Good afternoon, welcome everyone. Today we will review and discuss early phase I monotherapy results from our first in-human biomarker-driven phase I/II TRESR study of our ATR inhibitor, RP-3500, in patients with advanced solid tumors harboring synthetic lethal genomic alterations, which hereafter we'll refer to as our TRESR or the TRESR phase I trial. The call will begin with an introduction from our President and CEO, Lloyd Segal. Our lead investigator on the TRESR trial, Dr. Timothy Yap of The University of Texas MD Anderson Cancer Center, will then provide a recap of the data he presented at the virtual AACR-NCI-EORTC cancer meeting earlier today. Dr. Maria Koehler, our Executive Vice President and Chief Medical Officer, will then discuss next steps on RP-3500. This will be followed by concluding remarks by Lloyd and Maria. Lloyd, Maria, and Dr. Timothy Yap, along with Dr. Michael Zinda, our Chief Scientific Officer, and myself, will be available for Q&A after the prepared remarks. Questions can be submitted at any time electronically via today's webcast platform and will be answered at the appropriate time. Before we begin, I would like to remind you that we will be making forward-looking statements during the call. Various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for the purposes of Private Securities Litigation Reform Act of 1995. Forward-looking statements are based upon our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and our stage of development. There are a number of reasons why our results may differ materially from these forward-looking statements, and we refer you to our latest SEC filings, where you will find a more detailed discussions of these risks and uncertainties. In addition, any forward-looking statement represents our views as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so even if our views change. As a reminder, the audio and slide from today's event will be made available on our website later today. I will now turn the call over to Lloyd. Thank you, Steve, and welcome everyone to this virtual event. I am delighted to have this opportunity to share our highly anticipated early monotherapy data from our TRESR phase I study with you all today. Before doing so, I'd like to take this opportunity to thank our entire team for their hard work and dedication, and for getting us one step closer to fulfilling our mission to be the leading precision oncology biotech focused on novel synthetic lethality medicines that meaningfully improve the lives of cancer patients. As Dr. Yap noted earlier today, this data set is unprecedented in its scale, scope, and innovation for an ATR inhibitor monotherapy trial, and we believe it sets a new benchmark for the field. This is a testament to Maria and the tireless and innovative team at Repare, who have delivered this early trial result with the highest levels of integrity and rigor in a tremendously short period of time. I would also like to thank all our patients, their families, and physicians, and other caregivers, without whom all of them we would not be here today. Finally, I would like to thank and acknowledge Dr. Timothy Yap of MD Anderson, our distinguished guest and principal investigator on the TRESR study, for his critical participation and for joining us here today. Repare is singularly focused on DDR synthetic lethality in the broader field of precision oncology, and we are proud to have built such a robust pipeline of product candidates using our proprietary SNIPRx and STEP2 technologies. Our focus today is to discuss our exciting early monotherapy results on RP-3500, but as highlighted here on the right, you can see that we expect next year to be a data-intensive time for us, with anticipated milestones across all our most advanced programs, including not just final monotherapy phase I data for RP-3500, but also early PARP combination data for 3500, as well as early phase I readouts for RP-6306 and IND-enabling studies for our Pol Theta program later next year. On slide 8, we highlight by histology the potential we see in our platform technology to identify additional expansion opportunities for RP-3500 within a broad range of clinically relevant clinical populations representing unmet medical needs beyond ATM loss, our initial target of interest. The expanded patient opportunity we have ATM alterations to approximately a 10% prevalence when we include our additional 16 STEP2 genes. The data Dr. Yap presented earlier provided early insights into these patient expansion opportunities identified by our SNIPRx platform for ATR inhibition, and we believe has provided early clinical validation for the use of our STEP2 process to prospectively identify patients with tumors predicted to respond to our clinical candidates. Here we highlight the scale of innovative trial design and execution our team has achieved in what we see as a very short span of time, given that our trial started enrolling patients in only July 2020. I'm glad to announce that as of the cutoff of August 15, 2021, we enrolled 101 monotherapy patients into our TRESR trial and achieved the trial's critical objectives of identifying a recommended phase II dose and schedule. RP2D and schedule were the core objectives of the phase I portion of the TRESR trial, and we're pleased to report that this important objective has also been achieved today. Before I turn the presentation over to Dr. Timothy Yap of the MD Anderson Cancer Center, who will walk you through this exciting data set that he is reprising from earlier today at the conference, I would like to note that the opinions expressed during this upcoming discussion belong to Dr. Yap and do not necessarily reflect the opinion of his affiliated institution. Dr. Yap, please go ahead. Thanks very much, Lloyd, and thank you all for being here. Very excited to share some of the data that were presented earlier today at the meeting. Next slide, please. These are my disclosures. Next slide, please. Sorry, I was having an issue with my audio. As you can see, in terms of the background, DNA damage, especially DNA double-strand breaks and replication stress, really activate the DNA damage response or DDR with the protein kinases ATM and ATR sitting at the apex of this signaling network. Really targeting the ATM/ATR axis through synthetic lethality is really an attractive therapeutic opportunity, which really has led to the clinical development of different ATR inhibitors, including the potent and highly selective ATR inhibitor, RP-3500, as shown on the right-hand side, which has indeed demonstrated single-agent activity in different tumor models across different histologies and DDR defects. Importantly for this program, Repare's CRISPR-based STEP2 strategy really has expanded the molecularly driven patient population beyond ATM alterations, as Lloyd has alluded to already, and they've identified 16 additional predictive biomarkers of response for sensitivity to RP-3500. These will be referred to as the STEP2 genes during my presentation. Next slide, please. This is the clinical trial design. You'll see here that the inclusion criteria are pretty standard for phase I trial in terms of patients being at least 18 years of age with advanced solid tumors that were very highly refractory, resistant, or intolerant to standard therapies. What was really important is that every tumor, in terms of their molecular selection, was centrally reviewed to have a confirmed deleterious STEP2 alteration. This was centrally reviewed independently here at MD Anderson by our Precision Oncology Decision Support Group. Every patient needed to have a deleterious STEP2 alteration. All patients were otherwise fit for clinical trial, ECOG performance status of 0-1. Hemoglobin cutoff was 9.5 grams for decilitre. Platelets, pretty standard at least 140, ANC of 1.7 or greater. You'll see the primary and secondary endpoints and exploratory endpoints, pretty standard for a phase I trial in terms of establishing the safety, tolerability, and recommended phase II dose and schedule. Also looking at PK/PD. We had a huge emphasis on really determining and confirming PD in paired tumor biopsies. Also, of course, looking at preliminary anti-tumor activity, even though this is a phase I study. Also very exciting, very interesting data to look at the kinetics of circulating tumor DNA. Next slide, please. Before that, it's very important to note, of course, that these are early data. The data cutoff was just above a year beyond that. August 2021 was the data cutoff. Already at the data cutoff, you'll see that we had a total of about 101 patients, males and females, pretty generally well-balanced. More females than males because of the preponderance of ovarian and breast patients. Median age, 63. All patients had an ECOG performance status of zero-one. You'll see there lines of therapy, pretty heavily pre-treated. Half of patients really had four more lines of therapy, very heavily pre-treated, including prior platinum, prior PARP inhibitors, and also prior IO. In terms of the tumor types, most commonly, we included patients with ovarian, prostate, and breast cancers, as well as pancreatic cancers and sarcoma. Most common genotypes included those with ATM alterations, BRCA one and two, CDK12, and also other STEP2 alterations as listed there on the right-hand side. Next slide, please. Here are the results. Essentially, we tested single-agent RP-3500 at multiple different doses and schedules. We used an adaptive Bayesian design. What's so unique about this trial, you'll see the large cohort sizes to really ensure confidence that we were making the right decisions in establishing the MTD and a recommended phase II dose. I really think there is strength in numbers. You'll see there on the right-hand side, just going through this, we started off at lower doses before escalating up, firstly, exploring a 5/2 schedule before moving to a 3/4 schedule. As shown in the green boxes there, we have established the MTD and recommended phase II dose at 160 mg QD, once a day, three days on, four days off. You'll see that we looked at this in a total of 24 patients and only had one DLT of anemia. We also looked at alternative doses and schedules so that we had plan B for patients if and only if they required a dose or schedule reduction. You'll see there again, we also explored 160 mg QD, three days on, four days off, or two weeks on, one week off. You'll see again a large number of patients, 18 patients, but only one DLT. We also explored a slightly lower dose of 120 mg QD, three days on, four days off continuously, and we did this in 25 patients, without DLT issues. Overall, I think what's unique about this whole trial design are really strength in numbers in terms of building confidence that we have indeed established an optimal maximum tolerated dose in RP2D. In terms of the DLTs, I will discuss that in the coming slides, but they were certainly consistent with what we have seen with other ATR inhibitors in terms of anemia. What was very pleasant to see was the really void of any other toxicities that were observed. Next slide, please. As you can see here, I've shown the toxicities in terms of the treatment emergent adverse events. The 5/2 schedule on the left, 3/4 schedule in the middle, and all patients on the right-hand side. Where I would like to draw your attention to is the anemia, which I've boxed up there in green. You'll see there with the 3/4 schedule, which is the schedule that we have established as the recommended schedule, grade 3 anemia really down at 14.5% in a total of 76 patients. Again, strength in numbers and a very low rate of grade 3 anemia. What's also important is that there were no grade 4 anemia observed on this clinical trial in 101 patients. Importantly as well, beyond anemia, we did not see neutropenia or platelets as a major issue. You'll see there that grade 3 toxicities were observed in maybe 5% of patients or 4% of patients with neutrophils and platelets respectively. These were really seen at doses that were beyond the recommended dose. Other toxicities that may be due to off-target effects, you'll see there very low rates of grade 3 toxicities in terms of fatigue, anorexia, nausea, and other GI side effects, really 1%-2% observed in patients. Overall, we were very confident and are very confident that we're establishing the MTD and recommended phase II dose at 160 milligrams QD, three days on, four days off, as we move forward to develop this drug as monotherapy, but also in combination with other agents where I think these toxicities are so important to bear in mind. Next slide, please. In terms of the anemia, this slide really just shows that anemia was indeed the most common cause of dose interruptions or modifications, These were really at low numbers. Again, at the preferred 3/4 schedule, dose interruptions, reductions, and transfusions were infrequent, and there were really no discontinuations related to RP35 adverse events. Next slide, please. In terms of PK, we showed that the half-life was approximately 6 hours. Cmax and AUC was linear and consistent across different doses. The doses of 100 milligrams QD and above were actually achieved predicted efficacious RP-3500 exposures. We did compare QD and BID dosing schedules, there really wasn't major differences in target coverage between both of these regimens. Therefore, a QD schedule was picked to move forward. We also did a food effect study and showed that RP-3500 can be given with and without food. Next slide, please. As mentioned, there was a big emphasis to confirm pharmacodynamic activity, and you'll see here robust pathway modulation in a total of 21 paired tumor biopsies, which is pretty impressive for a phase I trial. You'll see really consistent and statistically significant on-treatment increases of both gamma H2AX and phospho-KAP1, which are DNA damage-induced markers that we use typically in these ATR clinical trials. These were observed across different tumor genotypes. Next slide, please. Here are the efficacy data. I should mention that this is an early readout. The therapy is still ongoing, and more than half of all patients are on treatment. You'll see that as indicated by the green arrows. You'll see here that clinical activity was really observed across different cancer types and also STEP2 alterations. These responses included prostate cancer patients with ATM mutations, CDK12 mutations, post-PARP inhibitor failure patients with ovarian cancer. There were four patients with BRCA1 mutations and a patient with a RAD51C mutations who had failed prior PARP inhibitors who responded. We also had a BRCA1 mutated ER-positive breast cancer patient who had a robust response, a BRCA1 head and neck squamous cell cancer patient who had a response, and BRCA2 mutated melanoma patient who also responded. It's confirmed PR. Further analyses of all of their genomic data are currently ongoing, and we certainly hope to present more of those data at a future meeting. Next slide, please. In terms of the efficacy, we also wanted to show the broad spectrum and to highlight the doses and the schedules where these were seen in. You'll see that truly meaningful clinical benefit was observed in 49% of evaluable patients treated on this clinical trial. These were observed across the different STEP2 gene alterations. These also observed across different schedules and after PARP inhibitor failure. In total, we had 12 responders, eight RECIST confirmed and unconfirmed partial responses, Maria will provide updated response data as well. I can say right now, I guess, that out of the three unconfirmed PRs, actually all three are now confirmed. Just one, a fourth one, remains unconfirmed. The UPR rate is now three confirmed PRs out of the four unconfirmed PRs. We also had two patients who had PCWG3 PSA responses and two patients who had a GCIG CA125 response. You'll see that these were seen across different alterations as listed there. Beyond that, what was so important is the durability of the responses as well. 14 patients, as you can see, beyond those who had objective responses, had ongoing stable disease for greater than 16 weeks. Even in those patients, because this is an early trial readout, even those patients who have not reached that 16-week time point, eight patients have already shown early significant decreases in tumor markers and tumor shrinkage as well. What's interesting is in addition to early responses, we have also seen some late responses as well, with some patients showing initial partial response as late as week 16. This is something that we've also observed with other ATR inhibitors from other companies. Next slide, please. As an exploratory study, we really wanted to explore the circulating tumor DNA. For those who are not familiar with ctDNA, these are really fragmented tumor DNA in our circulating blood, which may reflect the entire tumor genome. It's something we call liquid biopsies. What's good about such a test is it allows us to actually track patients longitudinally at various time points from baseline on treatment to actually monitor a tumor response during treatment. It's important, there's plenty of data now published and also being presented at this triple meeting that early molecular responses in ctDNA may actually correlate with patient benefit during treatment with anticancer agents. What we show here are the ctDNA findings in terms of the decreases and the change in ctDNA levels on treatment. You'll see here across the different genotypes of patients, ATM, BRCA1, BRCA2, and other STEP2 gene alterations, that RP-3500 really does lead to early and significant decreases, so greater than 50% in variant allele frequencies. The ctDNA levels in tumors with multiple genotypes. Next slide, please. An early analysis as well of these patients also showed that patients with partial responses had early and frequently significant reductions in their variant allele frequencies that appeared to correlate with their response data as well. As you can see in the box plot on the right-hand side, patients who had a PR all had decreases in their variant allele frequencies in contrast to patients who had progressed. Certainly, these analyses are ongoing to try and correlate these ctDNA responses with the clinical efficacy so that we can try and evaluate the predictive power of serial ctDNA measurements to use in these treatments for the future. Next slide, please. To end, I'd just like to talk about some patients, because this is really why we're all doing this. This is a patient from Dr. Rosen's site. This is a post PARP inhibitor platinum-treated patient with ovarian cancer who harbored a germline BRCA1 mutation. The patient, as you can see on the right-hand side, achieved a partial response that was confirmed and also has an ongoing GCIG CA125 response. You can see on the left-hand side, in terms of the graphs, that GCIG CA125 response, really impressive CA125 decline and also ctDNA, very deep decreases as well, occurring very early on in treatment, as early as week three on treatment. You can see a complete reduction in that patient's ctDNA. Most importantly, patients are ongoing on treatment, tolerating treatment well with a partial response. Next slide, please. This is a patient of mine with pretty aggressive castration-resistant prostate cancer that harbored a somatic CDK12 mutation. This patient also, you can see, had a very nice PSA response that came on very early on at week three. It also correlated with ctDNA really declining at a very early stage. This patient went on to achieve a RECIST-confirmed partial response with decreases in the liver disease, as you can see there, and lymph node disease as well, and adrenal gland decrease as well, and on the CT scans are shown there on the right-hand side. You can see these effects as early as week 12 there. This was a very heavily pretreated cancer patient, six prior lines of treatments, including standard of care docetaxel chemotherapy, platinum, plus etoposide that the patient progressed on very quickly, and also immunotherapy with ipi/nivo. Next slide, please. This is another patient of mine with, again, prostate cancer, castration-resistant prostate cancer, this time round with an ATM mutation. Patient has an ongoing PSA response. You can see there on the graphs there, the PSA really dropping down quite rapidly as early as week six and also being accompanied by decreases in ctDNA levels. This was a 68-year-old man with prostate cancer, really multiple bony metastases, lymph node disease, and who had progressed on two prior lines of treatment already. When he came to me, his main issue was really intractable pain, and he was on opiate analgesia for his pain. Very pleased to share that since coming on treatment, he's actually now come off his painkillers. He doesn't have any more pain. He's still on treatment. You can see that his scans reduction in his left para-aortic lymph node and the top scans there, baseline compared with week 16. Baseline was 21 millimeters. It's gone down to 10 millimeters, so it's halved in size. The second row you can see is a retrocaval lymph node going from a 25 millimeter lymph node down to 9 millimeters and also a pelvic nodule as well that has decreased in size as well. This patient had an unconfirmed PR. I'm hoping that we will get a confirmed PR very soon as well. Next slide, please. To end, here's a summary of the data that we presented today. RP-3500 is safe, well-tolerated, mainly grade 1 - 2 anemia. I think importantly, in terms of the anemia, we only observed 21.8% grade 3 overall anemia but only 14.5% in the selected 3-4 schedule. Really, apart from anemia, which has been generally easy to manage, these off-target toxicities like fatigue or GI events were really infrequent, only maybe up to about 3% in grade 3 toxicities. We have established a recommended phase II dose for further evaluation at 160 milligrams QD, three days on, four days off. We have shown you PD biomarker data confirming proof of mechanism across different cancers with different molecular backgrounds. We've observed anti-tumor activity as discussed and really a meaningful clinical benefit in 49% of patients as listed there. I'm not going to go through that again. Next slide, please. To conclude, RP-3500 is a potent best-in-class, highly selective ATR inhibitor. I'm very proud to be part of this study. It is indeed the largest biomarker-selected trial selecting a single-agent ATR inhibitor. As mentioned earlier, this is a trial that's still ongoing and continues to enroll. I strongly believe that this early TRESR data certainly provide clinical proof of concept. It does validate the SNIPRx platform for the molecular selection of these patients and tumors, certainly a favorable and very differentiated safety profile alongside promising distinct early efficacy. Really offering a clear direction for the further development of RP-3500. The next steps will be, I think, discussed by Maria, but we're certainly looking at single-agent exploration in the phase II expansion cohorts and also combination studies. With that, I thank you very much. Next slide. I don't think I have very much else to say. Oh, yes. Apart from acknowledging all of my patients and their families, of course, and caregivers who make all of this possible. This is why we do what we do, for our patients and our caregivers. There have been multiple sites involved in this clinical trial, as listed there. Our independent PODS group here at MD Anderson, who have been screening patients for the alterations and, of course, the Repare clinical assay. Thank you very much. Thank you, Dr. Yap. I would now like to turn the presentation over to Dr. Maria Koehler, our Executive Vice President and Chief Medical Officer. Maria, please go ahead. Thank you very much. Thank you, Dr. Yap. Let me begin with a short summary of how the monotherapy arm of our TRESR trial has evolved since the triple meeting cutoff on August 15th. As of today, the initial single-agent module 1 is closed for enrollment with the planned 120 patients. We can confirm that the safety and tolerability profile reported by Dr. Yap as of 15th August cutoff remains unchanged. We have now more patients with longer observation time to feel very comfortable with our dose and schedule choices. In addition to the confirmed partial responses Dr. Yap reported today as of 15th of August, I will also provide some positive news on this. Dr. Yap already mentioned that most of them confirmed. We previously guided that the final results of this module will be available in second quarter 2022 because we do want to have 120 patients with at least one scan. The scans are done at six weeks, and this is planned for our next database lock. We will also share today our perspective on immediate next steps with RP-3500 development. Next, please. Here we highlight the 12 clinical responders from Dr. Yap presentation, and I would like to make three points about those patients. As you already heard, we had four unconfirmed responses and three of them now confirmed. In addition to the patients, for example, with non-measurable disease to whom the RECIST criteria do not apply, and those were assessed by established international criteria as listed here for both PSA for prostate cancer and CA 125 for ovarian cancer. Those patients were deriving benefit that could not be defined by the RECIST criteria. What is not included in Dr. Yap presentation, I would like to note an example of two patients with tumor marker decreases who stayed on study for prolonged period of time, as noted below the table, and who had significant tumor shrinkage close to 30%. This is just short of the PR criteria for RECIST. Those are the patients with two and three stars in the footnote below and are representing a large cohort of patients with significant clinical benefit. Finally, we show here responders were frequent both at 120 milligrams and at 160 milligrams, and also note that patients who started at the 5-2 schedule switched to the preferred 3-4 schedules, again, reinforcing our decision on the chosen dose and schedule. Next slide. You are probably very familiar with this slide on our TRESR study. We put the current 120 patients in the middle box here to indicate that we are ready, as guided, to progress to the phase II for further extension on our program. Please also note that the ongoing ATTACC study we added this summer is also listed here on the bottom of the slide. ATTACC is ongoing and evaluates combination of RP-3500 with olaparib and niraparib, complementing the TRESR module that is already evaluating talazoparib and that started in spring. Next slide. Here, I would like to talk a little bit about the module 2. As before, it has three arms. In the first arm, we will enroll only patients with tumors with ATM loss of function, and we will modify a little bit the criteria, for example, to include less pretreated patients than those in the dose escalation. It will answer the efficacy question firmly and has appropriate statistical boundaries around it. The statistical boundaries are also pertinent to arm 2 and arm 3. Our arm 2 will focus on 2 non-ATM genes, this will be a POC trial. Finally, arm 3 will attempt to answer the questions with sufficient power for the remainder of the STEP2 genes that were underrepresented in our 120 patients cohort to date. This module is ready to start pending IRB and ethics approval. We are pleased to report that we have extended the number of centers due to significant and continued enthusiasm among investigators who enrolled so quickly in module 1. We will enroll quickly to the module 2, and we hope to be able to report some early data later next year. Next slide shows the overview of the emerging clinical development program. You can see that they completed module 1, and I pasted here the details of the module 2 that I just discussed. We continue enrollment in the combination of talazoparib in module 3, and will open imminently two additional modules. One in combination with gemcitabine and another in pediatric population. As mentioned before, the ATTACC study is ongoing and we guided for the multiple PARP combination data in third quarter 2022. Finally, next slide. I would like to summarize that the early TRESR data definitely provides a clinical proof of concept and validates Repare Therapeutics' SNIPRx platform for molecular selection of tumors for ATR inhibitor therapy. To date, we observed a very favorable and differentiated safety profile along with promising and distinct early efficacy, offering a clear direction for further development of RP-3500. The off-target toxicity, most likely off-target toxicity such as fatigue and GI events, were very infrequent, up to 3%, and myelotoxicity was defined as anemia alone. The recommended phase II and schedule for further monotherapy evaluation is 160 milligrams given daily for three days, with four days off every week. Biomarker data confirmed the proof of mechanism across different tumors, and the preliminary anti-tumor activity observed in patients with cancers harboring selected genomic alteration continues to mature, and final efficacy and safety data are expected, as mentioned, in second quarter 2022. As Dr. Yap noted in his talk, we believe these two last points highly validate our STEP2 approach in identifying expanded patients population. So far, we observed meaningful clinical benefit in half of the evaluable patients. 12 of them had clinical responses, as listed here, both by RECIST criteria and by other international criteria. 14 patients have ongoing stable disease for very long time. You saw in the previous slide that some of them were nine months. Additional eight patients who were short on study had a significant decrease in tumor markers, plasma DNA, or tumor shrinkage, less than those required for RECIST criteria. This sums up the update and clinical outlook for the TRESR study and some of the other planned and/or ongoing trials. I will now turn it back, the mic, to Lloyd. Thank you. Thanks, Maria, and I really appreciate that. I think this slide that we now have up captures how effectively we have executed as a team in 2021. Starting with our RP-3500 combination module in April, through to this initial RP-3500 data readout in 101 patients today. For the next three quarters, including this one, we have a broad set of clinical data and pipeline advancements representing important expected advances for Repare. These events start with our first patient to receive gemcitabine and RP-3500 later this quarter, our initial planned pediatric patient in Q1 2022, followed by final readouts that Maria's described on the TRESR module one data set and RP-3500 combinations with PARP inhibitors later in 2022. We also expect to have news on our third clinical candidate, our Pol Theta program, also in mid 2022. To wrap up, today's data provide us with some key concluding perspectives to share. First, we have a clear clinical signal and support for moving forward along a data-driven development path, as Maria and Dr. Yap have both described, in a broad range of genomically selected tumors with the expanded TRESR and ATTACC studies, including combination therapy approaches with PARP inhibitors and chemotherapy. Second, a certain level of validation has been demonstrated with our SNIPRx and STEP2 platform capabilities to expand and prospectively select patients for our trials. I want to note as well the evidence, by virtue of the size of the diverse alterations for which we selected here, that these patients can be identified readily using available tools and platforms. I believe our team and collaborators have earned the recognition we and Dr. Yap provide them here today for the innovations presented. Particularly in respect of the application of ctDNA tools early in this clinical setting, we'll continue to closely follow the predictive capacity of these markers for the benefit of our patients. Our perspective is that TRESR thus far is a gateway to solidify our conviction on both RP-3500 as a potentially best-in-class agent and enhancing the broader opportunity for RP-3500 alone and as a combination opportunity. We are excited about the contribution we've made here today to the understanding of the potential of ATR inhibitors as a class, with a data set that we believe represents the new reference for ATR inhibitor monotherapy. We look forward to providing further updates from TRESR next year, as well as providing initial data from the ATTACC and RP-6306 studies. This concludes our prepared remarks, and I would like to now open the floor to Q&A and just remind you all that you can access questions and forward them to us via the platform on Cision for those of you who are in. Our first question, Marc, if it's okay with you, we've got from Marc Frahm at Cowen. You're asking two questions that are highly related that I'll ask Maria to take initial comments on. Essentially, if I just pull this up, sorry. You're asking broadly how we're dosing and whether we're just dosing patients to have a better safety profile, and is that at the cost of efficacy? I'm paraphrasing you a bit, Marc. You also ask, several patients appear to have been on five two or the combo and then moved to three four, how does that movement mesh with the statement that all responses were at or below the recommended phase II dose? Maria, I'll let you take that one on, please. Perfect. As this was the phase I study, we focused on establishing the safest and most tolerable dose for patients. We drew from what was known from the ATR clinic for the last five years with other ATR inhibitors and from our extensive preclinical data. We applied that to the design of the study. Among those 101 patients, we enrolled 25 patients at our chosen doses. We started, as Dr. Yap showed you on one of the slides. Maybe the slide can go up. We started at the 5-2 schedule, we established that the 5-2 schedule, even at lower doses, is not particularly well-tolerated. It was not about the DLT, but it was about the longer-term tolerability. As you saw, we showed the DLTs were very rare. However, what was important is the longer-term tolerability, which we were told by Dr. Timothy Yap is critically important to continue with the very well-tolerated doses. We also looked at the number of transfusions that were required long-term in these patients, and we concluded that there is no point to create a regimen that needs to be highly supported by transfusions. This is how we made the decision to go to three-four. We had only 25 patients at the 5-2, and majority of the patients, 76, were treated at the three-four schedule. We evaluated within the three-four schedule, the patients at 120, 3-4. After we learned that this is an excellently tolerated long-term regimen, we sequentially went to 160 milligrams and again enrolled 25 patients by now to evaluate longer-term toxicity. Stepped into just in case, as Tim said, plan B, with potentially 162 weeks on, one week off, which obviously was equally well-tolerated. I hope that this answers your question, and Tim, do you have anything else to add, sort of firsthand evaluation. I think you've covered it pretty well, Maria. I think for us, the key thing was really durability of response to the drug. How can we get patients onto doses that are extremely well-tolerated, that allows them to have a full and great quality of life, that they can continue on with their lives as normal, but to really still gain optimal clinical benefit. We wanted to give patients options in terms of both dosing and schedules. As Maria said, the three finalists, if you like, in terms of doses and schedules, really were huge cohorts of patients because we really wanted to be very sure that these are going to be safe and well-tolerated in the long run. At least, I think it was 24 patients at the MTD, 18 patients in the second one, and 25 patients in the third one, just to be 100% sure that the doses and schedules are truly optimized. There have been recent articles about how the FDA is really looking to try and require dose optimization of all oncology drugs. There's a nice article from Mark Ratain as well that does talk to that as well. It's so important, I think, just taking a step back in drug development in general, that we look at different optimal schedules. We're not just establishing a recommended phase II dose. We're actually looking at a recommended phase II dose range that will still be of benefit to patients, and most importantly, durable benefit to patients that will allow a high quality of life, and durable response. Thank you, Dr. Yap. I think that's a great question. Thanks for it, Marc. I'll refer you all to slide 16 of Dr. Yap's presentation. This presentation will be available online, on our website following this event. That, as Dr. Yap and Maria noted, presents a comprehensive picture of the systematic approach taken to arrive at our RP2D and schedule. Taken together with slide 33, which was presented by Maria on the follow-up post the cutoff, I think that there's a very clear picture to give us confidence in the integrity of both the recommended phase II dose and schedule recommendation and in our understanding of the efficacy demonstrated at that dose and schedule, which Dr. Yap has just described. Again, all these slides will be available in the follow-up. I'm going to move to the next question from Jeff Hung at Morgan Stanley. The question I'm going to aim initially at you, Maria, is that about half the patients have scans. Were the other half just enrolled later so that they don't yet have scans? When would you expect to have scans for all of the patients? Just to put some baseline, the scans are done every six weeks in the study. The first scan is on week six, and then every six weeks for three evaluations. According to both European and U.S. radiotherapy protection, you have to do the scans less frequently, so we are doing them I think every four weeks after that. We keep repeating it, because the study is very immature and the results are very early, out of those 101 patients, 21 patients, as written in one of the tables, 21 patients were not even available for the first scan, or maybe more. About that much were not available for the first scan. We are unable to comment, and that's why we selected the 69 patients for efficacy. Either they had a very low dose, so the efficacy would not be expected, or they did not have scan. We plan to have a final analysis and final data lock of the study after all of our 120 patients have at least one scan. We calculated it, that we now have these 120 patients. Let's say it's October, now, six weeks later, last patients presumably will have last scan. It is a very difficult decision because we also know that the responses are seen late, like week 16. There's one patient that Tim presented. There is a probability that some of the patients enrolled late still will benefit, and we will not see them even in the final analysis. We are still thinking how to do it best. The plan for next data lock is about in December, January. Great. Thanks, Maria. A question from Joseph Catanzaro of Piper Sandler. Can you say how many of the ATM patients were treated at 120, 160 for the three on, four off? For non-responding ATM patients who are still on study, can you speak to whether you're seeing tumor reductions and whether there is potential for future RECIST responses? Thanks, Joe for that question. That's very inquisitive question. I wish I could answer it. We had about approximately 10 patients in the 101-patient study who were treated below 100 milligrams a day. We've proven multiple times by our PK analysis that this is a dose that does not give you a sufficient exposure to hope for anything. We will present this type of details that you are asking at our final analysis, where we will have sufficient observation for the data. However, what I can say now is that it seems so from the very early look, and I will ask Timothy to confirm that, it seems so that the BRCA patients and for that matter, the CDK12 patients, responded already on the first evaluation at six weeks. These are indeed the patients with ATM loss that tends to respond despite the quick down of the plasma DNA, they tend to respond late. That's why we need to wait for those patients much longer. Timothy Yap, do you have any additional comments, please, on that? Oh, I think you summarized it pretty well. With the other ATR inhibitors, late responders responses have been observed with both ceralasertib and elimusertib as well. Not surprised that these responders are achieved, I guess, later on. In many ways, I guess it's good to have the ctDNA data as well to try and provide some preliminary evidence that there is benefit ongoing. Great. Thank you, Dr. Yap. Again, Maria, I think another one that both of you may want to weigh in on, but I'll aim it at Maria. This comes from Charles Zhu at Guggenheim Securities. You've highlighted PARP inhibitors as a combination partner, which presumably could be particularly potent in BRCA patients. As we look across the field of emerging novel DDR drugs, how do you see not only potential positioning of ATR inhibition, but also opportunities for other combinations across a heterogeneous biomarker landscape? Thank you, Charles, for that. From our clinical program, you can see that we are developing as a priority a PARP combination with ATR inhibitor because it is highly supported by our multiple preclinical data. Actually, we have a poster by Anne Roulston from our Montreal office to show some of the preclinical data on that as well. Our priority for combination indeed is PARP combination with ATR. As you know, almost all competitors are indeed doing the same combination because there is a phenomenal biology behind this combination. Having said that, the other combinations that we are excited about is combination with gemcitabine that is imminently starting. Combination with some other compounds that we will reveal very briefly. We are planning to show you the data for the three PARP inhibitors in latest third quarter, preliminary data third quarter next year. This will be a very profound evaluation, including multiple biomarkers, looking at early responses, and possibly differences between those three inhibitors. Thanks, Maria. Dr. Yap, is there anything that you want to add to that in terms of the combinations? Well, I was actually going to touch on the post PARP inhibitor setting, because I really think that looks very exciting in terms of the activity that was observed in patients who we did treat, particularly in ovarian cancer patients, where we have seen multiple responses in patients who have BRCA mutations. I think there was one RAD51C mutated ovarian cancer patient. All of these patients had progressed on a PARP inhibitor. PARP inhibitor failure patients who then went on to get this ATR inhibitor, RP-3500, as a single agent. We have seen responses in those patients, and durable responses as well, including a case study that I have shown of a BRCA1 mutation ovarian cancer who had a confirmed PR. I think it's such a critical area of unmet need right now. The standard of care treatment currently is chemotherapy for these patients with BRCA mutated cancers in a post PARP inhibitor setting. There is such a great need for that right now. Certainly, I'm very encouraged by these data and with multiple objective responses. I think apart from the combinatorial rationale that Maria's already mentioned and covered, I also think that in a post PARP inhibitor setting, we can also think about a single agent ATR inhibitor approach, yeah. Thank you, Dr. Yap. I'm going to move to a question from Paul Choi at Goldman Sachs, staying in the BRCA frame. Are you surprised that there is a BRCA responder, given that this has not been seen with other ATR inhibitors? Maria, why don't you start? This presentation and our discussion today is focused on the encouraging data from monotherapy for various STEP2 genes. However, we observed clinical benefit in almost one-third of the enrolled patients with the BRCA subgroup. I must tell you, it was initially only BRCA1, so we said, "Oh, BRCA1," and then suddenly we started to get the BRCA2 as well. This data is not yet complete as treatment is ongoing with most of these patients, and we anticipate complete reporting of available data in this subset and other subsets, including, as Tim mentioned, response to prior treatments and also response to prior PARP. Some of the BRCA responders did have prior PARP inhibitors and responded, and some of the rare alterations, we had patients who are not routinely treated with PARP inhibitors. We have responses also in patients like somatic breast alterations that also responded. We are looking forward to work on this particular segment of BRCA tumors, both for monotherapy and for combination, and we will present our possible registrational strategy in this area next year. Dr. Yap, anything to add? Yeah. I think just to answer that question directly, I'm not surprised that we have seen multiple responses in BRCA-mutated cancers. Ultimately, it is a synthetic lethal genomic alteration, right? That predicts for sensitivity to RP3500. I think it just validates the whole approach here. What's so amazing as well is that apart from the post-menopausal failure ovarian cancer patients who have BRCA mutations, we also saw it in the so-called non-BRCA associated cancers like a BRCA1 mutated head and neck squamous cell cancer patient. We also saw a BRCA2 mutated melanoma patient, both of which had confirmed partial responses. Really showing that with ATR inhibitors, we can actually go broad and go beyond your traditional BRCA associated cancers like breast, ovarian, prostate, and pancreas. I think that's highly encouraging here. Obviously, I don't need to add that the BRCA1 and BRCA2 was, according to our platform, a definite sensitivity gene to the single agent ATR. We are very glad that it confirmed. Yeah. To the extent anyone was surprised or not surprised, I think the important point is that BRCA1 and BRCA2 were both STEP2 genes used to select patients for this trial. Part of our pleasant view of the data that suggests that the platform is potentially highly effective in selecting patients. I'm going to move on to another question, just keeping an eye on the clock. I'll go back to Joseph Catanzaro and back to dosing and PK. Joe's question, Piper Sandler, is: "RP-3500's half-life is six hours and you're moving forward with once daily dosing, whereas Bayer and AstraZeneca half-life is 10 to 11 hours, but they utilize twice daily dosing. Can you elaborate on your decision to move forward with once daily, and what gives you confidence that you are sufficiently hitting ATR? Maria, I'll let you answer that, but Mike, if you want to weigh in, just put up your hand. I think that Mike can start because it will be about the rationale for that. I can tell you that we had small number of patients with twice-a-day dosing. Obviously once-a-day dosing is much more convenient and much more appropriate for patients with cancer, you don't forget. The compliance is better. It was very easy for us to make the choice of once-daily dosing. Mike, if you can give some. Yeah. Just say the time of cover per day on once or twice daily dosing was actually much more consistent on the once-a-day dosing, giving us higher confidence that the patient's getting the right time of cover. Really what gave us the confidence in the end about the time of cover was the preclinical work that we'd done, which is quite extensively across several different model systems, to be able to think about how long we thought was necessary to inhibit the target to drive efficacy. That really married up in the end with the data that emerged clinically as we were going through the dose escalation in the phase I trial. Thanks, Mike. Dr. Yap, I don't know if there's anything there you want to add. No. I think the comparisons made between BID versus QD, and at the end of the day, there really weren't much difference in the two schedules. If one had to pick, everything being equal, one would pick a once-a-day dosing. Thank you, Dr. Yap. I'm going to move on to a question from Marc Frahm at Cowen. Marc's asking, "Were the patients that achieved PSA or CA125 responses also evaluable by RECIST?" Maria, do you want to take that? We amended the protocol for patients with. The initial protocol was only with patients with measurable disease. We have chosen to do that just to clarify what everybody thinks are proper responses. We observed, and actually we encouraged the investigators led by Dr. Yap, that there is a lot of patients who do not have the responses and patients were coming to the study. This was a protocol amendment to allow patients with non-measurable disease later. Regarding the direct question, there was one patient among those responders who had up to the 15th of August, and I'm saying about the protocol amendment because the protocol amendment was reasonably recent. We now have more of those patients, but they are not included up to the 15th. Out of those patients who were evaluable, one had only PSA and the patient responded. There's this one patient on study for eight months, and this patient has PSA response, but he also has measurable disease. The measurable disease is between 22%-26% decrease for last six months, and the tumor will not move. The patient is doing great and is on study for eight months with that type of response. The other patient, so this is the other PSA patient. The patient who is the CA125 responder is actually the patient that Timothy Yap mentioned with RAD51C, and this is a patient who had two or three scans already and has a definitive CA125 response from hundreds to tens, and tumor shrinkage of 28.7% on the September 7th scan. We are hoping very much that the patient will define herself, but we are just learning, and I would like to ask Timothy Yap to comment on it, because it is the largest study of single-agent ATR inhibitor. We are learning what really the ATR inhibitors are doing. I will let Timothy Yap finish on that. Timothy Yap, could you finish on that concept? I think one of the patients that you mentioned, the ATM prostate cancer patient, was actually one of the case studies I presented. Yes. Who's got a very close to a RECIST response as well. I think 26%, 27% was his last scan. That was a patient who's got really remarkable clinical benefit. The patient has come off all of his opiate treatments and whose pain has just gone away, and he's come off painkillers. Still has a PSA response. Ultimately, many times we think about the limitations of RECIST criteria, which really was developed for chemotherapy, right? I think we need better ways of assessing our patients. Perhaps in the future, it might involve ctDNA, maybe it involves other measures of assessing patients. I think for me, especially in prostate cancer, I think clinical symptoms are so important, especially bony pains in a patient with bony disease. On top of that, it's the durability of the response. Ultimately, that is what will get this past, let's see, registration. I think that's going to be very important. Yeah. To add to these comments, I cannot help myself. I was 10 years in Pfizer and actually developing palbociclib. Palbociclib single-agent activity in breast cancer is in the range of 5%-7%, and this is one of the most successful drugs. We really cannot judge the drugs by overall response rate. I just cannot help myself but say it. Thanks, Maria. Appreciated. I'm going to move on to a question from David Martin at Bloom Burton. David's asking if hematological tox is an on-target effect of the ATR inhibitor class, what may be driving the apparently lower hemo tox effect of 3500? Is it other targets than 3500 that 3500 is not hitting that others are, or do we think it's something else? Maybe, Maria, you can start us and Mike can weigh in. Yeah. We always are saying that definitely anemia is on-target toxicity for ATR inhibitors. We are performing, as Tim mentioned in the AACR presentation, we are performing very extensive mechanistic studies to understand it better, and we are almost there, and we will present this mechanism sometimes hopefully mid next year. The ATR inhibition and anemia is definitely on target. Why is the on target limited for 3500 to anemia? We have a very simple explanation because of how clean the drug is and how on target the toxicity could be with very minimal other kinases inhibited with RP-3500. Maybe, Mike, you can add anything on that. Well, I think it's also very important to note dose and schedule. It is a key component of all of these types of things. There is the unknown that this is, I think, needs to be spoken, which is, at the end of the day, you look at the different PARP inhibitors, they have different impacts on myelosuppression each. It's not fully understood why. Again, there are things that we don't fully understand, but I think I would just reinforce what Maria said is that we do believe that anemia, based on a number of different reasons, is a non-target toxicity. The remainder, we think, is probably a combination of both the drug as well as picking the dose and schedule to progress forward with. Thank you, Mike. Our next question up is from Paul Young. He's asking if there's any evidence that the likelihood of anemia is linked to specific genetic backgrounds in patients. For example, ATM versus other STEP2 genes. Are we seeing any difference in the anemia profile based on the genomic alterations for inclusion? Maria, do you want to address that? Yeah. The answer is no, we do not see any differences between the anemia. Actually, thank you for the questions because we did have the task of evaluating the toxicity by not only tumor type or type of alteration, but also by germline or somatic alterations. We evaluated this reasonably carefully. We still are evaluating it, but we absolutely did not find any indication that anemia is related to specific subtypes. I just wanted to reiterate that the anemia with our drug is 14% grade 3 and no grade 4. It is a toxicity, but we don't have any other toxicity, so we are focusing on the 14% anemia. I think that it is one of the best tolerable drugs in oncology that talazoparib has 56% grade 3 neutropenia. Do you have any other comments on the genomic alterations and anemia from your PARP experience, maybe? I think Maria was addressing that at Tim. Yeah. I agree. I think we certainly have not seen any differences with anemia depending on genotype, so Maria is absolutely right. It's a similar thing with PARP inhibitors as well. I would say across different ATR inhibitors, we've certainly not seen greater sensitivity or greater levels of anemia depending on genotypes. Thanks, Timothy Yap. A question from Benjamin Burnett at Stifel. Why, in your view, Maria, was the response rate higher in BRCA1 patients versus ATM? Before you take the mic, I'll say, let's remember these are relatively small populations to be making pronouncements of higher. I think we're going to wait to see where that data comes out. Maria, I don't know if you want to elaborate. Sure. I would be very careful of saying that one is higher than the other because I do not believe that we have the final answer in the ATM. We also, as we are trying to weave through the presentation, we also don't know whether response rate is the ultimate measure of the benefit from ATR inhibitors. Just similarly to, sorry to bring this talazoparib again, but there is a lot of approaches to drug development where the nothing else but PD1 inhibitors, where the response rate is a definitive proof of activity but is not required for registration of a provision of benefit to patients. I would note, as we mentioned, the ATM responses tends to be, because we don't even know that, tend to be later, while the responses that we observed for the BRCA population tends to be at six weeks and then confirmed at 12. We enrolled a lot of patients with ATM and a lot of patients with BRCA, and we still continue to enroll other STEP2 genes, so I don't think that the biology of the ATR inhibitors is fully understood. Timothy Yap, I don't know if there's anything you want to add. I was just going to echo and say, I think the field, in general, is still working on ATM as a biomarker, which is still trying to fine-tune it, in terms of zygosity, monoallelic versus biallelic loss, in terms of just using ATM mutations versus looking at IHC loss. If you think about IHC loss, the question is where do you draw the bar for that? There's still a lot of fine-tuning that needs to be done for that. That's a question for the entire field. Yeah. Great. Thank you. We have a question that I think if I can include David Martin and Joseph Catanzaro and Marc Frahm have all asked how we think about a comparison between this early result and the results from the public FLAIR study. I'm wondering, Maria, if you can start that off and just give us a thought. Tim, obviously, you were deeply involved in these studies, and if you have a comment that you feel you can share, certainly love to hear it. Okay. I do believe that the beta data was in a very small study with 11 patients with ATM loss, and they indeed had four patients who had responses. However, the responses were observed at initial doses, we don't know anything after later doses, that were way above the double or 50% more than recommended dose. That's number one. Number two, we do not have any follow-up on the trial, and we don't have any bigger population of the Bayer since the original presentation in 2019. Third, the toxicity that was reported in Dr. Yap's paper in Cancer Discovery indicates that the anemia grade 3, everybody knows that, was 80%. Again, these are very small numbers. Our view on RP-3500 is that it is an extremely active drug in the STEP2 gene population that can be given for very long time at a tolerable dosage. We know that we designed the schedule to be able to do the weekly dosing, which we think is very important for the continuous sort of bugging the tumor weekly. We actually are extremely encouraged what we can do with this data and what would be our next steps to move on to bringing the drug to the patients. Dr. Yap, if you want to add anything, feel free, or I can sum up. Just to say, I think the Bayer data was very important to provide the initial proof of concept. As Maria mentioned, the responses in ATM loss cancers was important. Of course, as Maria said, that was 11 patients with ATM loss. I think what this trial does is it validates those findings in terms of the multiple responses that we have seen in ATM-mutated cancers. It also adds to the data in the form of responses that have been seen in all of these different STEP2 genes, in terms of CDK12, BRCA1, BRCA2, and RAD51C. It also expands it beyond the BRCA-associated cancers as well to include melanoma, to include head and neck cancers, so on and so forth. Also, I think ultimately with this study, it was the therapeutic window with 14.5% grade 3 anemia and no grade 4 anemia that I think is very significant. Thank you, Dr. Yap. I think our view, to sum up a question that we clearly have gotten and are going to continue to get, is that we've set a new benchmark data set. We established that new data set for monotherapy ATR inhibitors. Our view is that anybody looking at the field of ATR inhibitors today is going to look at our data set first, that is now published in its early data and ultimately when we complete that. Based on this very large phase I data set, we are very excited about the clear signals of clinically meaningful benefit across a wide range of genotypes and tumor types in just short of half of these heavily pretreated patients, even in this early evolution of the data. We look forward to sharing the next data updates with you in the first half of next year. I think we've got time for one more question. It's on BRCA1, BRCA2, and it comes from Brian Malik at Rowe Price. I'll aim it at Maria. Are all BRCA1 or BRCA2 patients in the trial resistant to PARP inhibitors? I know we have some data that we can share anecdotally, but I know we also don't have a complete data set there. Maria? What I can tell you is that some of those responders were patients who had BRCA alterations and never responded to PARP inhibitors. Okay? I would like to sort of take the time to evaluate the data, and we will keep enrolling the BRCA patients. We have more among those 120 patients, and we would like to do a proper analysis versus what we can do now, a very short-term analysis of the data. I can assure you that it was a very heterogeneous population, just like Dr. Yap mentioned, of patients with BRCA. Thanks, Maria. I believe we're just at the end of our time, so I'm going to thank everybody for participating today, in particular our guest, Dr. Timothy Yap of MD Anderson, and for all of you making the time late on a Friday night of a holiday weekend in both the U.S. and Canada. We apologize for that. It was AACR who selected the schedule, not us. We deeply appreciate your all being here, and we look forward to seeing as many of you as we can possibly fit in in the near term. Thank you very, very much for your attendance this evening.