in the clinic with metastatic disease. We have the discussion for recurrent disease no mets, and then for high risk as well.

So that's in regards to as far as germline testing goes. In terms of somatic testing, I also had one upfront. The reason why I get, if I have tissue and I'll use a tissue if I don't. I do liquid biopsy before I start them on systemic therapy. The reason why I do that is because it helps me to plan.

And I think as one of my former mentors used to tell me, I guess, was that as an oncologist, we always like to anticipate. And we always have a plan B. And I love anticipate. I hate surprises. I only like surprises at home. I don't like them at the office. And so having that information allows me to plan things when option A won't work for them.

So a lot of times, I get the testing here back. And I'm not even doing anything with it in terms of PARP inhibitor, for example, right? Because to your point, they are approved in the metastatic castration-resistant setting. And a lot of times, they do it for castration-sensitive settings. So what do I do afterwards? Well, that goes a little bit in the research side. We do a lot of serial sequencing, tumor sequencing, if you will. Germline, we only do it once.

And the reason for that is we do see changes over time, meaning exposure to treatments has the ability to impact the molecular phenotype or the molecular makeup of the tumor. So that's the reason why we do it. Does that happen a lot? I don't think, or at least that it's targetable, the answer, I don't think it is.

But for me, we published something about MMR/MSI, where we were show that MSI might be acquired over time. It goes beyond the germline. And so as an example, if I find one additional patient that is able to get benefit from a target therapy or immunotherapy that would not otherwise, and would never offer him the therapy, to me, that's a lot. That's very significant for that patient in front of me.

So having that repeated, it's important in that perspective. It's not ready for primetime in my opinion. I think we should. If we can, I think we should do it. But right now, the data is still lacking. The strong data is still lacking to provide guidance in terms of how often should we be testing these patients and when, right? And after what therapies?

So those questions remain unanswered, which are very important questions. I just say, if you have the ability to do it, why not do it? And so, Lisa, so it's kind of a good segue way to the next portion of it, which has to do-- we talk a lot about olaparib, rucaparib, similarities, differences. Can you basically expand a little bit about how do you choose them, and a little bit about the approvals, how that impacts your treatment decision? I know you talk a little bit about it. But can you highlight us on the safety profile and toxicity a little bit more?

LISA HOLLE: Sure. So you know, just to recap, the olaparib, which was evaluated in a PROfound study, looked at homologous recombinant repair gene mutations. So it sort looked at a broader group of mutations and had most benefit in BRCA1, BRCA2, and ATM, although some of the other mutations also had some benefit, and was studied after progression on enzalutamide and abiraterone. So that's what its indication is for.

Rucaparib is indicated for patients who have a BRCA mutation, germline or somatic, who progress after abiraterone or enzalutamide and at least one taxane. So that's sort of the difference in terms of the indications and how they were studied. As I mentioned, they both had good performance status patients. So we have to sort of think about that again when we're thinking about overall use of these drugs.

But in terms of differences, some of the key things that we think about are potential for drug interactions. As I said, many of these patients are on a lot of different medications. Rucaparib has several different cytochrome P450 interactions that can occur. So it has more potential for drug interactions than olaparib does.

Olaparib needs to be dose adjusted for patients who have renal dysfunction, has that incidence of VTE that was higher than the comparative arm in the PROfound study. So that's something to consider. And then, I think with olaparib, there are some other laboratory abnormalities that we don't tend to see with olaparib. So with rucaparib, we can see LFT elevation, elevations in triglycerides, alkaline phosphatase, so just something to be aware of. It doesn't often require a necessitation of discontinuation of the drug, but can happen and also is associated with a rash. So those are some of the differences between the drugs.

PEDRO BARATA: Yeah, that's a great review. In clinical practice, and I know you've used both, right, anything that you think differently? Like, when you have a patient on olaparib or a patient on rucaparib, is anything that is a red flag for you, or at least, like, rings a bell and say, hey, should be thinking about this? You know, tells us what you're thinking?

LISA HOLLE: I mean, one thing that for those providers who work with multiple tumor types, so we use these drugs in ovarian cancer patients, obviously. And in that population, there actually is the risk of developing myelodysplastic syndrome or acute myelogenous leukemia. And so far, at least with the data that we have in the PROfound and the TRITON studies, we didn't have any incidence of that reported to date, even though these patients had received potentially some other chemotherapy agents that could put them at risk.

So I think, if you use these drugs in other settings, that might be something that you're concerned about but we haven't seen in the prostate cancer population. And then, I think we do see cytopenias that can occur just as a result of the mechanism of drug. And we have to monitor the complete blood count with differential in these patients.

But I think as oncologists, we're very familiar with managing these patients. They often don't need dose adjustments or discontinuation due to cytopenias that are relatively mild. They also can cause nausea. So we just have to make sure our patients have an antiemetic at home. And we continue to make sure that they're benefiting from either using that or understanding that that doesn't necessitate skipping the drug because they're not feeling well. So it just requires some sort of monitoring of those patients. I think those are the biggest things that we tend to see in our patient population.

PEDRO BARATA: Yeah, no, that's good. And you remind me that those are very important points safety-wise. I was thinking, if I have a patient in front of me that has not received chemotherapy, for example, and he's now progressing on abira/enza, right? And let me say, because I just got a patient like that recently. And so when would be the time when I would probably not choose a PARP inhibitor and I would choose something else, right?

And so, as we learn a little bit more about the different homologous recombination gene defects, we start to understand that not all the dose defects are the same or mean the same in terms of what we expect from these therapies. And so I was thinking of a case where just based on the genetic information he had, so we basically came for a trial second opinion. He actually was-- he couldn't make the trials. But he happened to harbor a CDK12, which is approved, by the way.

If we look at PROfound, right? As you mentioned, this would be a patient-- we actually had a report, when I got the report back. And he was reading the report. Good, Doc, I'm going to get a PARP inhibitor, because they were there, right? He said CDK12 benefit PARP. And I was actually not convinced that would be the best option for him. And I'll tell you why. I mean, he actually was symptomatic.

And I basically showed him the breakdown of the PROfound data that basically suggests minimal activity of a PARP inhibitor for those patients, for example, right? Which is a little bit interesting to be in clinic with a piece of paper saying you're going to benefit from something. And the physician might be telling you, well, let's not go so fast, right? And this is why.

And I pulled PROfound. I told him the story about TRITON. They had a CDK12 cohort that was discontinued due to lack of activity. And so I end up-- I plot for him a different approach, a chemotherapy approach would be a better choice for him. And I did not go with the PARP inhibitor.

And I think, to me, as we learn more about what the different genomic alterations do mean and what we expect with them, I think we're going to have these discussions more and more, meaning it's not like, oh, you have a checklist of homologous recombinations in the facts. You should get the pill. I think the discussion goes beyond that and it takes into consideration several different factors.

I just gave an example about the type of gene, but also what you just said in regards to safety, in regards to patient comorbidities. And so this is a great option in my eyes. It's a fantastic option, actually. We have survival data now from PROfound as well, right? It makes them live longer. It prolongs time to progression. And so it's definitely a huge advantage that we got in the prostate cancer world, one of the recent developments that are truly meaningful to patients.

But I don't think it's still applicable to all of them, right? And so I'm just-- as you were talking about safety, et cetera, I just remind myself of that case because it reminds me, not all genomic alterations mean the same. And speaking of that, it will be interesting to see. One of the things that are coming up in the future is we do have these broad studies that test PARP inhibitors for unselected group of patients regardless of their molecular phenotype, right?

So that will be, to me, that's a very interesting group of trials. Because we don't know whether or not it's going to be-- we're going to see an advantage there. But I think it's very interesting to explore that concept because it would take us beyond a select group of patients based on the biomarker to a more broader application and use of those therapies in an advanced prostate cancer arena. I don't know your thoughts about that, Lisa, and whether or not you want to share other thoughts about what's coming up.

LISA HOLLE: No, I think that's an excellent point. And it'll be very interesting to see the results of those trials. Before we talk about some of the other things that would be interesting and what we hope to see from these drugs, it reminded me when you were talking about that patient who you chose not to use a PARP inhibitor, even though they had a HRR mutation. Do you, in your clinic, allow for more time in those conversations where you have to go over the results of their sequencing?

PEDRO BARATA: Yeah, great question. So because I do it in advance, right, I do it and I do it over time. So yes, the answer is yes. We go over the genetic information over and over again. And that's one of the reasons why I do it as soon as I meet with the patient because it allows me-- I don't expect this information to be well-captured the first time. It's very complicated. And sometimes, we still struggle ourselves in understanding exactly that what that means. And so repetition is very helpful, and to go over the data and just explain the data differently.

And so that, I mean, that happens a lot with me. So I do know, I have a number of patients who have constriction-sensitive, who I know they harbor BRCA or whatever, CDK12 or something else. And I do bring it up to our meetings, right? I do say, listen. It is great. This is working great for you. Remember, we have this genomic alteration that does this. And this opens the door to more options in the future, et cetera.

So I try to remind the patient and myself of that over and over, so that if we have to use that information, he's already familiar with it. I hate to chase the tumor. I hate to be behind a cancer. Like, you know that feeling when the tumor is progressing, you're chasing the cancer to regain control of the disease, right? So I like to, or try to at least be one or two steps ahead, anticipating what might happen, right?

And there's a lot of factors that help us to do that. But certainly, testing them early helps us to accomplish that. So that's something that I do. And it helps me as well to be more comfortable in clinic.

LISA HOLLE: Yeah, we do a similar thing in our clinic. I think it's really beneficial to do that because I think patients sometimes hear about precision medicine. And they feel like if they have this super medication that matches their tumor, that's going to be the silver bullet to their treatment, right?

And that, I think, is something that we have to often play down and explain what this really means, and that this is something that can be used later on and isn't quite as magical as they think it might be. So I think that's a good way to do it. I think one of the things that we don't know, and this is true of most targeted agents, like if you fail one PARP inhibitor, can you have a benefit from the other PARP inhibitor? Or should we use a platinum-based therapy first before a PARP inhibitor? And I think those questions are interesting and yet to be answered.

PEDRO BARATA: Yeah, that's a great point, right? I mean, I have the feeling that they might not work the same way, right? And so we don't have data so far that categorically shows us that one PARP after the other would work. However, we can look at our friends from other tumor types and see that that approach has not been followed. And so I wouldn't expect that to be the case.

In regards to platinum and PARP, that's a different story. I can see in the future, patients receiving platinum after PARP inhibitors and not the other way around. I mean, the other way around probably would happen if there's some difficulty with access to the PARP therapies. But we tend to use novel therapies more than the old ones, right? And platinum has been around for so long. And it's still a great therapy, especially combination, right? Because we now have got a piece of data we have the data from Houston group with cabazitaxel combined with carboplatin, right? Which was published about two years ago.

And so I do think, I have to say, I'm biased because we're doing a little bit of research on that. I know data will come up to answer that question will be better, real world data in terms of activity of platinum post-PARP activity of PARP plus platinum. And we'll see that data more and more over time. But you're right. We don't know the answer for sure.

And I'll be honest. Until I know it's definitely a no, I'm probably going to try if I don't have another option, right? So that's how we come up with those cases. And then we try to put them together and report their outcomes. And that's one kind of question that's out there. There's still an answer, to your point. Another one would obviously be we keep talking about PARP inhibitors. That's how great they are. And they got approved in their specific setting.

The question is, are they still benefiting patients in different settings? Like, hormone testing, for example or unselected group of patients, as we talked about earlier. And those type of questions remain unanswered. I do know they will get data that will help us to answer those questions. But that's definitely something that we'll pay attention to as we move forward.

And finally, combination regimens are being tested with different PARP inhibitors, including radium, including immunotherapy, chemotherapy, et cetera. So novel and monotherapies, I do think that it will be very interesting to see whether or not throw the sink with a PARP inhibitor in there versus sequencing the different therapies that we have available provides a different advantage to patients. What are your thoughts, Lisa?

LISA HOLLE: Yeah, no, I think all of those things are considerations that are likely to have answers in the relatively near future as we get through those studies. I think it's interesting to think, like, is there a group of patients who don't have metastatic disease, probably, who have these germline mutations that could maybe benefit from a PARP inhibitor very early in treatment so that they don't progress to metastatic disease? But that obviously is quite far in the future in terms of where we might have these drugs, but not something that we should consider and evaluate at some point.

I think novel other PARP inhibitors, I'm not aware right now of things advancing quite quickly in that area, but that's another area where we might have new agents that could have similar mechanisms of action that could be useful as well.

PEDRO BARATA: Right. No, that's great. That's a great point that you bring, thinking about the non-metastatic space, right? I feel like today, we've been talking a lot about metastatic in this setting. But you're absolutely correct. There might be an impact in the non-metastatic setting as well. No, I mean, I think this was a great conversation. It's always a pleasure to talk to you about any topic, really. But it was great talk about prostate cancer.

Let me ask you, Lisa, do you have any final take-home points for folks who might be on the other side hearing us?

LISA HOLLE: Yeah, I think the biggest thing is that this is an exciting new era, right, in this metastatic castrate-resistant setting, and that we need to be mindful of the data that's coming forward. So we have just recently, the overall survival data published from PROfound and updates that continually come out.

So I think it's important just to stay up-to-date with this information to make sure that you're aware of the toxicities of these new drugs as we continue to use them. And don't be afraid to have those conversations with patients about how this might be something that could be part of their therapy in the future, but have those conversations early.

PEDRO BARATA: Yeah, no, that's great summary points. For me, I would love to highlight the importance of testing. And I think we covered it. The safety, no less, that you did a great job at telling me and the folks out there about it. And exactly what you just said, what's coming up in the future. And these are, for sure, great, great news for patients who, unfortunately, were diagnosed with advanced prostate cancer.

All right, well, Lisa, it was a pleasure talking to you today. And thank you for ASCO for putting this program together and allowing us to discuss a little bit about PARP inhibitors in prostate cancer. So thank you. And have a good day.

LISA HOLLE: Yeah, thanks, Dr. Barata and ASCO. This was a great conversation. Thanks.

PEDRO BARATA: Thank you.

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