to be with you. And as usual, I feel like the opening statement I say in front of every virtual talk is that I wish we could be together in person. And that is truly the case. So thank you for joining us today. I'm gonna give a little bit of an overview of PARP inhibitors across the spectrum of ovarian cancer. It's been obviously a complete game changer, as we say, because it has changed the landscape. These are my disclosures. So, you know, I always try to find a nice way to share with how we can potentially feel that there may be an impact from this kind of treatment. And I use this slide a lot because I think it illustrates kind of the burden of disease, but also the value of what I think has been really the innovation of targeted therapy. So you can see here in this yellow and red lines that the incidence rates and the mortality from ovarian cancer in the United States, at least appears to be declining over the last two decades, but it's declining at the same rate. And in the background of that decline in both mortality and incidence, we see a increase in the number of patients that actually have disease at any one time. This is what we call prevalence. And you can see that around 2014, there was a big pivot in what would be the natural trend for this disease. And I think that what we're seeing here is that while the patients aren't necessarily being cured, they're actually living longer with their disease. And that's really a reflection of the dramatic improvement on our therapies. So if you look at the natural history of ovarian cancer, it kind of looks like this. We have patients presenting with symptoms and they undergo surgery or a neoadjuvant chemotherapy, induction phase, followed by an evaluation, consideration of maintenance. And this timeframe from diagnosis to first progression has changed dramatically in the last two decades. It was very common for us to talk about a one year progression for survival from diagnosis. Now it's much more common for us to talk about more than two years into the first progression. And hopefully, with new therapies, maybe we won't have so many progressions and we'll have more cures. But for the majority of the patients that do progress, there's a series of chemotherapy, maybe surgery, that becomes part of the natural approach for care. And in that process, we used to say, again, that was about a year after progression was what we expected patients to live. Now it's more than three years. And I think this has become important because the treatment landscape has now been annotated by the incorporation of targeted therapies, predominantly PARP inhibitors and antiangiogenesis inhibitors in the maintenance and treatment settings. And at least in the United States, you can see that the approval of PARP inhibitors are now being, have now been done for patients with third and fourth line therapy as treatment. So shrinking tumors as treatment, but also in primary and secondary switch maintenance strategies. And so it's because of this, along with the, I would say, with the better overall care of patients, along with the availability of, of, but it doesn't have as a PARP, as a antiangiogenesis inhibitor that joins PARP that allows this, I think the statistics to set. So why are we so interested in PARP inhibitors? Well, we know that we rely on chemotherapy as a strategy to, to cause differential impact on cells that are rapidly dividing. And we know platinum, for instance, causes DNA addicts to occur so that there is a strand breaks and stall replications, fork stalling that would lead to cell death. Well, we also know that single strand breaks occur very frequently. And PARP is among the repair targets that are available to help this fix this very common lesion. But when a double strand break happens, it requires a sophisticated mechanism that is highly toxic to the cell, but a sophisticated mechanism to actually repair that. So the thought process here, when we learned about how PARP inhibitors might work with repair, with respect to their normal function, if there is loss of DNA genetic material on a single strand, the template for the second strand is available to be read and PARP will engage this process and recruit various nucleotides to fix this defect based on the template read. But if this is blocked or trapped on the DNA so that a double strand break occurs, that it requires a more sophisticated mechanism as I mentioned, to induce a repair. Now, how does that happen? What we learned is that there is a, that the two ends of these DNA, since there's loss of the template, we have no way to know what was filling here. And so we see a trimming back of each individual strand of the double strand break. And we see invasion into the sister chromatid where there is an intact read on that gene. And you can see here in this process that with the template here, we have a single strand that can be repaired and ultimately rejoined to cause a complete repair of that gene with the known genetic material. So under normal conditions, a normal cell can do this or a cell that has lost this ability or has regained this ability once it had been previously lost, such as a reversion mutation can lead to cell survival. So our strategy with PARP in ovarian cancer and other tumors is that we induce the probability for a double strand break and rely on the inability of the cancer cell to repair that because it has a deficiency in this mechanism. And that's called synthetic lethality or synthetic sickness. Now, this was demonstrated over 15 years ago in two papers published in Nature. And what you can see here is that these cells, these are, this is a cell line experiment of two cell lines that are either homozygous or heterozygous positive for intact BRCA gene and one that has bioallelic loss. And in the presence of a PARP inhibitor, you can see that there's a thousand fold increase in cytotoxicity with a PARP inhibitor in the presence of this genetic state. So we have very strong evidence that this process is valid or this hypothesis can be demonstrated in at least in this case in vitro. So we became very interested in this ovarian cancer because these genes that regulate the process of homologous recombination repair are frequently altered in ovarian cancer, newly diagnosed ovarian cancer patients. And we're all very familiar with that BRCA mutation, at least in the germline, we see about 15% of patients. And in tumors, we see another maybe 5% to 7% of patients. And then there is a host of other genes that are responsible for the compliant repair of this process that can, doesn't necessarily mean they have to, but they can be responsible for a homologous recombination deficient state. And so what we've learned is that if we assess the genome for what we believe would be the result of having deficient homologous recombination, we can capture that by studying factors such as loss of heterozygosity. And so when we look at loss of heterozygosity across the genome in patients whose tumors are deficient in BRCA, we see a number of genes, which are a number of areas on the chromosomes where we see this particular feature of loss of heterozygosity. But we also recognized that there were a number of ovarian cancers that demonstrated loss of heterozygosity, but they did not carry a mutation in BRCA. And so we called this the BRCA-like signature for HR-deficient BRCA wild-type phenotype. And of course, this would be distinguished from a situation where loss of heterozygosity was low in the presence of wild-type BRCA. And so our thought was that if PARP inhibitors work in the BRCA state, they should work in the loss of heterozygosity or BRCA-like state, even if BRCA is mutated, or even if BRCA is wild-type, excuse me. And so we've come up with various tests, and these are starting to expand around the world to identify this vulnerability in tumors. And this is one such test by the Myriad company that assesses this loss of heterozygosity, large state transition and telomeric allelic imbalance that allows them to score the likelihood that the cancer cell actually has this deficient state. And so you can get this now on several different reports from various vendors now. But I want to highlight one thing before I leave this topic, and that's that BRCA mutation, irrespective of loss of heterozygosity assessment is always considered a amalgamated combination deficient state. So this was some very nice work that was presented by Charlie Gorley a couple of years ago that took the results of the SOLO-1 study, which we remember was all BRCA-1 patients and all BRCA mutation tumors. And I will highlight this study obviously in a minute. But we know the effect of the therapy for patients as in the all-comer population. And that's really represented by these solid lines in the background. But what they looked at in this total population is that there were a number of patients who had low scores, not a lot. You can see it was 27 patients here in a lap rib and in the placebo group was 19. And if we use a more restrictive criteria was 43 and 22. So about 65 patients in the total SOLO-1 population that had BRCA mutated tumors that had low levels of loss of heterozygosity. So it's not a perfect evaluation of potential vulnerability to PARP inhibitor or reflection of homologous recombination. We're gonna have some false negatives and false positives. Okay, so we've had tremendous success with these drugs and these are why we're so excited about it. We have now five, I have four on the slide but there's a fifth one I'll mention to you which was presented at SGO just recently. They had a test of the hypothesis in the primary setting. So SOLO-1, PRIMA, PALO-1 and PRIME were all trials that were looking at the inhibitors, lap rib and rap rib. And then valiparib was studied in Velia. I carve out Velia as a separate study in that series because this particular study used PARP inhibitors valiparib during the chemotherapy as well as a maintenance strategy. All of these were other studies. These four other studies were given as primary maintenance. And they have several different variables which I don't have really a time to go through that distinguish them but ultimately all of these trials were quite positive and I'll briefly go through them here. So SOLA-1 was a study that was looking at patients whose tumors were BRCA mutated. Most of these patients were identified by a germline mutation in BRCA1 or BRCA2. They all had to have surgery and they should have had a complete response if there was disease left behind. They were randomized two to one, to lapar versus placebo. And this was in the capsule formulation and the primary endpoint was investigated or assessed PFS. All of these patients who were to go on study were to have two years of treatment unless they progressed, but there were a few patients who were allowed to continue beyond two years if they demonstrated a response and thought would have clinical benefit. So at the initial report, this is the ASCO presentation, ESMO presentation that demonstrated a huge difference between these curves with a hazard ratio of 0.33. And this was followed up by a publication a year later, a presentation a year later in publication now subsequently by Susanna Banerjee, which continues to show these big differences in curve. Now, some very interesting components of this that I think are noteworthy. One is that after two years, which would have been the termination of the laparib treatment, we do not see that the curves come together, collapse, that so-called banana shape. They stay apart and they stay apart out to over five years. The other is that the event rate between the placebo and the treatment seems to be most notable during the first 15 to 18 months. But then after that time point, the event rate, even while taking the laparib, the event rate is the same as we see on placebo. And this might be a very significant observation that tells us that if we're going to use these therapies, we need to use them early because they are treating, as we would consider normal treatment, they're treating residual disease and are, in this case, obviously are being successful. Now, there were a number of secondary end points and too many to go through. The one point I wanted to highlight was that we saw this effect being very similar in both low-risk and high-risk cohorts. Now, I'm not a big believer that there is a low-risk advanced stage ovarian cancer patient, but prognostically they have different potential outcomes. And in both of these subgroups, which had been previously used to discriminate patients who were candidates for bivacizumab, at least in the presence of the PARP inhibitors did not seem to differentially affect them. You can see that there was effect in both of these cohorts. Now, PRIMA was a trial that was looking at a different PARP inhibitor called norepirib. It was randomized two-to-one against placebo in patients that were considered to be prognostically higher risk. And what I mean by that is that many of these patients had neoadjuvant chemotherapy, many of them had suboptimal cytoreductions, and so they were more likely to have disease at the completion of their primary therapy, or at least have the probability for recurrence. This particular study was amended midway to evaluate the weight and plate criteria to see if individualized dosing would be more beneficial to toxicity. And it had a hierarchical step down. So instead of just focusing on the BRCA population, it was looking at the BRCA and the hemoglobin recombination deficient, but BRCA wild type population that was combined together as called HRD, and then an attempt to treat population. And of course, you guys know this study well. It demonstrated, again, a very substantial effect between the two arms. Now, in this particular graphic, we see that it was followed out to 28 months. The therapy duration in this study was up to three years, so even beyond this time point. But you can see in this primary endpoint of the hemoglobin recombination deficient population, there was a big benefit. And of course, it would be less amazing, I should say, in the overall population because it included patients with hemoglobin recombination proficient type tumors. And the third study from that wonderful year we had with the introduction of PARP in the frontline setting was the PALA-1 trial. And this was, again, a frontline study that was looking at patients who got induction chemotherapy with Bevacizumab, with Bevacizumab. So this is an add-on study to GOG218. So it looked at Paclitax, Carplaten, and Bevacizumab, and at the time, followed by Bevacizumab. And then at the time of that completion of primary therapy, they randomized to LABOR versus placebo. And this was done in newly diagnosed high-grade serosovarian cancers. There were two primary endpoints that were assessed in this. One was the investigator-assessed progression for survival for the entire patient population. And the second was to look at PFS2. That was the second analytical endpoint. And again, what we showed here was that there was a separation curves hazard ratio of 0.59, which amounted to a tremendous reduction in the risk for recurrence. But I remember, I wanted to highlight here that remember that Bevacizumab, which would be this blue line, was better than a placebo in GOG218 and in ICON7. But of course, we don't have a placebo arm here to know what that magnitude effect is. So this 0.59 represent a reduction in the hazard for progression or death against an active control. So not against placebo, but an active agent. Now, there was various subgroups that were also evaluated here, and they're listed here. But I point this out because in the test-negative patient population, so BRCA wild-type test-negative, but for hemoglobin recombination, there was very little difference seen between these two curves. And while this was not an analytical endpoint, it was viewed on as, by the regulatory agency, at least in the United States, to be a non-effective potential sub-cohort. And they decided to carve that cohort out of the primary endpoint and approve it only for patients who have HRT test-positive tumors. As I mentioned, PFS2 was a secondary endpoint. Many people don't remember this, but it actually has a P-value because it was analytical and based on the probability or the significant results seen in the primary endpoint, which was PFS1. And you can see that in this population that the tails of these curves do separate and represent a little over 20% reduction in the hazard for progression, which I know is quite encouraging. Again, in this cohort, there was a subgroup analysis looked at for high-risk and low-risk. So that artificial category of patient. But this particular situation seems to be even more important, I think, because remember, bevacizumab was a, in many countries was just, its approval was dependent on this high-risk or low-risk category. And what we see here very clearly is that in the presence of parpengivitor, once again, that there does not seem to be any difference in the cohort. In fact, if you look at the difference in the quote, lower risk test positive patient population, the hazard ratio is less than 0.2. So very substantial effect. So if you put these together, you basically can see that all of these long bars that you see here on this graphic represent cohorts of patients that are annotated by some measure of mollusk recombination deficiency. And added to this, this year, and I'll close with this, was another study that was brought to us, the PRIME study. This was conducted largely in China. And this was looking at Naraprev as a maintenance strategy, very much similar to the PRIMA study. But the big difference here was that the individualized dosing was made a primary evaluation point rather than an amendment mid cycle. But again, and they also took a little less high risk cohort of patients. So more typical real world patients and stratify them by genomic BRCA status, HRD status, and then of course, their response to treatment and neoadjuvant. And the primary endpoint here was to look at progression-free survival by a blinded independent review in the intent to treat population. So there are a number of subtle differences between this and PRIMA. But one of the key take-home points we got from this study was to look at this prospective use of an individualized starting dose. So again, this is the patient demographics that were presented at the meeting. And you can see it differs a bit from the PRIMA study because they had less stage four patients. They had more patients with a complete response to therapy, but a similar kind of breakdown of patients with germline BRCA. And you can also see that our optimal post-op residual was higher in the study. So a little bit prognostically lower risk cohort. But once again, we saw in that lower risk cohort, a very substantial effect of the treatment with a hazard ratio of 0.45. And this is in the entire intent to treat population. So both BRCA, HRD, and wild-type patients are wild-type tumors. You can see the difference there. So quite substantial. There was also interest in looking at the homologous combination subgroup. So this would have been more along the lines of the patients that were reported out in PRIMA, excuse me, in PALO1. And you can see once again, a very strong treatment effect against placebo. And what I think is most interesting about this is that they were able to now validate prospectively that there was a reduction in the rate of high-grade, predominantly hematologic toxicity by using this individualized starting dose based on the weight and the platelet count before therapy. Again, many of us feel very comfortable now using this type of strategy for this particular perpetrator, but we can see that it bore out. So we're very excited about this field because very soon we will have the addition of four new, four studies, which will provide additional information predominantly with the introduction of immunotherapy in the frontline setting with these drugs. The first that we'll hear data from is the ATHENA study, which will be evaluating rupcaprab versus placebo. That'll be, we call that a phenomonal, mono. We believe and we hope that this will be available to us at ASCO this year. That will then be followed probably shortly after by first, the OB43 and OB46 or 2000 trial, and the ATHENA duo, which is to look at rupcaprab and the volumab versus placebo. So we're very excited about this framework of investigation as it is proceeding along. And we hope that we'll be able to improve our outcomes and our patients even better by the incorporation of these very important strategies in frontline ovarian cancer. And with that, I'll close. And thank you again for giving me the opportunity to speak and to adjust the schedule a little bit so I can make my other meeting. Thank you so much.

PARP inhibitors

ovarian cancer

treatment

overall survival rates

BRCA mutation status

combination with immunotherapy