What’s New with PARP Inhibitors and Ovarian Cancer?

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Unknown
We'll get started very shortly.

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Unknown
And there we are. Hello, everyone, and welcome to the webinar. What's new with PARP inhibitors and ovarian cancer? I'm Maggie Nicholas Alexander, the senior director of Gynecologic Cancer Patient Support and Education at Share. Before today's program begins, I'd like to tell you a little bit about share Shares, a national nonprofit that supports, educates and empowers anyone who has been diagnosed with breast or gynecologic cancers and provides outreach to the general public about signs and symptoms because no one should have to face breast, ovarian, uterine, cervical or metastatic breast cancer alone.

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Unknown
For information about upcoming webinars, support groups and our help. Please visit our website at Share Cancer Support DOT or. Now I'm going to go over some housekeeping items. All participants will be muted during the presentation. Once Dr. Herzog finishes presenting, we'll begin the Q&A discussion. Feel free to ask any questions through the Q&A section at the bottom of your screen.

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Unknown
Remember, Dr. Herzog is unable to give specific medical advice, so please keep your questions, General. We also have closed captioning available. You can enable this feature by clicking the live transcript button at the bottom of the screen and selecting the subtitle option. This webinar is being recorded and will be available on the share website soon, and we'll also email it to all of the registrants.

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Unknown
Now I'd like to hand it over to today's speaker who we're so excited to have joined us today. Dr. Herzog would you mind introducing yourself?

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Unknown
Thanks, Maggie. Yeah, hi. How's everybody? Yeah, I was laughing when you said I couldn't give any medical advice, and I just got done with the morning clinic and they probably said the same thing. So hopefully, hopefully I'll be able to get some advice that's helpful to you all. So we appreciate you being here today. I am a a Jew, an oncologist in Cincinnati.

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Unknown
I served as the deputy director of the cancer center at the University of Cincinnati and full professor. I came from Columbia University, where I was the division director and the fellowship director at Columbia and Cornell. And prior to that, I trained and spent forever at Washington University in Saint Louis, where I was also the fellowship director. And I was recruited to New York and then back here to Cincinnati, which is my hometown, to be the deputy director of the cancer center.

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Unknown
So that's where I am. when oncologist, I do a lot of research. As you can see, I have lots of papers and all that kind of stuff, lots of grants work. I had had a lab for a while. More importantly, though, currently I'm service the Georgi Foundation President, which is GS over G Partners, which does most of the industry drug development in the in North America as well as we now have sites in Brazil, Korea, we're working on Japan and we have a liaison committee with got in Europe.

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Unknown
So we have most of the globe covered in terms of large studies that that are done. Most of the registration trials that you see in G went oncology over the last five plus years have been with us. We're also over the G in energy and we just finished our energy meeting in Orlando this past weekend. So it's been a busy week coming back from that with clinic and surgery and so forth.

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Unknown
So that's who I am. Maggie, so back to you. Great. Thank you. So, yeah, if you want to go ahead and get started with the presentation right, I'm ready. Looks good on the slides. Okay. Yeah, Looks good. Okay, great. For those of you on here, I think what I'll do is a lot of this is on there for background, and then I'm going to sort of keep it at a high level.

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Unknown
try not to get too much into the weeds. There's some of you who are probably interested in some of the weeds. So every now and then we'll take a dive in where I find it interesting, or I think it might be enriching for you to have a little background. Otherwise what I'll do is sort of maybe even skip some slides, but I'll just tell you why they're in there and so we can look at them as we need to as we move through here.

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Unknown
So don't get too frustrated if we move around a little bit as we go through here. Okay. So start here. Okay. So those are my disclosures is I'll leave them up for a second so you can see. and my role was with drug development, obviously a lot of advisory boards, pipeline consultations and so forth in terms of trying to bring these drugs to our patients.

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Unknown
And that's that's a whole long story that maybe one of the questions will come around and we'll talk a little bit about. So we're going to talk about parts and parts have largely been relegated from and we'll explain the process, but they've largely been relegated from just treatment to more of a maintenance phase and then some some treatment as well.

00:06:38:09 - 00:07:26:06
Unknown
And so I'll explain what all that means. But what is maintenance? Maintenance is where we give additional therapy after we give chemo and we usually have completed the surgery and then the chemo, and then we move on to give something additional try to keep the cancer from coming back in, maybe even cure. So the thought process is if if we know that up to 70, 75% of the patients with advanced stage disease, stage three or four diagnosis, which is the vast majority of our ovarian cancers, and when I say ovarian and some of you say, well, I had fallopian tube or I have primary peritoneal all in the same family and I'm using ovaries as

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Unknown
an umbrella term here today, just that makes sense to you. And so why would I possibly want to get additional treatment? Well, if you know, the cancer is going to come back at three quarters, three out of four patients is going to come back in at least, why wouldn't we try to do something different? And up till now, I could take you through the maintenance of the history of maintenance and everything.

00:07:50:10 - 00:08:10:01
Unknown
But to shorten this talk, I took all that out. But suffice to say that we've done other trials where we've looked at prolonged Taxol, we've looked at other agents, and they haven't really shown an impact on overall survival nor a real strong impact on progression free survival. So those are two terms we're going to throw around a lot today.

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Unknown
Progression free survival simply means from the time that you go on to in the case of a study, when you go on that study until there's evidence that the disease has come back or progressed. So progression free survival or death, overall survival is looking only at death. And that death could be disease free survival, meaning ovarian cancer death, or it could be someone got struck by lightning at their golf course or they got in Iraq or they died of heart disease or something else.

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Unknown
So we look at both of those numbers very closely to try to understand how we can make treatments better over time. And the real optimism story about all this, if you take anything else home today, is that when I you know, I know I look old, I'm in clinic. It's been a long week, but I'm not that old.

00:09:06:03 - 00:09:43:23
Unknown
And I started doing this and the median survivals were 18, 20 months for advanced stage ovarian cancer. Overall survival. And now we're looking at where many, many women are well beyond 60 months plus. So tremendous improvement in where we've been with increasing the prevalence of the disease, so much so that this is no longer considered to be an orphan disease by the FDA, which kind of stinks because that was a nice shortcut to get trials done quickly because we could have less numbers and so forth.

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Unknown
But the good news is it's because we're keeping patients alive for so much longer than we ever have in the past. And so while the incidence has gone slightly lower, not much. The prevalence has gone up significantly due to the fact that more women are alive than they have ever been in the world with ovarian cancer. So that's that's a good news thing.

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Unknown
Getting back to this maintenance story, the idea is could we give why? What are the reasons why maintenance might work? So ovarian cancer is a relatively chemo sensitive disease. We have lots of tumor that's often in there at the initial surgery or the initial diagnosis. And frankly, getting back to the history of this reason why maintenance didn't work before is because our drugs just weren't good enough.

00:10:34:10 - 00:10:57:07
Unknown
Now, with the PARP inhibitors, it's quite a different argument and we'll look at that. And a lot of this is the idea of getting rid of these loans that are resistant. So these resistant clones from which the disease emanates and Jerry's part of this in terms of could we cure more people with being able to give maintenance therapy?

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Unknown
All right. So we spent a lot of time on that first slide. So we got to get rolling here. But this is to give you some idea of what we're talking about. So the treatments there in that green curve that that that goes down like a waterfall or like a like you're going down a big hill or rollercoaster shows to where you get down to disease that you can no longer see limit of clinical detections.

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Unknown
That white dotted line up there. And so you can see what happens naturally is the gray line. So that disease is very low and then there's tumor cells start multiplying and then you're up in to where you have billions and trillions of cells. And then that finally becomes able to be diagnosed clinically. See, 125 is elevated or something we can feel on exam or something we can see on imaging.

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Unknown
The idea of maintenance therapy is to try to keep that down so it goes down there and then we take that minimal residual disease and try to take it down further with that maintenance therapy. And that's really the idea behind all that. So what about PARP inhibitors? This is a slide I hesitated to show, but I'm going to tell you that there's probably at least ten different pathways involved in DNA repair that are important.

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Unknown
These are probably the five most important pathways, and one of them repairs. So when DNA tries to replicate, it creates nicks that create single strand breaks or two nicks and strands that are parallel to one another. I create double strand DNA breaks. And so cells are constantly doing this. They're constantly repairing in the body, merging, and they face a lot of stress external stress, sunlight, tobacco, smoke, alcohol.

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Unknown
Who knows what's in our foods? All the things, bacteria, everything, viruses, everything that your body gets exposed to, that's stressor that your DNA has to react to repair and so forth. And just to maintain the cells growing. Even if you had a low stress environment, no viruses, no bacteria, you're still going to have DNA repair these cells need to replicate and refresh.

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Unknown
And so what happens with the base excision repair pathway on the far left is that's related to single strand DNA breaks. And what's important is PARP inhibitors interfere with that repair process. Okay. And they can bind the enzymes, if you will, that are responsible for that in the case. And that's the key single strand DNA repair system. In the double strand breaks, there's a thing called homologous recombination.

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Unknown
And I know we're getting into things we don't want to get into, but what's important is this repairs, double strand, DNA breaks. And guess what's important here? BRCA mutations, Red 51, all these Margus recombination related genes that are responsible. Now, the bad news is if you have those genes, you're more likely to get cancer. The good news is that those genes, if if you already have a defect and then you pair that with a PARP inhibitor, you can actually kill cancer cells more frequently.

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Unknown
Okay. The reason you end up getting more cancers is because if you can't repair double strand breaks with homologous recombination that h.r. At the top there in orange, you shift to these non homologous end joining alternative and joining and they have lower really low fidelity. In other words, they make a lot of mistakes. So the proofreading goes out the window and you make a lot of mistakes and you become cancer prone again in cancer cells.

00:14:52:18 - 00:15:16:16
Unknown
We can then use the parts in patients who have BRCA one or homologous recombination deficiency from other reasons, such as loss of heterozygous Addie and some other DNA, things that can happen that actually give us a therapeutic opportunity to kill cancer cells at a much higher rate than we would with traditional chemotherapy alone. So that's a great thing.

00:15:16:18 - 00:15:43:23
Unknown
So is there is there one universal approach to look at this? Well, if you think about it, starting on the bottom, we used to think, well, PARP inhibitors are probably going to work in those with these BRCA mutations. Right? Right. So if you if you your mom or your father gave you passed along these mutations, meaning their germline, then we know that's about 15% of the population.

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Unknown
What we didn't realize fully was that 78% more will have spontaneous mutations that give you a BRCA mutation test positive situation by what happens during the course of your lifetime. So you develop a new BRCA mutation so you didn't get it from your mom or dad. But but the tumor now has it because it's developed on its own while tumor was forming.

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Unknown
You then look at these homologous recombination genes and they bring it all the way up to 35%. Then if you look at what I call loss of heterozygous genetic things, you now have 50% of the population that would clearly benefit from a PARP inhibitor and 52% and some of them 48%. So you get the picture. So it's the the role of parts is expanded tremendously.

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Unknown
And then we have some studies where people are already test negative, meaning there's no BRCA mutation, none of these tests came up positive. They still benefit from a PARP. Why? Probably false positives for the tests. Okay. And we can get into that a little bit. So, you know, I think we've gone into enough of this, but this just shows you the different etiologies of what makes up that pie.

00:17:04:00 - 00:17:24:23
Unknown
And you can see on the far right those that are homologous recombination, proficient should not respond to a PARP, but some of them do. And I'll show you examples of that in clinical trials, probably again, because of those false positives, everyone else in that pie graph there, a little over 50% on this one would likely respond to a PARP.

00:17:25:00 - 00:17:54:08
Unknown
So where did this all start? Well, it goes back quite a ways. you know, it's been 15 years where we've looked at the first data that really came out and it was phase one. Phase one is, you know, is for patients that are getting usually experimental type drugs and we don't know the right dose and we don't even know if it's the right disease.

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Unknown
But sometimes you hit on a winner. And I've got many examples I've known over my career where the first person's in the Gleevec, they had gastrointestinal tumors and they were cured. And some of the hematologic malignancies where we've seen them, this is such an example and you won't see too many Phase one studies in the New England Journal of Medicine.

00:18:15:18 - 00:18:37:21
Unknown
It's just that this was such an impressive mechanism of action in terms of how it worked and it worked so well. When it works that it made it in as a Phase one study, which is really impressive and you can see the clinical activity there was c r meaning complete response p r meaning partial response, and SD means stable disease.

00:18:37:23 - 00:19:01:21
Unknown
So look at all the responders that were there and those are platinum sensitive patients on the left, platinum resistant patients. Still, a lot of them responded, not so many with refractory meaning that you grew through frontline platinum. So really impressive for those patients. Now, this brings us to who should be tested. Everyone should be tested who has epithelial ovarian cancer.

00:19:01:23 - 00:19:32:17
Unknown
And there's different ways of doing it and so forth. We don't have to get into that, but everyone should be tested. These are how how good the benefit can be. Just briefly, what do we learn by testing? We can tell what the likelihood of your journey would be. We can never say what one person's journey can be, but we can say with pretty good certainty, What if we took 100 patients with certain characteristics, what their journey is going to look like collectively?

00:19:32:19 - 00:20:04:02
Unknown
And as I said, there will be some that don't respond like they should have, and they'll be some that respond much better than even the average of what we see in that hundred. But generally, we'll get a pretty good idea when we look at large numbers and we and we look at this and we know those with BRCA mutations have better prognostic outcomes, meaning they live longer, they respond better to these DNA, damaging drugs for the reasons I talked about in that first couple of slides there, with all those pathways giving you headaches.

00:20:04:02 - 00:20:44:05
Unknown
Again, we can also predict the likelihood of response to DNA damaging drugs such as PARP inhibitors. And so we would then use this a strategy to help the patient have exposure to better treatments. It also helps us screen in the individual patient. I saw a patient in clinic this morning who's BRCA and has not been following up on breast cancer screening as as we had prescribed and really counseled are pretty tersely that hey, we does knowledge is power and that we're able now to with this information, prevent you from having breast cancer.

00:20:44:07 - 00:21:30:07
Unknown
And she she could consider risk reduction measures as all kinds of things to do there. But you know this all got picked up from her ovarian cancer. And then really importantly is this saves lives. So we're able then to contact family members, find out if they indeed have these mutations that have been passed on, yes or no, and if yes, avail themselves to these risk reduction surgeries, risk reduction medications and much better and closer follow up to try to catch these cancers early if they don't avail themselves to to some of the other modalities that we have to reduce their risk.

00:21:30:09 - 00:21:55:01
Unknown
All right. So this is the first treatment, if you will, that came out and you can see quite a bit later. So 2009, phase one now we're phase two and I think this is animated, so it goes pretty fast. Me go back one there, but it just shows you that they had a 26% response rate, including platinum sensitive and resistant patients, which was pretty, pretty impressive for a single drug.

00:21:55:03 - 00:22:16:02
Unknown
And here's where we are now. So primary therapy for Frontline, we're going to talk a little more about and then platinum sensitive recurrence. And these are the bulk of our indications for PARP inhibitor use right now. And these are two different trials that have been done with the different PARP inhibitors. And I'm going to sort of take you through each of these and show you what's been done here.

00:22:16:02 - 00:22:43:00
Unknown
So so two was a maintenance trial that looks at olaparib versus placebo. And these are in patients that had platinum sensitive relapse and there's really I got a nice table that summarizes all of them. So in the interest of time, what I was pointing out was you could see the difference in MDS. There is 8% with they had the PARP versus 4% if they did not have the PARP.

00:22:43:02 - 00:23:16:02
Unknown
And so certainly, you know, we have to be mindful of this. And in terms of the toxicity from these for for long term because that's obviously something that we want to avoid. So so three, we'll skip that. NOVA was the study that was done with no approved in platinum sensitive disease and they really had two cohorts and you can see there's a big trials, 553 patients randomized to niraparib versus placebo, 2 to 1.

00:23:16:08 - 00:24:00:24
Unknown
The rapper being the PARP. And again, these are patients that platinum sensitive recurrent disease, meaning that had been more than six months since they had recurred and they're then placed into this study and we'll show you the results from these. And you can see here the big difference between these curves. Look at how big the differences are. So if you if progression free survival was 21 months versus 5.5 months as the ratio below point three, meaning you have a 73% improvement in the risk of progression or death, you could see the p value highly statistically significant and you can see the landmark analysis sort of which curve would you want to be on?

00:24:01:01 - 00:24:26:23
Unknown
Well, at 12 months a year out, 62% of the patients are doing great. 16% in the control arm. In 18 months, 50% are still doing great, 16% still in the control arm. So not so good. And you can see the different subgroups here, whether the test for HRT, positive or negative, is there you can see the patients that are HRT positive do much better as we would predict based on that.

00:24:26:23 - 00:24:59:24
Unknown
Those are those pathways I showed you those repair pathways at the beginning of the chart. HRT negative. There's there's a benefit, but it's only if of less than a few months. And the hazard ratios okay, it's it's pretty good but the final on that was 0.68. Aerial three was another one that was done with a different PARP rucaparib which has been on and off the market as their company went bankrupt last year, a year and a half ago.

00:25:00:01 - 00:25:24:16
Unknown
They're now back with pharma and, and getting re marketed and retooled with the phase one study. We can talk about that. That should be out this year. So again you can see these curves best for BRCA slightly less for HRT and then not quite as good the intent to treat population. But even there it looked pretty good. And here's all the all the curves and all the all the different studies.

00:25:24:16 - 00:25:49:09
Unknown
So area three was Rucaparib in the orange and the blue is nova, which was niraparib. And then in purple is Solo two, which is a lapper and then there was a phase three, a phase two study 19 that included all subtypes because Solo two only did germline BRCA mutated patients with a handful somatic mutations that were in there.

00:25:49:11 - 00:26:25:10
Unknown
But you can see, look at the placebo, you can see that all those are pretty close around five plus months or 5 to 5 plus months. And then you can see the tremendous improvement based on the different subsets. And again, if you have a BRCA mutation, the most benefit from a PARP wildly crazy hazard ratios almost down to point eight, we need 80, you know, 80% or point to 80% improvement in outcomes versus if you're just positive, still very good, but not quite as strong.

00:26:25:12 - 00:26:49:20
Unknown
But still you're seeing hazard ratios below point five, still very impressive. And then you get into the all comers where they actually tested negative for homologous recombination deficiency and there's still some benefit 0.68 and I'll show you some later data in our frontline trials. So this is the newest and greatest data. This is the data that's all come out in the last few years.

00:26:49:22 - 00:27:21:19
Unknown
And the first one, we compare it to G2 18 because that's bevacizumab. So that's another maintenance strategy, right? Bevacizumab by itself. Solo one was a study that was conducted solely in those who had BRCA mutations. Okay? They could have germline or somatic. Most of them are all germline. Freema was a study with Niraparib in high risk women, and we'll show you the data from that, but took all comers in terms of molecular subtypes.

00:27:21:21 - 00:28:06:03
Unknown
And Paola one was bevacizumab plus olaparib. And again, very large trials get to 18 1800 patients. Paola One 800 patients. PMA 733 Solo one 391 So big trials. You can see how you can't completely compare these because there's some differences of when the clock starts. Georgi 218, started right after the surgery when they went on their chemo. These PARP trials started after they had a response to Frontline, to Frontline platinum, and then at the end of that they got randomized to maintenance, platinum or placebo, but they had to have a response.

00:28:06:03 - 00:28:34:15
Unknown
So that's one of the criteria that was in the in these trials. Okay. Different thing about Paloma. One is that it's an active comparator because the, the only one that didn't go up against placebo because it was a lapper plus. Beth versus Bev bevacizumab, okay, which is an antiangiogenic agent, meaning it keeps new blood vessels from forming, which we previously had shown improves progression free survival in ovarian cancer.

00:28:34:17 - 00:28:57:06
Unknown
So these are the types of patients that you see in these trials. The most the worst population was prima because they eliminated patients that had been to Bork down to no gross disease. And stage three, they excluded them because they were trying to get their end points to occur quickly so they could get catch up on the on the trial.

00:28:57:08 - 00:29:29:13
Unknown
You could see slightly different ways of testing for HRT. And I talked about the randomization point that being different 4 to 18 previously, you could see neoadjuvant was not allowed and you get to 18 when you give the chemo before the surgery, you can see the highest rate of stage four is done in the prima trial. So just to get a feel for these different trials and here's the numbers from these trials, these hazard ratios, they tell you what's going on across the entire curve rather than just the median.

00:29:29:15 - 00:30:01:08
Unknown
So if people say, well, the median at that's just at where 50% of the patients fail therapy or the therapy fails them, rather, you see the that line versus the hazard ratio where he looks at what's the difference across those curves, across their entirety. And you can see, again, same principles if you have a BRCA mutation, these are all the BRCA mutation mutated patients, of which solo one was only those patients.

00:30:01:08 - 00:30:23:06
Unknown
The solo one kind of drops out comparison wise after this. Okay. But the hazard ratio was an incredibly impressive 0.33. We have long term follow up that looks really promising that we're super excited about. So these again, are the patients that are BRCA wildtype, meaning they did not have a mutation, but they were already test positive. Again, look at these hazard ratios.

00:30:23:06 - 00:30:52:12
Unknown
0.50.43. Really impressive. Bev doesn't help and it doesn't make a difference if you're BRCA mutated or HRT positive with bevacizumab, but it does for the parts and these are the patients that do not test positive for HRT, but you still see some advantage here. Not for the Apollo one. We're bevels in the control, but you do for prima and we'll show you some other data that gives you some pause too.

00:30:52:14 - 00:31:13:20
Unknown
So this is solo one. And the reason I'm showing this, this is more recent data. It was updated, but I want you to look at those curves. They're just not going down. And we're now out at 96 months on this plot after almost 100 plus months. And you can see those curves aren't going down. This begs the question, are we curing more women with ovarian cancer?

00:31:13:22 - 00:31:36:04
Unknown
With this strategy in patients with BRCA mutations? The answer clearly, I think, is going to be yes. This is the lapper plus barve the the longer term data. And you can see again, when you get out towards six years, five years and beyond, there's a sustained benefit, even though you only gave the PARP in this case for two years.

00:31:36:06 - 00:32:04:10
Unknown
So sustained benefit there Niraparib. This is some of the follow up data for the longer look from the Prema trial. And again we're seeing as curves flatten out nicely. Okay. So we're excited about that safety profile. I think most of you are familiar with the differences between some of these different parts, but the big thing is bone marrow, diarrhea or GI fatigue.

00:32:04:12 - 00:32:27:13
Unknown
And those are the big ones that we usually see. And you can see the highest discontinuation rate was was with where we gave ARB and bevacizumab at the same time. But otherwise these drugs are pretty well tolerated. Again, looking at the side effect profile and then I mentioned the MDS and AML, but the more common things are, they're in the purple and the blue.

00:32:27:15 - 00:32:57:24
Unknown
Those are the more common things that we see with these PARP inhibitors. Okay. One other trial, this is what I was talking about with the Rucaparib was a frontline trial. This is the Athena Mono, which will have the data on meaning that that's also a part of this is being done within I-O, meaning immuno oncology drug. So it's also being given with nivolumab, but we won't have that readout for probably another year and a half or so.

00:32:58:01 - 00:33:30:10
Unknown
But you can see here that we'll have updated readout on overall survival very shortly. And we had the original read out on PFS that was in at ASCO. Now not last, not this past one in June, but the one before. So coming up on a year and a half. So here you see that the different again with the front line trials, you can see the medians, you can see with the medians and hazard ratios are if they're BRCA mutated.

00:33:30:12 - 00:33:52:18
Unknown
And I've added in another one, I snuck another trial in on you prime. That's a trial with Niraparib from China that also looks very promising. And if you look at the HRT test, negative press have hazard ratio impressive and we see pretty good hazard ratio with Athena 0.65 although again the median is not that great. But look at the big differences.

00:33:52:23 - 00:34:15:19
Unknown
You know, in those that are BRCA mutated in terms of outcomes are really quite different in terms of PFS. All right. So we have all these, you know, these guidelines now that sort of tell us what to do. And it would probably take us 10 minutes or so to go through all this. But it's all based on this data, It's all based on premise.

00:34:15:19 - 00:34:34:04
Unknown
So the one prima duty to 18 and then and then the same trials. So the big decision first is are we going to operate first or not? Are we going to new adjuvant or are we going to primary site of reduction? Second thing we're going to think about then are we going to do bevacizumab MAB yes or no?

00:34:34:06 - 00:34:56:23
Unknown
And then what is the molecular marker? If the molecular marker shows BRCA or HRT, we have certain options. If it's a test negative, we can still use a PARP, in this case Niraparib versus the others. The lab Ribas used with with the bev. So there's a lot of different things based on the indications from these trials that make a difference.

00:34:57:00 - 00:35:22:22
Unknown
Interest At time I'm going to skip over some of the resistance mechanisms and so forth here so we can get to the questions. So some of the things that happened that later on and you know, I started off with saying we've been relegated to front line maintenance, platinum sensitive maintenance and not so much treatment. And that's because we used treatment in this case, olaparib, which had very good progression free survival.

00:35:22:24 - 00:35:47:11
Unknown
But what we started looking at was overall survival from these and found that if if you had not been as heavily pretreated, you did really well in terms of overall survival, but heavier treatment, those patients didn't do very well. Hazard ratio actually went the other way, 33% in the risk of death. And so they started generating dear health care provider letters.

00:35:47:11 - 00:36:12:16
Unknown
So to keep their health care provider letter, they started coming out for all of them. Now, we don't necessarily feel that that this is something that is a real phenomena because there was so much crossover to pass in these patients. So it's not like we had one population that had PARP and maybe got more PARP and then another population where they didn't have that.

00:36:12:17 - 00:36:33:04
Unknown
Instead, it was incredibly high crossover rates as time went on because of the success that patients and their doctors had seen with the PARP inhibitors. So the patients that were in the control arms ended up getting PARP. So it's a little hard to account for when you look for five six regimens down the lane and try to attribute it all.

00:36:33:04 - 00:37:00:14
Unknown
It must be the PARP that causes that problem. So we started seeing that with all the area for this Rucaparib same problem. When they got to plot and resistant, the hazard ratio was 1.5. They didn't like that, so they pulled that one and got a letter. Then we saw a quarter with Niraparib and care for this either because again, the heavily pretreated patients didn't like this.

00:37:00:14 - 00:37:31:23
Unknown
So we spent the better part of the last year and a half pulling different indications. So these are the approvals now. And as and if you can see the slide very well, you can see the cross outs. So treatment indication for olaparib. We crossed it out for a number of of of those things in the treatment indication they're pretty much gone maintenance they've extensively limited that as well to largely BRCA patients in the platinum sensitive setting.

00:37:32:00 - 00:38:03:10
Unknown
So that's that's been a big problem too and a further taking this table from here to to where we are today with those being fairly limited to just BRCA mutated patients in some cases. H r d you might be able to get through, but no treatment there anymore. Now where are we going with all this? And this is really, I think, important as we look at this in the future.

00:38:03:12 - 00:38:29:03
Unknown
And really where we're going with this is combinations. So I mentioned the Athena Monitor, which we have the data, but we'll be getting the Athena combo where we have the checkpoint inhibitor Nivolumab, which turns the immune system on against the cancer cells. It removes the brakes that shouldn't be there because your your immune system should recognize those cancers as foreign.

00:38:29:05 - 00:38:51:21
Unknown
But unfortunately, that doesn't happen sometimes, and that's what allows the cancer to proliferate. So that's why these checkpoint inhibitors have been highly successful in many diseases. You've heard of things like KEYTRUDA. We don't usually use brand names, but people probably start nodding there now. Yeah, I've heard of that. We call it pembrolizumab AB. You can see that's in some of these trials as we move forward here too.

00:38:51:23 - 00:39:15:00
Unknown
So a number of very interesting trials that have or will report within the next year, year and a half. So again, we're super excited about this. We got a press release on the floor of five. This is a monoclonal antibody to see a 125. We've seen a long history with this negative trial, positive trial, negative trial, positive trial negative try.

00:39:15:01 - 00:39:41:23
Unknown
Every time we do the bigger, more registration and type trial becomes negative. And unfortunately, four or five with sort of a last ditch effort to do the trial the right way. And in the we don't have the data yet, but the press releases that it's a negative trial, which is very unfortunate and we were hoping that would not be the case duo has reported and this is the trial in this report it at ASCO this past year.

00:39:42:00 - 00:40:16:21
Unknown
So in Chicago, this is the data that came out. And you can see what they did is they they used up a in the orange, the maroon or the maroon, rather, not the orange. The maroon. You can they used bevacizumab as maintenance, a checkpoint inhibitor durvalumab, and then olaparib, a PARP inhibitor. So three different drugs versus in the second one, they did the the Bev and the Darva with a with with no olaparib.

00:40:16:21 - 00:40:42:16
Unknown
The olaparib was a placebo. I personally I don't know that, you know, they didn't do the olaparib bevel arm alone, which would have been much more informative. And so it's a little hard to know what the contribution of the derma durvalumab was in this. And so these are different arms here. I'm not seeing a big difference between the black and the blue curve.

00:40:42:16 - 00:41:21:06
Unknown
They're maroon curves clearly separates from the control arm. But for me, I'm not seeing a huge difference. But we're still working out subsets and so forth that so to see how this goes. So we're interested in these other trials where maybe we might get a better understanding of the contribution of the checkpoint inhibitor or the immune drug. And so what we expect key link, these are all of these are G trials that you can see will come out and then we'll see the Athena combo nirvana.

00:41:21:08 - 00:41:45:06
Unknown
And so, you know, part of the problem is that we didn't have we didn't have in a lab or of only arm in in Paola one and in then we didn't have the checkpoint inhibitors. So we're going to have a lot more information. And as I said, all these are going to report very soon. So we're excited to see all this new data.

00:41:45:08 - 00:42:16:15
Unknown
My concerns obviously are toxicity from combining all these drugs, not only physiologically or biologically, but also financially. So we'll see where it takes us. But I just wanted to wrap it up here to allow ample time for questions. So maintenance has really given us a great strategy for ovarian cancer treatment now that we have an effective and effective compound class of compounds with the PARP inhibitors.

00:42:16:17 - 00:42:47:19
Unknown
Till then, maintenance was not looking as favorable as it could or should. So we're excited that the PARP inhibitors have arrived and finally made maintenance therapy effective. Biomarker development is very important as we move through this and we're starting to understand the subsets from all these trials that have reported such as duo. But we'll also see the subsets from all those four or five other trials that will report shortly.

00:42:48:00 - 00:43:12:07
Unknown
Some at GIO, some at ASCO this year, some asthma this year and then some in the next year. But we'll have all those done. We should have almost all those wrapped up in about a year from now. And it will not only be the primary analysis, but also these subsets where we look at these different biomarkers to best understand who who've benefits from these different drugs and in what combination.

00:43:12:09 - 00:43:38:21
Unknown
So that's really key talked about combinations. And the next bullet point there with anti vascular such as bevacizumab, the immuno oncology drugs and the PARP inhibitors all being combined or or as doublets. We have to look at the cost effectiveness and the clinical value such as toxicity and everything else. We really see a transformation now in the outcomes of frontline ovarian cancer with parts.

00:43:38:23 - 00:44:00:11
Unknown
There's no doubt in my mind they should be used sooner if the patient's a candidate not not saved for later, because the greatest, the hazard ratio is basically a percentage of what the gain is. And in frontline, the difference is you can see that the numbers are so big. So you're getting, you know, where you're up to 30, 40 months, that type of thing.

00:44:00:13 - 00:44:25:20
Unknown
You're getting that that percentage of that gain versus when you recur, you get much smaller in terms of benefit. You make it the same ratio, but you're looking at less than a third of the number of months that are realized. So I think it's important to use these drugs in frontline. Surgery is still really important for ovarian cancer patients, and maximal removal of disease is still critical, in my opinion.

00:44:25:22 - 00:44:51:13
Unknown
I'm still concerned by the FDA's stance on OAC pushing the PARP only to almost frontline in some some platinum sensitive indications, and we may get more data from these trials that we see a change in label once again. So we'll see what happens. And again, I want to thank everyone who's ever been involved in the clinical trial because you're the one that's bringing new knowledge and gives us new options as we are here today.

00:44:51:15 - 00:45:22:16
Unknown
So thank you for doing that. All right, Maggie, I'll turn it over for any questions that we have. Great. Thank you so much for that presentation and being able to hop back on so we could now begin the Q&A discussion. You can still submit questions in the Q&A section at the bottom of your screen. We will try to get through as many questions as possible, but we may not be able to get to all of them due to time constraints.

00:45:22:18 - 00:45:52:20
Unknown
So by far, the most ask question is really around how long to stay on a PARP inhibitor, especially the safety benefit of taking one for a longer than, say, two years. So how long should patients stay on a PARP inhibitor? Yeah, I knew this would likely be a question. It's one that I get in the clinic every day, so I'm sure I spy that.

00:45:52:22 - 00:46:39:17
Unknown
So thanks for bringing that up. We don't know the answer. We you know, these these numbers were flushed rather arbitrarily, just like B&B was given 18 months. All the parts were given for two years except for Niraparib, which was given for three years. So, you know, do we know the answer as to which is better? We don't. You know, I think we'll get some more long term follow up from Prima, which will be helpful in terms of, you know, what's that doing or MDS, myelodysplastic syndrome and AML rates, which would really be the main concern because as you know, patients that are on it, two years, three years, they're usually tolerating it pretty well.

00:46:39:17 - 00:47:01:08
Unknown
The ones that didn't tolerate it very well have long been weeded off. So they're usually tolerating the drug pretty well. They've learned how to use it. They've learned how to adapt and and bring it into their life. So that doesn't you know, they've learned when to take it relative to food, relative to bed, time for sleep and for for lack of nausea and things like that.

00:47:01:10 - 00:47:23:20
Unknown
So we were really usually in pretty good shape with these patients. So I think the real question then is, is how do you make that determination? And I think that for me, it it's it's it's a shared decision making where I talk to them about the pros and cons. I had a patient last week who's, you know, had really high risk stage ovarian cancer.

00:47:23:22 - 00:47:44:18
Unknown
She's in a number of support groups. She's very nervous about coming off. I said, well, we don't have to You know, she's on one of the two year perps. I said, Well, look, Niraparib data is out to three years. Why don't we do another three months and see how we feel? And my goal is to get her off by three years, but we'll see where that goes.

00:47:44:18 - 00:48:15:19
Unknown
But I have no rapport. Patients that have insisted on staying on and I've. I've done it. So, you know, I think it's it's really an individual decision until we have more data in general, I think you're probably safe to come off by three years. Are you safe to come off by two years? You probably most certainly are. And so much so that there are some people proposing a study right now looking at one year versus two years.

00:48:15:21 - 00:48:49:00
Unknown
So, yeah, so that gives you some safety if you're like, look, I really don't in a lot of patients are like this. I don't really feel myself. Yes, I've learned how to control the symptoms, but I don't feel 100% myself. That's the case. And it's two years I would come off. Yeah. And so sort of along those lines about people who maybe don't tolerate it as well, we're also getting a question around reducing the dose and when patients have to do that.

00:48:49:00 - 00:49:18:19
Unknown
And how confident are you in the efficacy of lower doses or how do you feel about that? Yeah. So for me, I think it depends on where we started. So with with the wrapper you may or may not be familiar with, but they do we do individual starting dose based on the weight of the patient and the platelet count.

00:49:18:21 - 00:49:47:16
Unknown
So very small. We start at a lower dose and platelet count was was low. We started the lower dose. Having said that, if we're then coming down another dose, just because you don't feel well, we're now like a third of the dose that makes me nervous. But other than that, that first dose reduction, we're probably fine. These are drugs that bind at a very high affinity and probably do their job at that first dose reduction coming down to dose levels.

00:49:47:18 - 00:50:21:02
Unknown
We just don't have the data. But I have no problem coming down one dose level if it if it helps tolerance and keeps patients on on the drug. So the going down, too, doesn't mean it won't work. It's just that we don't have data to back it up. Okay, great. Thank you for that. And then we're also getting a lot of questions around like PARP inhibitor use when there's not genetic mutation or other biomarker presence.

00:50:21:02 - 00:50:48:04
Unknown
So what are the considerations of using a PARP inhibitor in those instances? Yeah. So you have say front line, for example, you would have the option of no maintenance not doing anything and then you're sitting there with the going back to the beginning of my talk, will you say, well you see you're just going to have a 75% chance of this coming back and you're not going to do anything about it.

00:50:48:06 - 00:51:15:06
Unknown
But, you know, I have many patients that, you know, that are frail, that barely got through the chemo and they just don't want to do anything else. And that's fine, but most do, in which case then if they're already negative, BRCA Wildtype mean, a mutation in their HIV test is negative. You have the option of niraparib by label or you can do bevacizumab.

00:51:15:06 - 00:51:41:11
Unknown
And so there's your two options there. The hazard ratio is pretty similar for the clinical benefit. The hazard ratio. So from that prime study, which is another niraparib study that was done in China looks much better. And then the Rucaparib looked good, reinforcing the idea that you probably have a 30 plus percent chance of reducing your risk of progression.

00:51:41:13 - 00:52:14:04
Unknown
Now can you do Bev plus PARP, you would be off label in that circumstance, the Bev plus PARP and specifically olaparib based on the Pilar one study is the indication there and that's only for those that test HRT positive. So that's sort of where that puts that. So becomes a discussion with your physician what you think you're best going to tolerate as it's going to affect subsequent treatment and so forth.

00:52:14:04 - 00:52:44:03
Unknown
But there's certainly a strong rationale for going onto a PARP and slightly less for me, but still there. Is that going on? Bev Bevacizumab Okay, great. Thank you. And then it looks like there may be some confusion about the role of folic receptor alpha. So I guess maybe you could clarify how that does or doesn't play a role with PARP inhibitors, doesn't play any role at all.

00:52:44:03 - 00:53:22:09
Unknown
So for receptor, Alpha is a target. It's overexpressed in about 80% of ovarian cancers, but highly overexpressed and only about 30 to 40% of ovarian cancers and more of a toxin MAB So Avastin was recently had the data come out at ASCO and the accelerated approval had occurred previous to that. And then the pivotal trials come out. And so people are using Marv, as we call it, in the platinum resistant setting for treatment.

00:53:22:11 - 00:53:55:15
Unknown
So it has nothing to do with maintenance, has nothing to do with pops. And so that's where testing can be done and it can be done upfront so that we know whether that's a candidate or whether you're a candidate for that. Some of the other antibody drug conjugates of which Marv is are in studies looking at using cutoffs that are lower than that 75% expression for for folate receptor alpha staining.

00:53:55:17 - 00:54:28:04
Unknown
So again, talk to your doctors if you're in a platinum resistant setting or what trials are out there with such agents. Great. Thank you for that, for clarifying that for people. If the cancer recurs, should the same PARP inhibitor be used? If you tolerated it really well and you didn't progress on the PARP, there's absolutely no reason to go to switch if it gets a little fuzzier than that.

00:54:28:04 - 00:55:10:24
Unknown
The integral wasn't as long as you'd like and maybe had some side effects. I for one, the biggest reason to switch would be for symptoms. So we think the toxicity profiles are slightly different. We don't think there's a big difference in efficacy between between the three. Okay, Thank you. And then this person is asking for your thoughts about long term super responders and the same treatment in what see in and going off treatment.

00:55:11:01 - 00:55:42:24
Unknown
Yeah, I did have a number I'm trying to see which one I think this person was has been on it for almost ten years. Yeah that's like it. Going back to that discussion of, you know, after three years, you're probably in good shape. After two, you're probably fine as well. I think ten would be. Yeah, I'd come off and unfortunately we're almost out of time, so I am going to try to get through one or so more questions.

00:55:42:24 - 00:56:20:07
Unknown
But I'm just mindful of that. And so just wondering your thoughts on PARP after PARP. Yeah, not a lot of data and there's limited data array of study. If you want to look up a study, it looks like Oreo showed that data, but it was pretty small cohorts. If you believe in PARP after PARP, it reinforces it. If you then you'd say these are unicorn patients and it doesn't change my opinion.

00:56:20:09 - 00:56:45:17
Unknown
But for me personally, I if I have a patient sitting in front of me, I will give them the benefit of the doubt. If they have BRCA mutation or HRT positive, I make it. I make them prove to me that their tumor is not going to respond before I dismiss a very, very effective agent. So did they progress on a part of the answers now?

00:56:45:17 - 00:57:09:07
Unknown
I'm probably coming back to it. Yeah. Great. Thank you for that. And it looks like we're out of time. So I guess I just want to end it with is there anything else you think that you think we haven't covered or anything that you're particularly looking forward seeing the results on in the realm of PARP inhibitors or just anything that you want to add?

00:57:09:09 - 00:57:33:07
Unknown
no, it's just that clinical trials are really what it's all about. And if we can, you know, in your groups and encourage clinical trial enrollment, it's really how we make the most progress. The and so I think that's really incredibly important. One question here real quick, perhaps ever appropriate for low grade serious? We don't need data on that because they grow in a very different way.

00:57:33:09 - 00:57:57:23
Unknown
And then it says our primary peritoneal room or primary peritoneal, I include it in ovarian. So primary peritoneal cancers can respond. The parts, but the low grade serous histology, we usually don't. Thank you. Maggie, appreciate it. Yes. Well, thank you so much, Dr. Herzog, for such an informative program. And thank you to everyone who participated and submitted questions.

00:57:57:24 - 00:58:28:18
Unknown
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00:58:28:20 - 00:58:42:10
Unknown
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