Welcome to the Zentalis Pharmaceuticals' azenosertib clinical update call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. You may type your questions via the Ask a Question box on the webcast platform at any time. If you would like to verbally ask your question, please press star one on your telephone keypad. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this event is being recorded. I will now hand the call over to Adam Levy, Senior Vice President, Investor Relations at Zentalis. Thank you. You may begin. Good morning. Thank you for joining us today for our azenosertib clinical update call. Before we begin, I'd like to take care of a few housekeeping items. I invite you to visit the investors section of our website to view the webcast slides, today's press release on our azenosertib monotherapy dose optimization data, and our May 25 press release on our azenosertib plus chemotherapy combination data, which was also presented yesterday at ASCO as abstract 5513. During today's presentation, we will be making forward-looking statements. Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those described in these statements. Additional information describing these forward-looking statements and the related risks is included on slide two of the webcast slides and in the press releases issued today and on May 25. These risks are further described in the Management's Discussion and Analysis and Risk Factors sections of our most recent annual and quarterly reports filed with the SEC. The forward-looking statements on this call speak only as of the original date of this call, and except as required by law, we do not undertake any obligation to update or revise any of these statements. With that, I would like to introduce our CEO, Dr. Kimberly Blackwell. Thanks, Adam. Thank you all for joining today's call. During the call today, I will be providing an update on the clinical progress we've made with azenosertib, a highly selective WEE1 inhibitor for the treatment of solid tumors that we believe has the potential to be both first-in-class and best-in-class. We will be reviewing four main topics today. First, the exciting data from our phase 1 monotherapy dose escalation trial, which led to our declaration of a new monotherapy dosing regimen for azenosertib. Second, an overview on ongoing and planned clinical trials with azenosertib as a monotherapy in gynecologic malignancies. Third, the phase 1b clinical data presented yesterday at the ASCO annual meeting, demonstrating the impressive activity and safety profile of azenosertib in combination with chemotherapy in platinum-resistant ovarian cancer, particularly in those patients with Cyclin E1 positive tumors. Fourth, our plans to expand the azenosertib franchise, which includes a proposed Phase 3 study in Cyclin E-positive, platinum-sensitive ovarian cancer, comparing azenosertib plus single-agent chemotherapy, followed by maintenance monotherapy azenosertib to a chemotherapy plus chemotherapy doublet, followed by placebo. At the end of the call, we will be opening the floor for questions. For the Q&A portion of today's call, I'll be joined by Zentalis' Chief Medical Officer, Dr. Carrie Brownstein, and Dr. Funda Meric-Bernstam, Chair of the Department of Investigational Cancer Therapeutics, the Phase 1 program at the University of Texas MD Anderson Cancer Center. She's also a member of our scientific advisory board and a senior investigator on our Phase 1 dose optimization trial of azenosertib. Zentalis was founded in 2014 and has grown exponentially. Our mission is to bring first-in-class and best-in-class therapies against known cancer targets to patients facing cancer. Our lead asset, azenosertib, meets all the criteria for fulfilling Zentalis' mission. WEE1 is a high potential validated cancer target in multiple hard-to-treat tumors. Azenosertib is a selective WEE1 inhibitor with intentionally designed pharmacologic properties, monotherapy activity, and great tolerability, with over 400 patients treated to date. In the past year, my executive team and I have led the transformation of the company into a clinically focused biotech. We've assembled a team dedicated to strong execution in the clinic, including adding a new chief medical officer and chief translational officer. These expanded teams, the co-founders, our investigators, and the patients that participated in our trial, are responsible for the exciting data I'm sharing with you today. Close behind azenosertib, we have a BCL-2 inhibitor and a degrader platform. Before diving into the data, I would like to highlight that we will be reviewing 2 very large phase 1 datasets around azenosertib. I would like to quickly summarize what we at Zentalis are excited about. First, I'm pleased to share that our efforts over the past year to optimize the monotherapy dose of azenosertib have been successful. At intermittent dosing, we have achieved a confirmed objective response rate of 36.8% in a cohort of patients facing ovarian and uterine serous carcinoma. While azenosertib was very well tolerated as a monotherapy given on a continuous dosing schedule, we have improved tolerability not only over our previous dosing schedule, but markedly demonstrating a better safety and tolerability profile compared to an older experimental WEE1 inhibitor. Second, in our combination study reported at ASCO yesterday, we showed that the combination of azenosertib with single-agent chemotherapy impressively improves response rates and durability over chemo alone in patients with platinum-resistant or refractory ovarian cancer. When combined with paclitaxel, we have a confirmed objective response rate of 50%, a duration of response of 5.6 months, and a median progression-free survival of 7.4 months. For carboplatin, our confirmed objective response rate is 36%, with an 11.4-month duration of response and a 10.4-month median progression-free survival. Finally, these highly promising data sets have helped us set the course for a comprehensive development strategy with azenosertib in both USC and ovarian cancer. We have ongoing phase 2 monotherapy studies in USC and ovarian, Cyclin E-positive, platinum-resistant ovarian cancer. We also added an azenosertib monotherapy arm to our ongoing Phase 1/2 niraparib combo study in patients with PARP inhibitor and platinum-resistant ovarian cancer. Based on the data we presented at ASCO yesterday, we are proposing a Phase 3 study to evaluate azenosertib in combination with either paclitaxel or carboplatin, followed by maintenance monotherapy azenosertib in Cyclin E1-positive platinum-sensitive ovarian cancer. Let's get started with the clinical data supporting the new azenosertib monotherapy dose. The exciting take-home messages from the monotherapy dose optimization work are: We have a new recommended Phase 2 dose, or RP2D, of 400 milligrams orally, 5 days on and 2 days off. Compared to the previous continuous or everyday dosing schedule, intermittent dosing more than doubles exposures, which has led to a close to doubling in the confirmed objective response rate in USC and high-grade serous ovarian cancer. Specifically, the confirmed response rate in this combined patient population is now an impressive 36.8% with intermittent dosing. At the same time, we have maintained or improved tolerability with this new intermittent dosing schedule. Before we dive into the data, I'd like to start with why WEE1 is such a critical and important cancer target and the mechanism of azenosertib, which is designed to selectively inhibit WEE1. We believe selective inhibition of WEE1 has made azenosertib a more refined drug to develop in the clinic than previous small molecules targeting WEE1. Intact, undrugged WEE1 phosphorylates CDK1 and CDK2, inactivating the CDK cycling complexes and turning on or further augmenting the G1S and G2M cell cycle checkpoints. These checkpoints allow for DNA damage to occur, allowing for subsequent normal replication to occur, even in genomically unstable cancer cells. Azenosertib inhibits WEE1, which leads to dephosphorylation of both CDK1 and CDK2, thereby removing or lessening both the G1S and G2M checkpoints. The cell cycle progresses out of control without sufficient DNA repair. These rapidly cycling cells accumulate DNA damage, resulting in either apoptosis or mitotic catastrophe. Azenosertib's mechanism of action and early observations of monotherapy clinical efficacy made dose optimization of this exciting agent critical. We set out to optimize the monotherapy dose of azenosertib to achieve improved clinical outcomes for patients. We knew that a continuous dose of 300 milligrams a day had a favorable safety profile and resulted in monotherapy activity in multiple cancer types, including colorectal cancer, non-small cell lung cancer, uterine serous carcinoma, and ovarian cancer. We also knew from both preclinical and early clinical data that an intermittent dosing schedule at higher dose levels could possibly allow for increases in exposure and maximum concentrations, while at the same time maintaining or even possibly improving tolerability. ZN-c3-001 is a phase 1, first-in-human study, evaluating escalating doses of azenosertib, starting at 25 milligrams all the way up to 500 milligrams, given either on a continuous daily schedule, QD, or on an intermittent schedule, either 5 days on, 2 days off, or 5-2, or a 4 days on, 3 day off schedule, or 4-3. More than 180 patients have been enrolled and treated in the study to date. The primary objectives of the study were consistent with any or most phase 1 studies, to examine the safety and clinical pharmacology of azenosertib. The rest of this monotherapy presentation today will focus on patients treated in what we consider to be a reasonable therapeutic range, which are those patients who received at least 300 milligrams daily on either a continuous or intermittent schedule. The safety evaluable patient populations were similar between the dosing schedules. Patients were heavily pre-treated, having received, on average, over four lines of therapy. Roughly 20% had seen a PARP inhibitor, 40% had received an experimental therapy, over half had seen a VEGF inhibitor. Forty-one percent had seen a PD-1 or PD-L1 inhibitor. Patients enrolled in the study represented over 20 different tumor types, typical of a phase 1 first-in-human study. No biomarkers, biopsies, or prior therapies were required, and tissue was available in only a limited number of patients. Because of the previously described activity of WEE1 inhibitors in USC and ovarian cancer, there was a referral bias for enrollment in the study for patients with these two tumor types. The next two slides outline the beneficial effects of intermittent dosing of azenosertib on the clinical pharmacology endpoints. Shown from left to right are the steady state exposures from 300 milligrams continuous schedule to 500 milligrams intermittent 4-3 schedule. In general, intermittent dosing resulted in a doubling in the exposure compared to continuous dosing at a lower dose. For instance, at the now recommended dose of 400 milligrams 5-2 intermittent schedule, a more than doubling in exposures was observed compared to the exposures with 300 milligrams continuous dosing. As the 4-3 dosing schedule did not optimize exposures or impact tolerability and safety, we are no longer pursuing that dosing schedule. The other clinical pharmacology endpoint that benefited from higher dosing on an intermittent schedule was maximal concentration, or Cmax. Intermittent dosing, shown on the right-hand side of the slide, resulted in a more than doubling of the mean Cmax. We know from preclinical models that this increase in Cmax also plays a small but not insignificant role in driving the efficacy of azenosertib monotherapy. I will now show you the promising efficacy results from the non-biomarker selected group of USC and ovarian cancer patients enrolled in the phase 1 monotherapy study. 51 patients with either USC or ovarian cancer were enrolled in a study after multiple lines of therapy. 45 out of 51 were deemed response evaluable, having had measurable disease at baseline and having completed at least one post-baseline disease assessment scan per protocol. Reasons for the 6 patients being non-response evaluable include 2 treatment-related AEs, 2 non-treatment related AEs, 1 patient was missing for follow-up prior to the first scan, and 1 patient withdrew consent. USC patients had on average 3.4 lines of prior therapy, and the ovarian patients had on average 5.3 lines of prior therapy. 100% of these patients were platinum resistant. Prior therapies are consistent with current management. Two-thirds of ovarian cancer patients had a prior PARP inhibitor. Three-fourths of both patients types had seen a VEGF inhibitor, and three-fourths of the USC patients had seen prior IO therapy. Here is the main efficacy analysis for the combined patient populations. Although azenosertib was active on the continuous dosing schedule shown on the left-hand side of this slide, with a confirmed response rate of 19%, intermittent dosing results in a confirmed response rate of 36.8%. When both dosing schedules are combined, the confirmed response rate is 26.7%. I think an equally impressive representation of the activity of intermittent dosing of azenosertib is shown here. The dark blue lines represent the USC patients, and the teal lines represent the ovarian patients. 89% of the patients enrolled on the intermittent dosing schedule have had a reduction in the size of their target lesions. 12 and 19 patients remain on therapy. The median follow-up is 4.4 months. The median progression-free survival is 5.68 months. Finally, 10 of the 13 ovarian cancer patients shown here have been treated with a prior PARP inhibitor. I would like to take a moment to highlight some of the impressive responses seen in patients. The first patient faced a Cyclin E-amplified ovarian cancer and had received over 10 lines of therapy in the metastatic setting before enrolling in this trial. With azenosertib, the patient experienced a 71% tumor reduction and remained on treatment for over 11 months. Another ovarian cancer patient, this time with a germline BRCA1 mutation, 7 lines of prior therapy, including a PARP inhibitor, having never achieved a partial response on any therapy, has had a 48% tumor reduction and remains on treatment after 5 months. I will now outline the impressive monotherapy safety profile of azenosertib. Having worked on multiple successful cancer agents in my career, I can comfortably say that azenosertib's anticancer activity is complemented by a favorable safety profile and makes this agent highly competitive compared to other agents commonly used in the clinic and benefiting patients today. Shown here are the treatment-related side effects observed in at least 10% of patients and the safety evaluable population receiving 300 milligrams or above of azenosertib. Additional treatment-related side effects that occur in fewer than 10% of patients are included as well. Moving from left to right, continuous, intermittent, and total, you can see that continuous dosing of azenosertib has a good safety profile, with the only grade 3/4 treatment-related adverse event occurring in over 10% of patients being fatigue. When you move to the blue middle columns or intermittent dosing schedules, you see that for the most part, GI and fatigue is improved with a slight increase in anemia and neutropenia. Notably, no febrile neutropenia was observed in either dosing group. It's also worth noting that there were no intra hemoglobin requirements for the study, and 20% of patients on both dosing schedules entered with baseline grade 2 anemia, and 5% of patients enrolled with grade 3 anemia. The improved tolerability of intermittent dosing is demonstrated on this slide. The intermittent dosing schedules of azenosertib resulted in half the dose reductions and significantly fewer dose discontinuations as a result of treatment-related adverse events. There were no treatment-related SAEs in the intermittent dose patients. To try to put the excellent safety and tolerability profile of azenosertib into perspective, shown here are dose reductions, drug interruptions, and drug discontinuations for monotherapy azenosertib in blue. Historical data, not head-to-head, from another experimental WEE1 inhibitor, adavosertib, is shown in the two gray bars. It's used as a monotherapy in USC in the dark gray and ovarian in the lighter gray, and historical data from the recently approved antibody drug conjugate mirvetuximab in purple. Across the board, azenosertib seems to be well, if not better tolerated than these other agents. Taken together, the results of our monotherapy dose optimization study support our ongoing trials using the new dose of 400 milligrams 5-2 in gynecologic malignancies. An optimized dose and biomarker enrichment plan is foundational to our potential accelerated approval clinical development strategy. The top-line science here is that tumors with high amounts of genomic instability, such as most high-grade serous ovarian cancers, are highly sensitive to azenosertib. In our strategy, these genomically unstable tumors are further refined on top of the tissue type in one of two ways, either through amplification or overexpression of Cyclin E1, which I will refer to as Cyclin E1-positive, or homologous recombination repair defects, also known as HRD positivity. Cyclin E drives accelerated entry into S-phase through its partnership with CDK2, thus overloading the replication machinery and resulting in genomic instability. HRD positivity also results in genomic instability through the tumor's inability to repair double-stranded DNA breaks. On the right-hand side of the slide is a Cyclin E1-positive tumor model. You can see that the addition of single agent azenosertib in increasing doses leads to significant increases in DNA damage and apoptosis markers. We have 3 phase 2 monotherapy programs ongoing, where we are currently recruiting patients. The first is our Zentalis ZN-c3-004 study, also known as TETON. This study is evaluating azenosertib administered at the 400 milligram by 2 intermittent schedule in women with second-line or greater advanced USC. The second monotherapy study is the Zentalis ZN-c3-005 study or DENALI. The study is enrolling platinum-resistant ovarian cancer patients into 1 of 3 cohorts: Cyclin E1 amplification, Cyclin E1 positivity without gene amplification, or Cyclin E1 negative, either defined as non-amplified or Cyclin E1 negative. The third ongoing phase 2 trial is our Zentalis ZN-c3-006 MAMMOTH study, where we are comparing azenosertib monotherapy to azenosertib, either in combination or alternating with the PARP inhibitor niraparib, in patients facing PARP-resistant ovarian cancer. With these three ongoing monotherapy clinical trials, we are thoroughly interrogating azenosertib's monotherapy activity and safety in platinum-resistant ovarian cancer and USC in a way that we hope will advance this agent as quickly as possible to patients facing these two difficult-to-treat cancers. Let's sum up the monotherapy study results. Azenosertib is a highly active agent with a favorable safety profile in ovarian cancer in USC. The recent work we have done with dose optimization and a new recommended phase II dose has paid off with a 36.8% confirmed response rate that is durable with the intermittent dosing schedule. The majority of patients that have been placed on the intermittent dosing schedule remain on therapy. Looking ahead, I'm pleased to announce that we plan to present a more mature data set from the ZN-c3-001 monotherapy study in the second half of 2023. We plan to update the timelines and other deliverables for the TETON, DENALI, and MAMMOTH trials in the second half of 2023 as well. Let's now move on to discuss the data that was presented yesterday afternoon at the ASCO meeting by Dr. Joyce Liu, focusing on the results of a phase 1 study combining azenosertib with four different chemotherapy backbones and platinum-resistant ovarian cancer. For those of you who are looking for the full details of this presentation, I would refer you to the ASCO website for abstract 5513 or to the Zentalis corporate website. The key messages of yesterday's presentation are highlighted on this slide. With over 100 patients enrolled, a recommended phase II dose was established for azenosertib, combined with paclitaxel or combined with carboplatin, or combined with pegylated liposomal doxorubicin, or what I will refer to as PLD. Of note, the recommended phase II doses use standard doses of full-dose chemotherapy, the recommended doses of azenosertib use intermittent dosing schedules of 5/2, which you will note is identical to the dosing schedule we just walked through for the monotherapy. Although you will see that the gemcitabine combination has promising and durable activity, we have not reached a recommended phase II dose, work on dosing for this combination is ongoing. Finally, the study demonstrated a strong and durable efficacy signal across chemotherapy backbones. For the entire population, the confirmed objective response rate was 34%, the confirmed duration of response was 8.3 months, and the median progression-free survival was 9 months. The study also demonstrated that Cyclin E1 positive status has a significant correlation with both higher response rates and much longer median progression-free survival for the azenosertib chemotherapy combinations, the significance of which I will discuss in a few minutes. Zentalis 002 was a phase I study where the primary objectives were to determine a recommended phase II dose and clinical activity of azenosertib in combination with one of the previously mentioned chemotherapy backbones for patients facing platinum-resistant or refractory ovarian cancer. Entry criteria allowed for up to 3 prior lines of therapy, and all patients had measurable disease. Shown here are the patient characteristics for the trial. 115 patients were enrolled. The majority of the patients were platinum-resistant, with about 20% or 1 out of 5 being deemed platinum refractory. This is a population of ovarian cancer patients typically excluded from clinical trials. About a quarter of the patients had received a prior PARP inhibitor, and 40% of the total study population had seen prior bevacizumab. The next slide shows the clinical activity of azenosertib in combination with the various chemotherapies. Of the 115 patients enrolled in the study, 94 were response evaluable, meaning that they had measurable disease by RECIST 1.1, and received a protocol-defined set of follow-up scans. The disposition of the 21 patients that were deemed non-response evaluable included 11 patients who remain on drug with measurable disease but have not received their first set of scans. Five patients who withdrew consent or had a patient preference decision to not continue on the study. Four patients had adverse events, including two who were in the gemcitabine combination arm, and one patient had clinical progression at day 10. I now draw your attention to the colored row, which shows a confirmed objective response rate of 50% for the paclitaxel arm, 35.7% for the carboplatin arm, 38.5% for the gemcitabine arm, and 19.4% for the PLD arm. The durability of these responses is demonstrated on this slide, which is the Kaplan-Meier curve for the progression-free survival endpoint. As deemed on the top right, the median PFS for paclitaxel was 7.36 months, 10.35 months for the carboplatin arm, 8.31 months for the gemcitabine arm, 6.28 months for the PLD arm. These next two slides put the impressive clinical activity of the azenosertib combinations into perspective, with either single agent chemotherapy combinations with the other experimental WEE1 inhibitor, adavosertib, or the recently approved ADC mirvetuximab in platinum-resistant ovarian cancer. The first slide demonstrates the objective response rate shown via historical data of weekly paclitaxel, adavosertib and weekly paclitaxel, mirvetuximab from both the phase II and phase III studies. Azenosertib plus paclitaxel from this phase I study is in yellow. On the right-hand side, the median progression-free survival of 7.4 months is compared to the historical median progression-free survival for these same regimens. This slide is the same information as the previous slide, but in this case, it represents for carboplatin alone, platinum doublets, adavosertib doublets, Phase 2 and Phase 3 mirvetuximab, and the azenosertib carboplatin doublet. As in the previous slide, the median PFS of 10.4 months is very impressive compared to the historical median progression-free survival for similar platinum-based regimens, especially considering these patients were either platinum resistant or platinum refractory. I want to finish by outlining why we believe Cyclin E1 positive ovarian cancer, and perhaps other Cyclin E1 positive solid tumors, represent a patient population where azenosertib plus chemotherapy has further potential to improve outcomes for patients over chemotherapy alone. Shown here is an extensive literature review highlighting that for close to over 2 decades, Cyclin E overexpression or amplification, which I will refer to as Cyclin E1 positivity, has been demonstrated to be a poor prognostic factor for patients facing cancer and being treated with chemotherapy in the metastatic setting. Shown here and indicated by the bars to the right of the Y-axis, the majority of the studies have shown that Cyclin E1 positivity portrays a worse outcome in multiple tumor types, including urothelial, ovarian, esophageal, endometrial, and breast cancer. Probably even more relevant to today's discussion is the correlation of Cyclin E1 positivity and poor outcome in ovarian cancer patients treated with platinum-based chemotherapy. Very similar to the previous slide, Cyclin E1 positive tumors predict a worse outcome in the setting of platinum-based chemotherapy, with all of the studies demonstrating a hazard ratio greater than 1. These six studies involved 5,404 patients, In the four studies where timing of tissue collection was available, all patients were platinum sensitive, meaning the tissue had been collected after no chemotherapy or after a single course of chemotherapy. The remaining two studies did not disclose the timing of tissue collection. Cyclin E amplification and overexpression were determined differently in each study, A general conclusion can be made that Cyclin E1 positivity is a common phenomenon and a poor prognostic factor in ovarian cancer, including platinum-sensitive ovarian cancer. With this background, the study investigators set out to examine the role of Cyclin E1 positive tumors in the setting of the Zentalis 002 study. Shown here is how common Cyclin E1 positive tumors are in the setting of tumors collected from platinum-resistant patients enrolled in this study. When a standard cutoff of greater than 50 H4 is applied, 87% of patients had tumors that would be considered Cyclin E1 positive. Though 43 of the 94 patients did not have gene status determined, there were still 40 patients that were determined to be positive, even in the absence of gene amplification. Shown here are the take-home results from the Cyclin E1 analysis. When patients whose tumors were Cyclin E1 positive were treated with azenosertib and chemotherapy, the median progression-free survival was triple that of patients whose tumors were Cyclin E1 negative. This result suggests that Cyclin E1 positive tumors can be used to identify patients who benefit the most from azenosertib. This is even more remarkable considering the breadth of data we just reviewed, showing that these patients with Cyclin E1 positive tumors should have done worse if treated with chemotherapy alone. Let's finish the topic with a comprehensive overview of the safety data of azenosertib when added to chemotherapy, particularly when given at an intermittent dosing schedule of 5/2. Shown here are all treatment-related adverse events that occur in greater than 20% for any dosing schedule with any combination of chemotherapy from the study. Intermittent dosing will be used for all recommended Phase 2 doses going forward. As mentioned previously, a recommended Phase 2 dose for the gemcitabine combination has not been reached and additional dose levels are still being explored. No untolerated dose level has been seen in the paclitaxel arm. The highest adverse event with intermittent dosing of paclitaxel is grade 3, 4 neutropenia at 26%. This compares very favorably to the grade 3, 4 neutropenia rate of carboplatin chemotherapy doublets, which range from 39%-50% in the published literature. Similarly, the most common grade 3, 4 adverse event for carboplatin dosing is thrombocytopenia, which is at 25% for intermittent dosing and has no neutropenia. This compares very favorably to the hematologic toxicity profile of carboplatin chemotherapy doublets. From a clinical standpoint, the safety of azenosertib, given at an intermittent dose, is manageable, better than if azenosertib is given continuously, and better than chemotherapy doublets that are the standard of care for platinum-sensitive ovarian cancer currently. These phase 1a/1b azenosertib plus chemotherapy combination data are foundational for supporting a phase 3 registration-intent study examining the doublet of either azenosertib plus paclitaxel or azenosertib plus carboplatin against the standard of care carboplatin-based doublet chemotherapy regimens. The data presented at ASCO yesterday would suggest that azenosertib has the potential to replace 1 of the 2 chemotherapies, thus improving tolerability and efficacy and setting a new standard of care, even in a biomarker-unselected patient population. We, alongside of the investigators, including those who participated in the phase 1b study, are supporting a trial design that will enroll only patients with Cyclin E1-positive tumors who are known to benefit less from chemotherapy and, based on our data to date, benefit more from azenosertib. Azenosertib has a favorable safety profile and has demonstrated antitumor activity as a monotherapy and will be included at the recommended phase 2 dose for monotherapy as a maintenance component on this study. We anticipate disclosing more details regarding the trial size and further specifics, regulatory considerations, timelines to completion, and the timing of data readout in the second half of 2023. In conclusion, the data presented yesterday at ASCO by Dr. Joyce Liu and colleagues, and reviewed here, is highly supportive of the safety and efficacy of azenosertib single-agent chemotherapy combinations, especially in Cyclin E1-positive tumor populations. I want to conclude by reiterating our excitement around both the azenosertib monotherapy and chemotherapy combination activity in ovarian cancer. We believe that this activity is driven by high amounts of genomic instability in ovarian cancer, either through Cyclin E1 positivity or HRD positivity. Taken together, these enrichment strategies create a large opportunity for azenosertib, with ongoing trials selecting for patient populations that encompass about 88% of all high-grade serous ovarian cancer patients. We have plans to study the promising activity of azenosertib in multiple lines of therapy, including as a monotherapy in platinum-resistant ovarian cancer in USC and in chemotherapy combinations in platinum-sensitive ovarian cancer. These are near-term plays that have the potential to lead to either NDAs or final data readouts between 2026 and 2029 and, if successful, address over 58,000 treatment-eligible patients in the United States and EU5. We don't see the opportunity just stopping there. azenosertib has potential applicability outside of ovarian cancer, with a previously disclosed program in BRAF mutant metastatic colorectal cancer and undisclosed opportunities to build a franchise in HRD-positive and Cyclin E1-positive tumors outside of the gynecologic malignancy space. This non-gynecologic malignancy strategy would have the potential to expand the universe of treatment-eligible patients to cover over 140,000 patients annually. This past year has been a really productive one at Zentalis. We have made great progress in the understanding of azenosertib's potential to change cancer care, especially for those patients facing ovarian cancer and USC. We have seen amazing antitumor activity and a favorable safety profile across both of the monotherapy and chemo combination trials. We are now positioned to quickly execute on our strategy with 3 currently accruing monotherapy trials in platinum-resistant ovarian cancer and a proposed phase III study in platinum-sensitive ovarian cancer that we anticipate will initiate in the Q1 of 2024. Given the progress that we have made in just 1 year around azenosertib, I'm really looking forward to many more great things to come from the Zentalis team and our partners in the year ahead. Before we begin the question and answer section of today's call, I wanted to take 1 minute to thank all of our collaborators and, most of all, the patients and their families for their contributions to this research. I will now turn it back over to the operator to start the question and answer portion of today's call. Thank you. Ladies and gentlemen, the floor is now open for questions. If you would like to ask a question, please press star one on your telephone keypad at this time. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Participants connected on the webcast may use the Ask a Question box located on the left side of your screen. Again, for audio participants, please press star one on your telephone keypad at this time. We will start today with audio questions. The first question today is coming from Mike Ulz of Morgan Stanley. Please go ahead. Yep, good morning, everyone, and thanks for taking the question. Maybe just on the biomarker selection strategy, it seems like the majority of the patients are biomarker positive. Just curious if it, why it makes sense to use a selection strategy, versus not, or is that still sort of a consideration here? Thanks. Yeah, thanks. Thanks for the excellent question. We agree with you that the expression of Cyclin E positivity is pretty common, especially from the trial population where tissue is available. Our perspective is we've done work on thresholding of the cutoff, and we've defined 50 as an optimized cutoff. I'd like to turn it over to Funda to see if she has any additional thoughts on Cyclin E cutoff in particular. Thanks so much. You know, the Cyclin E space is a interesting space as a biomarker. I think there's a lot of preclinical as well as clinical data emerging in this space. You're right, there's more work still to be done. I think this Zentalis approach is really exploring both the Cyclin E amplification and overexpression hypothesis, while, you know, exploring combinations and monotherapy beyond that. I think, you know, looking across the program, we'll be getting the information and learning more about the value of Cyclin E for selection. Thanks for the excellent question. Yep, thank you. Maybe just 1 quick follow-up here. Just on the phase 3 strategy for the combo and moving into platinum-sensitive patients, can you talk about what gives you sort of the confidence there that you will sort of be successful? Is it more to do with the selection strategy? You know, maybe you have a better response in selected patients, in sort of the sensitive patients versus versus the platinum-resistant population? Thanks. Yeah. Thanks for the question. We have reason to believe we'll be successful because of the efficacy and safety we saw in the data presented yesterday at ASCO, because we have the Cyclin E enrichment strategy that makes sense scientifically, and we also have a safe and effective monotherapy dose that can be used in the maintenance setting. I'll turn it over to Carrie to add some additional color or thoughts around the reason we believe we can be highly successful in the platinum-sensitive space. Thanks so much, Kimberly. I agree with everything that's been said so far. I think that one of the other pieces that's important to know is based on the data that we showed yesterday, that the Cyclin E-positive patients, which does make up a large proportion of even the platinum-sensitive setting, don't do well with chemo. I think we have a really good shot of being successful when we're taking patients, that even though they're in the sensitive setting, they're probably the ones who don't do as well when they get chemotherapy. Got it. Thank you. Thank you. The next question is coming from Akash Tewari of Jefferies. Please go ahead. Good morning, this is Ivy on for Akash. Thanks for taking our question. We have two. The first one is, for the phase 1b chemo combo trial, how many treatment cycles were these patients on? The second one is for the phase 3 study. With a median PFS of around nine to 11 months for carboplatin doublet in sensitive setting, what would be a reasonable assumption on powering for the phase 3 trial and hazard ratio? Also, how much PARP use do you expect patients will have had in your phase 3 study? Thank you. Thanks, Ivy, for that excellent two-part question. I'll turn it over to Carrie to answer both of those questions. Thanks so much, Kimberly. Could you just repeat the first part of the question, and then I'll go to the second part? Sure. The first one is about the phase 1B chemo combo trial. How many treatment cycles were patients on? Yeah. The study was designed to continue treatment till progression. We didn't define a specific cycle that they'd be treated for. What the second half is about the proposed trial? Yes. Yeah. We haven't disclosed the full details of that trial yet in terms of the statistical analysis plans and things, that you're getting to, but we'll share when that's further ready to do so. Ivy, I'll just follow up. I mean, we haven't disclosed, but I think our hazard ratio and effect size would be similar to other drugs that have been successful on a phase 3 randomized study in early lines of therapy for any disease, but in particular, ovarian. Thanks for the excellent question. Got it. Thank you. Thank you. The next question is coming from Andrew Berens of SVB Securities. Please go ahead. Hi, thanks. Wondering what you think the rate of neutropenia, what's acceptable in second-line platinum-sensitive setting? I know you had a rate of 26% in the paclitaxel chemo arm with the azenosertib. What do you think that rate may change to when you move into the platinum-sensitive setting? Also the second line, platinum-sensitive setting has a number of effective therapies that are available beyond chemo. I'm wondering, are you going to let PARP inhibitors be used in the control arm, and what about that? Lastly, can you give us some color on what you saw with the 4-on/3-off intermittent dosing cohort that led you to choose 5-on/2-off? Sure. Thanks, Andrew, for those questions. I'll turn it over to Carrie. She could start working through those. I'll follow up with any more details. Sure. Thanks so much. You know, I think that it's a really good question. Obviously in earlier lines you would expect, you know, the willingness, let's say, to have higher rates of neutropenia to be lower. That said, I think what we've been seeing in our study, you know, the data look very strong and safe, you know, based on what we've seen in other studies, both in PSOC and PROC, the grade three has been with platinum doublets that are the normal, usual standard of care in around 30% range. I think we'll stack up very favorably in that setting, and I'm not concerned that we should have any more difficult safety in that, in that perspective. Then what was the next half of that? There was a lot of questions there embedded there. Yeah, just, in the second line, the various, PSOC setting, you have a lot of different options, doctors and patients do. Are you going to let PARP inhibitors be used in the control arm, what about Avastin? Just some color on the, what you saw with the four-on/three-off intermittent dosing. That's great. relative to 5-2. Yeah. Let me start with the third, the second part of that question, which is, in the 4-3, the 4-3 dosing also was safe and effective. We went with the 5-2 mainly because we think that's a better schedule for patient compliance, having the 2 days off. I think if you looked on that, on the slide with the clin pharm, the exposure did look a bit lower even when you were getting the same cumulative dose. Since we, you know, since we saw that, as well as it being as well tolerated, we thought it would be a better schedule for going forward. Lastly, in terms of the chemotherapy combination for the study, I mean, again, we haven't disclosed all the full details on what the study would be like. That said, given that we have such great data, we think there's a very good way of designing a study that makes sense and that's appropriate for patients based on what their underlying disease is and what would be the standard of care for that patient. Okay. Thanks, Carrie. Andy, I'll just add a little bit more color around your second question, which is, therapies available in the second line setting, because I think some clarity is needed here. We're proposing a study after the initial first-line chemotherapy for platinum-sensitive ovarian cancer, which for all practical purposes, is carboplatin Taxol, at least in developed countries, that's followed by a PARP inhibitor where appropriate, although there are some moving lines around that, it's typically a HRR mutant or HRD positive. Then the inclusion of bevacizumab and not a small population of patients. We certainly will have to allow for those prior therapies, but the study is designed to enroll patients after progression of their, what I'll call, first-line maintenance therapies. We will be allowing maintenance PARP and at the time of progression, allowing patients to go on the study and same with maintenance bev. We know that patients post-PARP tend to have a worse outcome on second-line platinum-based regimens. Because we believe that our drug restores or improves sensitivity to platinum, especially in Cyclin E, we're actually more than willing to allow patients post-PARP because we, what we see in the Cyclin E space is very encouraging. Hopefully that provided some more details on the patient population we plan on enrolling and the allowance for prior therapies. Okay. Yeah, thanks, and congrats. Thank you. Thank you. The next question is coming from Michael Schmidt of Guggenheim. Please go ahead. Hey, guys. Good morning, and thanks for this comprehensive update. I didn't see the monotherapy broken out by cyclin E status, perhaps because you didn't have the biopsy data for those patients. Is the enhanced activity in cyclin E positive patients, a phenomenon that is only being seen in combination with chemo, or do you expect that to occur in monotherapy studies as well? Great. Thanks for that excellent question. I would say that we're encouraged by the activity in the monotherapy trial across the board. Just point out that previous biopsies had not been required for enrollment in the study. As you can imagine, we're collecting as much data, either at the point of care at the sites that were sent as part of standard of care or other markers when these specimens are available. Funda, I wanted to see if you had any other thoughts, given that this is a phase 1 study, and there was no predetermined biomarker for this population to be enrolled, sorry. Thanks. I think clearly, you know, the Cyclin E hypothesis is one that makes one recognize when patients have Cyclin E amplification. You know, but the, you know, this drug likely has activity beyond that, and, you know, clearly, diseases like USC, there is other drivers, not just Cyclin E, genomic or expression alteration. We'll be learning a little bit more while we go as well, but I think the Cyclin E hypothesis is being well tested with the study designs in place. Right. Thanks, Funda. And then in the, um- Go ahead. Go ahead, one more. In the combination study, I think 87% of patients were positive based on your cutoff. You know, is that frequency is something that you would expect to see in the general population, or was the phase 1b combo study enriched for, you know, by bicloster enriched for Cyclin E high patients? I'll let Funda chime in, but I just want to remind the audience that this was a very heavily pretreated population of patients, classic for a phase one study. You know, we believe that Cyclin E expression in particular, drives chemoresistance, and the literature would support that statement. I'll turn over to Funda for any other thoughts about the incidence of Cyclin E expression from our study. Yeah. Thanks, Kim. I think that really, I think captures it well, because, to be fair, I think the evolution of Cyclin E expression or amplification is not as well studied. You know, we all believe that's an important variable to consider. Again, of course, as an investigator, I can say that when I see a Cyclin E amplified patient, I especially like get excited about being able to enroll patient in the WEE1 inhibitor. There may have been some investigator bias, but definitely I think we're looking at it in both patient populations. Thanks, Funda. I think we have time for one, or maybe one or two additional questions, so I'll turn it over to the next participant. Thank you. The next question is coming from Bradley Canino of Stifel. Please go ahead. Hi, good morning, and congratulations. Now, I recognize the PSOC trial design is still being refined, but I just want to know how much of that trial's potential for success is tied to the maintenance azenosertib component in your minds, and how important is the dose optimization that was completed today in relation to that? Thank you. Sure. I'll let Carrie answer that question. Great. Thanks, Kimberly. That's a really great question. I think that there's, you know, we're really excited about the monotherapy data. We're really excited that we had a safe dose, that's well tolerated and that can be given in the maintenance setting. I think that's super important. That said, however, I don't think necessarily, the maintenance piece is the only trigger or supporting reason for why we have a strong feeling that we can have success in this area. I think it goes back to everything we've been saying about these patient populations, particularly those that have the Cyclin E expression, that typically based on the literature that we've seen, do not respond well to chemotherapy. Potentially, we are picking these patients out before they fail. Since we were able to flip that in the phase 1b study, in terms of how well these patients are doing, when we add in the WEE1 inhibitor to the chemotherapy backbone, we think that also is an extremely important piece of the trial design. That's helpful. Can I ask. Great ... quick data question? There were 2 monotherapy, USC and ovarian patients that were not responsive viable due to treatment-related adverse events. Can you disclose the tumor types and the schedules for those 2 patients if you have them? Thank you. Yeah. I mean, I don't think we're disclosing the specific details, but needless to say, the toxicities that we saw with these patients, again, they're very heavily pretreated, and go along with what we were showing in terms of in our safety slide, that are the expected toxicities with the agent. Sorry for jumping in there, Kimberly, go ahead. All right, Carrie, thank you for your succinct answer. I think we'll have time for one more question from the participants. Thank you. Our final question for today will be coming from Tyler Van Buren of TD Cowen. Please go ahead. Hey, guys. Good morning. Congratulations on all the data presented at ASCO this morning. Had just a couple hopefully quick ones on the Phase 3. As we think about the chemo combo platinum-sensitive Phase 3, the azeno carbo combo response rate does not look dramatically higher than some of the carbo-pac doublet combo data you presented on the slide. I appreciate that CCNE1 positive patients do worse on the carbo doublet, but what gives you confidence in the 10.4-month median PFS holding up in the Phase 3, given the smaller sample size? The second question is just the Phase 3 trial schema has the two active arms that combine azeno with PAC. Will the Phase 3 have two active arms that combine azeno with PAC or carbo, or are you going to decide among them? What factors are you considering? The lack of Grade 3 plus thrombocytopenia with the PAC combo is, of course, attractive, but carbo is obviously used heavily and is in the control arm, so that could make sense. It'd be great to hear your thoughts. Sure. I'll turn it over to Carrie. I will say that, you know, the amount of activity and the safety in particular of our combinations give us confidence that we can beat a carbo-Taxol doublet even without the cyclin. The cyclin further enriches, I think, the patient population that's most likely to benefit from our drug and less likely to benefit from a chemo-chemo doublet. Carrie, do you have any other thoughts to address Tyler's question? No, I think that's exactly right, and it's, you know, basically what I answered in the last question. I think we're going to be enriching this patient population for a group that may not do as well when they're treated with carbo. I think that our data is strong, and from all the other answers we've given to date, I think that we have a very good chance of success with this trial. Great. Thank you, Carrie. I think before closing today's call, I'd like to turn it over to Funda first and then Carrie for any closing thoughts. Thanks, Kimberly. I, you know, just to reiterate, I think, this is definitely an exciting class of drug. You know, over the last year, we've really seen a lot of progress with the drug so that we now, you know, have a dose and, you know, that is now tolerable and, you know, quite efficacious for a monotherapy agent. You know, this is a promising program. Yeah, I'd like to thank you for your support of the trial and continued support. Carrie, any closi ng thoughts? Yeah. I just want to add that we're really excited, as we've said a few times now, having monotherapy activity in these heavily pretreated patient populations that, you know, really didn't have any other therapies, with a tolerable safety profile, with, you know, minimal reductions and interruptions, we're really looking forward to continuing to bring in this data. I also wanted to make sure we thank all of our investigators and collaborators, in particular the GOG, who we've been working with very closely to help us bring this therapy with the combinations as well to the patients. I think without their support and all of our collaborators and the patient support, we're not going to be able to bring this really promising therapy to patients as quickly as we'd like to, which is what's good for them. wanted to thank them. Thanks. Great. I think with that, hopefully you've enjoyed today's call, and I thank you for participating. Have a great last day of ASCO. Ladies and gentlemen, thank you for your participation. This concludes today's event. You may disconnect your phone lines or log off the webcast at this time, and enjoy the rest of your day.