ORIC Pharmaceuticals, Inc. (ORIC) Earnings Call Transcript & Summary

Good day, and thank you for standing by, and welcome to the ORIC Pharmaceuticals Business Update Conference Call. [Operator Instructions] I would now like to hand the conference over to your speaker today, Dominic Piscitelli, Chief Financial Officer. Please go ahead.

Good morning, and welcome to the ORIC Pharmaceuticals Business Update, AACR-NCI-EORTC Conference Call. This morning, we issued a press release highlighting initial clinical and translational data from our ongoing Phase Ib trial of ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer as well as preclinical data on ORIC-114 in HER2-positive breast cancer. You may find the press release posted on the Investor page of oricpharma.com. We have per-recorded our prepared remarks, after which we will host a live Q&A session. So please bear with us if we have any technical difficulties. Before we begin, starting on Slide 2. During this conference call, we will be making forward-looking statements. ORIC's actual results may differ materially from those expressed in or indicated by such forward-looking statements. For a description of risk factors associated with investing in ORIC, please refer to our recent filings with the Securities and Exchange Commission. ORIC specifically disclaims any obligation to update any forward-looking statements, except as required by law. This presentation contains interim results based on initial data from the ORIC-101 clinical trial in combination with enzalutamide as of the database cutoff date of August 20, 2021. During this presentation, we will not be speaking to any additional data subsequent to such date. Now turning to Slide 3, I'll briefly walk you through our agenda and introduce our speakers. During today's call, we'll discuss background on glucocorticoid receptors and ORIC-101, followed by the initial data from the ORIC-101 plus enzalutamide Phase Ib trial and next steps, and finally, a brief summary and pipeline update followed by Q&A. Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CFO; and Pratik Multani, CMO. Now let me turn over the call to Jacob.

Thank you, Dominic. Turning to Slide 4. It's our pleasure today to share our first clinical data set for our lead program, ORIC-101, in combination with enzalutamide in metastatic prostate cancer. The unmet need within this patient population is significant. While treatments for early line prostate cancer have made meaningful advancements in recent years, once patients progress on a novel anti-hormonal like enzalutamide, their options are limited, primarily to highly toxic chemotherapy. For a patient progressing on single agent enzalutamide switching to abiraterone or another novel anti-hormonal like apalutamide offer next to nothing in terms of response or added duration. While it's still early days for this study. During this call, we'll discuss why we are enthusiastic about these initial data from our Phase Ib trial of ORIC-101 in combination with enzalutamide for patients who are progressing on single-agent enzalutamide. First, we've identified a well-tolerated recommended Phase II dose of ORIC-101 in combination with standard dose enzalutamide, with primarily Grade 1 or 2 treatment-related adverse events and no DLTs. Importantly, the combo regimen has a safety profile consistent with that of single agent enzalutamide. Second, our PK and PD data showed the exposure of ORIC-101, as the recommended Phase II dose exceeded the threshold needed for GR inhibition, and we were able to demonstrate this through consistent suppression of GR biomarkers and patients. Furthermore, we saw no evidence of drug-drug interaction impacting enzalutamide. Third, through our extensive translational efforts and detailed tumor profiling, we found GR expression levels were moderate to high in 75% of patients, and this prevalence was consistent with the published literature. And finally, with this early look at the expansion cohort data, we were able to identify potential patient selection factors, including the absence of AR resistance variants and markers of lineage plasticity and the presence of moderate to high GR expression as a means to identify a target patient population for ORIC-101. Importantly, in patients with these key selection factors, we are already seeing evidence that the addition of ORIC-101 after progression on enzalutamide, alone, enabled continued time on enzalutamide treatment. Now a natural question in the evaluation of a novel mechanism of action like GR is whether patient outcome is deferred depending on the underlying level of GR expression in a patient's tumor. Turning to Slide 5, and with all the appropriate caveats about the preliminary nature of these data and small sample size, our early experience has shown that time on treatment for ORIC-101 in combination with enzalutamide in select patients, with moderate-to-high GR expression levels compared quite favorably to the duration for patients with low GR expression levels. Later in the presentation, we'll dive deeper into the tumor heterogeneity of post-enzalutamide prostate cancer, specifically the role of AR resistance variants and lineage switching in causing tumors to become AR independent. Of the 8 patients who did not have any AR resistance variants or markers of lineage plasticity and were evaluable for GR expression, 6 had moderate-to-high GR and 2 had low GR. The 2 patients with low GR at baseline shown on the left side of the page, quickly came off treatment at less than 2 months. In contrast, we observed better outcomes in the 6 patients on the right side of the page with moderate-to-high GR. 2 patients were on treatment for over 7 months with another 4 patients at varying durations still ongoing at the time of the data cut. If anything, absent therapeutic intervention with the GR antagonist, one would expect high GR expression to confer a worse outcome versus low GR expression, but it was actually opposite in this case. Patients with moderate-to-high GR expression appear to be staying on treatment with enzalutamide and ORIC-101, longer, compared to the low GR patients, which is notable and underscores the potential therapeutic value of ORIC-101. With that, let me hand it over to our CSO, Lori Friedman, to walk you through a brief refresher on GR and related preclinical rationale before our CMO, Pratik Multani, dives into the clinical data.

Thanks, Jacob. Turning to Slide 7, I'll give a background on the role of the glucocorticoid receptor in prostate cancer therapeutic resistance and a brief overview of the preclinical characteristics of ORIC-101, our GR antagonist. There are several lines of evidence implicating GR as a mechanism of therapeutic resistance in prostate cancer. The diagram on the left depicts the development of enzalutamide resistance in cell-based studies where AR inhibition up regulates GR and activates GR as a bypass resistance mechanism. Shown on the right is the impact of this activation of GR. The transcriptional gene signatures of AR and GR have significant overlap, supporting the hypothesis that GR activity can bypass enzalutamide-mediated AR inhibition by regulating the transcription of a significantly overlapping set of genes. In the lab of Charles Sawyers, a co-founder of ORIC, preclinical studies were performed in vivo, as shown on Slide 8. On the left is a mouse model of prostate cancer that was treated with AR inhibitors, enzalutamide or apalutamide. This experiment was carried out for over 30 weeks to allow for the development of resistant tumors. These resistant tumors were then molecularly characterized as shown on the right, and the important observations were made that GR mRNA levels increased as shown in the dot plot and GR protein levels increased as shown in the western blot at the top. Thus acquired resistance to anti-androgen treatment correlated with up-regulation of GR expression in these in vivo studies. On Slide 9, in translating this molecular discovery to clinical samples. On the left, our data published by the Sawyer's lab, which showed that patients with high GR level at baseline had poor response to enzalutamide. Even more notable, after 8 weeks of enzalutamide treatment, GR levels increased significantly, in particular, in those patients who had a poor response to enzalutamide. The right side is an independent clinical study with samples collected from early-stage prostate cancer patients at the time of radical prostatectomy where patients were followed for 10 years. The patients with high GR tumor levels in the hormone-naive prostate cancer setting relapse more quickly than those with low GR with a median PFS of 13 months versus 43 months, respectively. This observation of higher GR expression levels correlating with worse clinical outcomes has been observed across multiple tumor types and in relation to multiple anticancer agents. With these compelling preclinical data in hand, ORIC initiated a drug discovery program, which resulted in the discovery of ORIC-101 shown on Slide 10. ORIC-101 is a potent GR antagonist with single-digit nanomolar GR inhibition and importantly, with no AR agonism. Careful attention was paid to the CIP profile of ORIC-101 to minimize the potential for drug-drug interactions as compared to other GR antagonists. We believe that this profile ought to allow us to dose 101 to higher levels of GR exposure without problematic drug-drug interaction when combining with anticancer therapeutics that carry their own safety liabilities. Further preclinical characterization of ORIC-101 is shown on Slide 11 and an experiment in prostate cancer cells grown in culture. In this study, the control shown on the far left indicates cell growth, which is dependent on AR. Enzalutamide treatment blocks cell growth, and in the third column, when GR is activated by adding a GR agonist into the culture medium, bypass resistance occurs and cells escape from enzalutamide. This resistance is overcome when ORIC-101 is added to the enzalutamide as shown on the far right. I'll now hand off to Pratik, who will give an update on the Phase Ib clinical trial.

Thank you, Lori. Turning to Slide 13. We are conducting 2 clinical trials of ORIC-101, each examining a distinct mechanism of action of GR inhibition to reverse cancer resistance. One study is a combination of ORIC-101 with nab-paclitaxel in patients with advanced solid tumors, for which we have provided a clinical update at this year's ASCO conference. The second study is a combination of ORIC-101 with enzalutamide in patients with metastatic prostate cancer, who are progressing on enzalutamide and is the subject of 2 triple conference poster presentations being presented today. I'll now review the highlights of these new data. Turning to Slide 14. The enzalutamide combination study is a multi-sector open-label trial that is being conducted in 2 parts: The first part, which has been completed is the dose escalation portion in which patients with metastatic prostate cancer, who are progressing on enzalutamide as their first and only AR modulator, are enrolled independent of baseline GR status at successive dose levels of ORIC-101, along with the standard dose of enzalutamide of 160 milligrams daily. The primary endpoint of part 1 was to identify the recommended Phase II dose of ORIC-101 in combination with enzalutamide along with their respective pharmacokinetics. The second part, which is the dose expansion portion and is currently ongoing, is enrolling the same patient population with all patients now receiving the recommended Phase II dose of ORIC-101 in combination with standard dose enzalutamide. The primary endpoint of this portion is efficacy as measured by disease control rate, PSA response and progression-free survival. In addition, an extensive biomarker plan was incorporated in both parts of the study, including GR immunohistic chemistry of tumor biopsies, disease and GR-related pharmacodynamic markers in tissue and blood and an assessment of tumor mutational status, consisting of DNA and RNA sequencing for AR resistance variants and markers of lineage plasticity. While the pharmacodynamic analysis was used to determine biological activity and target shutdown of ORIC-101, the tumor profiling, both through immunohistochemistry and cell-free DNA and RNA analysis was used to identify the appropriate patient population for GR inhibition therapy with ORIC-101. Slide 15 shows our progress as of the enrollment cutoff of July 15. We examined 3 dose levels of ORIC-101, ranging from 80 milligrams to 240 milligrams once daily, in combination with the standard labeled dose of enzalutamide 160 milligrams daily. Through dose escalation, we determined the recommended Phase II dose of ORIC-101 to be 240 milligrams. No dose-limiting toxicities were observed, and the pharmacokinetics of ORIC-101 was dose proportional. And importantly, we saw no evidence for drug-drug interaction effect of ORIC-101 on enzalutamide exposure. The determination of the RP2D was based upon clear demonstration that we were achieving on-target PD modulation of the glucocorticoid receptor pathway to our peripheral blood mononuclear cell biomarker data and that further dose escalation would not result in further target modulation. Slide 16 depicts the baseline characteristics and disposition for the study patients. A total of 25 patients were enrolled as of the enrollment cutoff of July 15 across Parts 1 and 2, of which 18 were treated at the recommended Phase II dose, while the remaining 7 patients received non-Phase II doses of ORIC-101 during dose escalation. The baseline characteristics are, as you would expect, for a metastatic prostate cancer patient population post-first-line enzalutamide. The median age was 70 years old with a median of 20 months on enzalutamide prior to study entry. Almost all patients had bone involvement of their disease with approximately 40% with lymph node involvement and 12% with visceral involvement. The median baseline PSA of patients was 19, which again, is in line with the literature for similar patient populations. Slide 17 shows the safety profile of the combination therapy. In particular, at the RP2D, the regimen was well tolerated with a safety profile consistent with single agent enzalutamide. The vast majority of treatment-related adverse events are grade 1 or 2 with only 4 grade 3 treatment-related adverse events, consisting of 2 events of syncope and 1 event each of nausea and hypokalemia, all of which resolved upon dose interruption. There was only 1 treatment-related discontinuation at the RP2D and 1 dose reduction. Slide 18 summarizes our pharmacokinetic analysis. On the left, you have the Cmax and AUC of ORIC-101 at the 3 dose levels study. The exposure of ORIC-101 increased with dose. Furthermore, the plasma Cmax at all dose levels exceeded the projected threshold for GR inhibition based upon preclinical models, including at the lowest dose level of 80 milligrams. On the right, you have the pharmacokinetics of enzalutamide on day minus 1 and over the course of the subsequent cycles for each of the 3 dose levels of ORIC-101. You can see that enzalutamide levels remained relatively stable over time with a fair degree of inter-patient variability and that there is no relationship between mean enzalutamide concentrations and the dose level of ORIC-101, indicating no evidence for a drug-drug interaction impact of ORIC-101 on enzalutamide. This was an important objective of the ORIC-101 target product profile. Slide 19 depicts, for an exemplar patient, our pharmacodynamic studies to quantify GR pathway inhibition by measuring the expression of GR target genes in peripheral blood mononuclear cells. The blue bars represent expression levels of one such target gene, FKBP5, on cycle 1, day 1 and again on cycle 2, day 1. Also shown are levels of cortisol, which is an important co-variant, since cortisol is the natural ligand of GR and drives the pathway. Because of a negative feedback loop, we see that cortisol rises in response to GR inhibition. And despite that rising cortisol level, which should drive increased expression of this GR target gene, the target gene expression is instead decreased on day 1 and remains suppressed even at the predose time point on cycle 2, day 1, indicating sustained pathway shutdown. This PD suppression was observed as early as day 1 in 22 of 23 patients for which we have these data, confirming that the selected dose of ORIC-101 achieves its biological objective in patients. This study also included a comprehensive translational effort to profile patient tumors and to discuss this work, I'll ask Lori to cover the next 3 slides. Lori?

Thanks, Pratik. Slide 20 illustrates the molecular characterization of GR in tumor biopsies from patients on trial. On the left bar plot or IHC data indicating the level of GR protein present in pretreatment tumor biopsies. 3/4 of the patients with tissue available for assessment at a GR H-score above 100 in tumor tissue, indicating moderate-to-high GR expression model. On the right side is an example of 1 patient with a high pretreatment GR H-score. In the on-treatment biopsy at the end of cycle 2, we observed a reduction in GR-positive sales, which may suggest treatment-induced tumor cell death. Overall, preliminary GR IHC results from this trial indicates that the majority of prostate tumors had moderate-to-high GR levels, following enzalutamide treatment, which is consistent with the literature. On Slide 21, we look beyond GR to other well-characterized mechanisms of resistance that arise in advanced prostate cancer. On the left are examples of AR resistance variants that confer resistance to AR-directed therapeutics, such as enzalutamide and includes splice variants like ARv7, point mutations like L702H and AR amplification. The right half depicts a second source of tumor heterogeneity in advanced disease. In this case, the tumor cells evolve through lineage plasticity to give rise to AR independence. One example of which is a neuroendocrine phenotype that is unresponsive to enzalutamide. In the scientific literature, biomarkers for the lineage switch are P53, RB1 and PTEN mutations or loss, and the lineage switch is defined as the presence of 2 out of the 3 biomarkers in a tumor. This tumor heterogeneity in post-enzalutamide patients was anticipated in our trial. On Slide 22, we more fully characterize the tumor heterogeneity observed in our own Phase Ib patient population. Tumor biopsies from patients were assessed in multiple assays, including DNA and protein analysis and a brief summary of the heterogeneity observed is shown in the pie chart. Approximately 40% of the tumors carried relevant molecular changes in lineage markers or AR resistance variants, such as AR point mutations, ARv7 splice variants or AR amplification. These 40% of tumors in our trial would not be anticipated to be responsive to enzalutamide, which is consistent with published data sets, such as Stand Up to Cancer. The potentially addressable patient population is estimated to be 60% of metastatic prostate cancer in the post-enzalutamide setting before taking into account GR status.

Thank you, Lori. Based upon this important tumor information, Slide 23 shows what a potential patient selection strategy might look like to account for these resistance factors. Starting with patients with metastatic prostate cancer who are progressing on enzalutamide, we might expect to filter out or exclude patients whose tumors have AR resistance variants because enzalutamide would not have activity against these tumors even if we block GR. We would then exclude tumors that harbor markers of lineage plasticity because they will be transitioning to an AR-independent state and again, would not be amenable to combined AR and GR blockade. And finally, we would select out those with low GR expression. The remaining patient population we would consider candidates for ORIC-101 combined with an AR modulator, which represents approximately 40% to 50% of the whole and remains a sizable proportion of addressable patients. With that as background, the next 2 slides show you outcome data for our entire Phase Ib population. On Slide 24, we have the waterfall plot for the 25 patients enrolled on or before July 15 with data as of August 20. The bars represent the maximal change from baseline of PSA for each patient. The bars are coded by dose level, with red representing patients treated at the RP2D. Along the bottom, there are 3 annotations for each patient, representing when available the tumor characteristics we just discussed. The baseline androgen receptor mutational status, the presence or absence of markers of lineage plasticity and the baseline GR H-score. Again, you'll see that despite being a population that only has ever seen enzalutamide in the castration-resistant setting, there's a high degree of tumor heterogeneity. The waterfall plot itself is separated into patients whose tumors harbor AR resistance variants on the left and those that have either wild-type or other variants not known to confer resistance on the right. You can see, as expected, all of the instances of PSA decrease are in those patients who have AR wild-type or nonresistant variants. In fact, the PSA decreases are predominantly limited to cases known to lack, not only AR resistance variants, but also markers of lineage plasticity and with moderate-to-high GR expression, again, as expected. Slide 25 presents the corresponding swimmers plot of the same 25 patients with the bars representing time on treatment with symbols depicting points of PSA progression, radiographic progression or clinical progression. The bars are coded by dose level with red representing patients treated at the RP2D. As with the waterfall plot, the same data with respect to the status of AR variants, markers of linage plasticity and GR H-score are presented along the y-axis. You'll note that many patients remain on the combination of ORIC-101 and enzalutamide, and this time on treatment correlated strongly with patients whose tumors did not harbor AR resistance variants, markers of lineage plasticity and low levels of GR expression. Let me break down this swimmers plot in more detail on Slide 26. This consort diagram starts at the top with the 25 patients in our current data set. We then sort them into those patients whose tumors harbor AR resistance variants and/or markers of lineage plasticity, features that would make them resistant to enzalutamide, regardless of GR expression. 9 patients fit this profile. And as you would expect, they have a very short time on treatment with enzalutamide and ORIC-101 at less than 2 months. Of the remaining patients, we weren't able to profile 4 of them, but 12 still had wild-type androgen receptor or had mutations that would not be expected to diminish their sensitivity to AR inhibition with enzalutamide, which explains why their median time on treatment with enzalutamide in ORIC-101 was 6.5 months in this group. Sorting this group of 12 by GR status, we found 8 patients where we could get biopsies and assess GR expression levels. 6 of these 8 or 75% were positive for moderate-to-high GR expression and their outcomes are depicted on Slide 27. Of the 8 patients who didn't have any AR resistance variants or markers of lineage plasticity and were evaluable for GR expression, 6 had moderate-to-high GR and 2 had low GR. Note that for the purposes of our analysis, we used a GR H-score of greater than or equal to 100 to indicate moderate-to-high GR, but we will continue to refine this, as we enroll more patients. The 2 patients with low GR at baseline, shown on the left side, quickly came off treatment at 1.8 and 1.9 months, respectively. In contrast, we observed different outcomes in the 6 patients on the right with moderate-to-high GR. 2 patients were on treatment for over 7 months with another 4 patients at varying durations still ongoing at the time of the data cut. If anything, absent therapeutic intervention with a GR antagonist, we would expect high GR expression to confer a worse outcome versus low GR expression, but it was the opposite in this case. Patients with moderate-to-high GR expression appear to be staying on treatment with enzalutamide and ORIC-101 longer compared to the low GR patients, which is notable and underscores the potential therapeutic value of ORIC-101 and the importance of our strategy to focus our target patient population. So let me summarize on Slide 28 and then discuss next steps. First, we've identified a well-tolerated recommended Phase II dose of ORIC-101 in combination with standard dose enzalutamide, with primarily Grade 1 or 2 treatment-related adverse events and no dose-limiting toxicities. Importantly, the combination regimen has a safety profile, consistent, with single-agent enzalutamide. Second, our PK and PD data show the exposure of ORIC-101 at the recommended Phase II dose exceeded the threshold needed for GR inhibition, and we were able to demonstrate this through consistent suppression of GR biomarkers in patients. Furthermore, we saw no evidence of a drug-drug interaction impacting enzalutamide. Third, through our extensive translational efforts and detailed tumor profiling, we found GR expression levels were moderate to high in 3/4 of patients, and this prevalence was consistent with the published literature. And finally, with this early look at the expansion cohort data, we were able to identify potential patient selection factors, including the absence of AR resistance variants, markers of lineage plasticity and the presence of moderate-to-high GR expression as a means to identify a target patient population for ORIC-101. The addition of ORIC-101 after progression on enzalutamide, alone, in these patients with these key selection factors enabled continued enzalutamide treatment, which is our ultimate development objective to offer patients an alternative to currently available in often toxic therapies post-progression on an AR modulator. Moving to Slide 29. As I stated earlier, enrollment continues in the expansion cohort. We have not yet implemented prospectively the selection factors just discussed. Rather, we will await additional enrollment in the expansion cohort before conducting an interim analysis where we expect to have sufficient data to make a determination. Our potential path forward will depend on the nature of the efficacy signal and in which patient population it resides. If the interim analysis bears out the patient selection factors we have been discussing, then our plan forward would be to prospectively enrich for such patients and identify those whose cancer remains AR-dependent without resistance alterations and potentially use as GR as its predominant pathway of resistance through high GR expression. We would look to incorporate a screening prospective blood test to select these patients with metastatic prostate cancer lacking AR resistance variants and markers of lineage plasticity. We would likely also update the cohort size and statistics based upon a revised efficacy objective of extending time on treatment with enzalutamide. Ultimately, our registrational strategy in this patient population will require a randomized controlled trial in which patients with metastatic prostate cancer progressing on a second-generation AR modulator, whose tumors remain AR-dependent without resistance alterations and express moderate-to-high levels of GR would be randomized to the combination of enzalutamide in ORIC-101 versus a second novel hormonal therapy with the primary endpoint of radiographic progression-free survival. Such a trial, we believe, would enable full regulatory approval. Back to you, Jacob.

Thanks, Pratik. As you can see, we're pleased with this initial data set for ORIC-101 in metastatic prostate cancer. While our immediate next steps are focused on completing enrollment in the expansion cohort throughout the remainder of this year and into 2022. We are highly encouraged by the early data, and we're already thinking through potential next steps we would pursue in response to more definitive efficacy signals we may see across the full set of expansion cohort data. We look forward to providing another update on this study next year. Now stepping back, beyond ORIC-101, as you can see on Slide 31, we've assembled a robust pipeline of differentiated product candidates sourced, from both, our internal discovery efforts and targeted opportunistic business development. We remain on track to file 3 INDs or IND equivalents this year and by early next year, we anticipate having an additional 3 programs beyond ORIC-101 in clinical studies. While the focus of today's call was the ORIC-101 clinical data throughout this year and including at this Triple Conference, we've presented substantial preclinical data on our next 3 programs that make the case for the potential best-in-class profile of each of these product candidates. For just a few minutes, we'd like to remind you of those highlights including new EGFR and HER2-focused data for ORIC-114. Slide 32 shows a snapshot of ORIC-114, a brain penetrant, orally-available inhibitor targeting EGFR and HER2 Exon 20 mutations, which we in-licensed last year. The outcomes for patients with EGFR Exon 20 mutations have been subpar thus far as molecules in the field have been limited, first, by a lack of selectivity for the target versus wild-type EGFR and various off targets. And second, by a lack of CNS activity, which is critical when over 1/3 of patients develop CNS metastases. Our comprehensive preclinical profiling of 114 demonstrates an exquisitely clean kinome tree, good therapeutic window versus wild-type EGFR, significant tumor regression in multiple in vivo models without signs of meaningful toxicity and compelling brain exposure and intracranial antitumor activity. We remain on track to file a CTA in Korea for 114 in Q4, after which we intend to initiate clinical studies. Since in-licensing this program, we've continued to conduct additional preclinical characterization to understand its differentiation versus other compounds targeting either EGFR or HER2. Lori will now cover some of these highlights, including from data presented today at the Triple Conference. Lori?

Thank you, Jacob. On Slide 33, we further characterized ORIC-114 in a head-to-head in vivo study in an EGFR Exon 20 insertion lung cancer model in which ORIC-114 demonstrated greater antitumor activity than the competitor compounds. A 90% complete response rate was observed for ORIC-114 at a well-tolerated dose of 3 mg per kg once daily. In contrast, no complete responses were observed for BDTX-189 and only 2 complete responses were observed for CLN-081. Additionally, the CLN-081 cohort had 25% of animals that had to come off study due to significant weight loss. Together, these in vivo data indicates the potential for a broader therapeutic index of ORIC-114. Switching gears to HER2 on Slide 34. One of the aspects of ORIC-114 that excites us is its potency, not only against Exon 20 mutations in EGFR, but also its potency against HER2 amplifications and Exon 20 mutation. This HER2 amplified breast cancer patient population, in particular, is highly prone to CNS metastases. At this conference, we are presenting preclinical data in support of the potential to leverage ORIC-114 brain penetration to address the high unmet need of these HER2 positive patients with brain metastases. HER2-positive breast cancer is around 25% of all breast cancer and approximately half of HER2-positive breast cancer patients develop brain metastases over the course of their disease. Most HER2-directed therapies are not effective at crossing the blood-brain barrier. And recently, tucatinib was approved for HER2-positive breast cancer patients with brain metastases. We hypothesized that tucatinib activity may be limited by modest brain exposure of the parent drug and effective metabolite. Thus, we initiated preclinical studies to investigate the opportunity for ORIC-114 in this disease setting. On Slide 35, the left bar plot has a cell growth results for a panel of breast cancer cell lines where a subset of the lines are HER2-positive, defined as HER2 amplification or overexpression. ORIC-114 cell potency EC50 values are strong, below 100 nanomolar and more potent than lapatinib and tucatinib. The selectivity is indicated by the activity only occurring in the HER2-positive cell line and not the HER2-negative or HER2 low lines. The in vivo results shown on the right indicates that ORIC-114 has strong antitumor activity systemically in a subcutaneous HER2-positive breast cancer model with tumor growth inhibition of 111% and 2 complete responses. A similar study with the tumors grown intracranially is being planned to better characterize the CNS activity of ORIC-114 versus tucatinib. In terms of what's already been characterized on ORIC-114's brain penetrant, slide 36 shows an example of extensive preclinical PK studies assessing brain exposure as presented at this conference. A key feature of ORIC-114 differentiation is that it was designed to optimize brain exposures across multiple parameters, including pump engagement, physical chemical properties and free unbound fraction in the brain. Together, these compound characteristics translate in vivo into a high brain-to-plasma ratio in mice of nearly 1, as shown in the graph on the right, which is plotted with the y-axis on the log scale to easily distinguish which compounds have high brain-to-plasma ratio. Importantly, ORIC-114, high brain-to-plasma ratio was maintained at both 1 and 4 hours, and the graph depicts the free unbound fraction. The pre-brain-to-plasma ratio of ORIC-114 is superior to other Exon 20 directed agents such as mobocertinib and CLN-081, and is also superior to tucatinib and its active metabolite. In summary, the limitations of current therapies to address brain metastases in both the Exon 20 mutant population and the HER2-positive patient population present an opportunity for ORIC-114.

Thank you, Lori. Rounding off briefly on the rest of the pipeline, starting on Slide 37. ORIC-533 was designed internally at ORIC as a small molecule inhibitor of CD73, with picomolar potency, good oral bioavailability and retain significant potency and function even in a high AMP environment, more so than any other CD73 inhibitor or adenosine receptor antagonist we've tested. Importantly, and different from the rest of the field that is pursuing combination studies for their CD73 inhibitors, we plan to initiate clinical trials in Q4 as a single agent in an undisclosed tumor type in which we've observed compelling single-agent activity in patient-derived models. Turning to Slide 38. On the left, our recent clinical proof-of-concept data for CD73 inhibition in non-small cell lung cancer, in the coast randomized trial with checkpoint inhibitor combination. oleclumab, an anti-CD73 antibody, improved PFS with an impressive hazard ratio of 0.44 and the median PFS not yet reached. In preclinical studies, such as shown on the right, in head-to-head comparisons, ORIC-533 is much more potent at inhibiting adenosine generation as compared to oleclumab. Additional studies not shown here also indicate ORIC-533 is more potent at T cell activation. We believe the collective set of features of ORIC-533 of potency and high AMP, slow off rate and oral bioavailability have created a potential best-in-class profile for targeting CD73 and addressing immune suppression in tumors. Thus, as competitors generate compelling combination data in the clinic, we believe the read-through to our CD73 program is strong because of ORIC-533's potential best-in-class profile. Importantly, as I mentioned earlier, and different from the rest of the field that is pursuing these combination studies for their CD73 inhibitors, we plan to initiate clinical trials in the fourth quarter of this year as a single agent in an undisclosed tumor type in which we've observed compelling single-agent activity. This allows us to seek out an efficacy signal even faster and more definitively than combination approaches. Finally, turning to Slide 39. ORIC-944 is an allosteric PRC2 inhibitor that we in-licensed last year for Mirati. This molecule targets the EED subunit of PRC2 and has been optimized to overcome some of the biological and drug property limitations of the EZH2 inhibitors. The first-generation approach to tackling PRC2-related epigenetic dysregulation. With this molecule, Mirati demonstrated in vivo preclinical activity superior to that of an approved EZH2 inhibitor in a DLBCL model. ORIC has further demonstrated compelling in vivo activity in 2 different enzalutamide-resistent prostate models. We are on track to file the IND for 944 in Q4, after which we intend to initiate single-agent studies in prostate cancer. We'll wrap up our prepared remarks on Slide 40. We're very proud of the team and pipeline that we've built in ORIC. Today's initial prostate cancer data readout for ORIC-101 helps further support the role of GR as a novel target in oncology resistance and the potential best-in-class profile of ORIC-101. We look forward to providing additional updates on both the enzalutamide and Abraxane ORIC-101 combination studies in 2022. Beyond ORIC-101, we've put together one of the most robust pipelines of potentially best-in-class molecules in small-cap biotech going after an array of validated targets. Before we open it up to Q&A, I'd like to thank all the investigators and the entire ORIC team who've worked valiantly throughout the COVID pandemic to continue tackling our mission on behalf of patients. And most importantly, I'd like to thank our patients and their families whom we hope to help overcome resistance in cancer. With that, let's open it up for Q&A.

[Operator Instructions] Our first question will come from the line of Anupam Rama from JPMorgan.

Just 2 quick ones for me. Why are you using time on treatment instead of, say, PSA or PFS? Is time on treatment an appropriate sort of regulatory endpoint for measuring antitumor activity? And then for the 6 patients where you talk about time on therapy, being pretty good durability. How does that compare to historical benchmarks, particularly in the context of -- I think some of those patients also were noted in the swim lane plots to have PSA progression.

Anupam, I'll ask Pratik to take those.

Sure. So just answering your first question in terms of time on treatment. So I mean our overall therapeutic objective in this patient population that's progressing on enzalutamide is to extend their time on enzalutamide before they have to go to more toxic therapies like chemotherapy, which would be indicated at that point. And that's why we focus this initial analysis on a durability-based measure such as time on treatment. And actually, if you look at the prostate cancer working group guidelines, they recommend this approach in early phase studies. So that you capture the important events, including PSA progression, clinical progression, radiographic progression all the way up to the time that treatment is ultimately discontinued so that you can capture the full scope, the full range of potential patient benefit. But time on treatment does serve as a general proxy for time to radiographic progression, which would be a more -- which would be sort of a more standard regulatory endpoint. If you look at the swimmers plot, which has the 25 patients that we presented on today, 9 are still ongoing, but of the 16 that are remaining, half of them discontinued at the time of radiographic progression based upon our study protocol of scans at the 8 weeks. And of the remaining 8 patients, they all discontinued before radiographic progression. So time on treatment, in fact, is shorter than their time to radiographic progression. So it does serve as a general surrogate for us. And in fact, it might underpredict for the radiographic progression endpoint. But you're right, that's for a registrational study, we would use an appropriate regulatory endpoint, which would be radiographic PFS. And with more follow-up and more patients, we hope to make an estimate of that on this study as well. Your second question about the benchmarks. So since we're doing patient selection here, which we sort of set out to do, we can't really compare to historical data set easily because we're looking at patients whose tumors have high GR expression versus low. And that sort of breakdown is not present in other published experiences. And the patients that are GR high and without the other AR resistance or lineate switch markers, 4 of the 6 are still ongoing as of the data cutoff. So we can't calculate a median, but the closest comparator, overall, would be the Call of Paper. This was published a couple of years ago where they crossed over patients. They first treated patients with enzalutamide or abiraterone and then progression, cross them over to the opposite and continue to follow them. So our closest comparator would be the patients who started out on enzalutamide and then at PSA progression crossed over to abiraterone and their time on treatment median was 3.6 months. So if you couple that with the observation that high GR expression correlates with worst outcomes not just in prostate cancer, but other tumor types as well. I think our data here, right now, compare quite favorably.

Our next question comes with Maury Raycroft from Jefferies.

Congrats on the update. I'm just wondering if you could remind me if the patient selection strategy of selecting patients with no AR resistance variants or markers of lineage plasticity and with the moderate-to-high GR, was that all part of your prespecified selection criteria? Or were some of those criteria developed retrospectively?

I can take that. So we fully expected that we would have to perform patient selection, which is why we planned from the very beginning with the first patient full genomic profiling of tumors, biopsies for GR expression because we knew that there were other well-described mechanisms of resistance to AR modulators that we've discussed here, alterations to the androgen receptor through point mutations or splice variants as well as these markers of lineage plasticity indicating lineage switch, which is something that is not just unique to prostate cancer, but seen in other tumor types as well. So this was something that we've made part of the protocol from the very beginning. And then an important aspect of the study was to determine how we could identify these factors to potentially screen patients with platforms that would allow us to do this prospectively. And I feel we have developed such an approach that we could implement down the road.

Got it. That's helpful. And then can you talk about the limited PSA responses you're seeing to date? And based on the underlying biology, would you expect to see PSA responses in this population at all and maybe comment on why or why not?

Sure. So we wouldn't actually necessarily expect PSA to go down based upon the mechanism of action of ORIC-101, which is working through inhibition of the glucocorticoid receptor. So as you know, normally PSA is a target gene of the androgen receptor, but we selected patients for a trial on the basis of a rising PSA on enzalutamide, which means that AR inhibition with enzalutamide, at this point now, was no longer affecting the patient's PSA. They were on enzalutamide, but the PSA was rising. So there was no connection now between AR and PSA target expression. Now PSA, as I said is a target gene of the androgen receptor, but it's not one of the overlapping genes also targeted by the glucocorticoid receptor. So if you look back at that Venn diagram we showed, it's not in the overlap region between AR and GR. So by inhibiting GR and preventing bypass through that pathway, we wouldn't necessarily expect to restore the ability of AR inhibition to decrease PSA. So actually, PSA is not a very good readout for ORIC-101 activity.

Got it. Okay. And maybe last quick question. Just going back to the patient selection strategy and thinking bigger picture, I guess, how would you respond to the argument that your patient selection strategy is only selecting patients expected to do well?

So we are selecting patients as we just discussed. And that's really driven by our understanding of the mechanism of GR inhibition and the GR pathway. So the GR bypass pathway still relies on the cell being AR dependent and that enzalutamide is able to inhibit AR effectively. So that means we do need to screen out patients whose tumors are no longer essentially the androgen receptor and that tumor is no longer sensitive to enzalutamide, either through a point mutation, splice variant or they've undergone lineage switch. So that is the first cut, and that is essentially mechanism-driven. The other half is also mechanism-driven. We need tumors that are GR high, but GR high doesn't necessarily mean those patients will do well. In fact, the literature would tell you the opposite would be true. In prostate cancer, tumors that are GR high predict for a poor response to enzalutamide and early progression and in other solid tumors, as we've discussed before, with our ASCO presentation on our Abraxane study, high GR predicts for worse outcomes in endometrial cancer, ovarian cancer and breast cancer. So these results that we presented today would be the opposite of what you'd expect and doesn't suggest that we're just merely selecting for the better prognosis patients.

Our next question will come from the line of Michael Schmidt from Guggenheim.

I had a few. Maybe first one on the ORIC-101 data. Just wondering if there was a dose response in any way that may have been observed. And then just following on the prior question, just on the fact that you wouldn't expect a PSA reduction, I guess, just confirming whether the study entry criteria. I thought the patients had to be progressing on prior AR antagonist and whether that would include patients with rising PSA at study entry, I just wanted to confirm that. And then the last question on this was just on, it sounds like you're trying to generate more data here into the expansion cohort. And I was just wondering what you would like to see here and what the go, no-go criteria would be in 2022 to potentially advance this program? And then I had a separate question after that.

Thanks, Michael. Let's have Pratik take those.

Sure. So with respect to your first question about dose response. So as you saw in the presentation, our PK did demonstrate that with higher doses we were getting to higher exposures, but even at the lowest dose level of 80 milligrams, which is where we started, we were reaching plasma concentrations that were above the threshold for GR inhibition based upon our preclinical studies. So that's why we didn't really observe a dose response in our pharmacodynamic biomarker readout, but we did see a higher rate of adverse events as they went up, mostly just higher rates and grades of fatigue and nausea. But in terms of GR inhibition and our pharmacodynamic readouts, we did not see dose response because I think we were actually already in the range from the very beginning. Then on your question about progression on PSA as an eligibility criteria, and you're correct. So we did use the PCWG criteria for PSA progression as a criterion for study entry. So that was my point earlier that these patients on enzalutamide were having a rise in PSA. And so that connection between AR and PSA as an AR target gene was essentially not present at the point of study entry and GR wouldn't be expected to restore that signaling connection, which is why PSA is not something that we're focusing on. And then your last question about what we would need to see. So as I said earlier, our therapeutic objective is to maintain patients on enzalutamide by adding ORIC-101 to the regimen. And so I think in broad terms, if we can maintain patients in our target patient population on this combination of ORIC-101 and enzalutamide for an additional 6 months after PSA progression on single agent enzalutamide, we'd feel that we'd have something that will be clinically meaningful and worth further development. So that's what we hope to look for in our cohort expansion.

Okay. Super. And then just a follow-up on ORIC-533, your CD73 inhibitor. I was just wondering how you interpret the recent data from AstraZeneca at ESMO and whether that has changed or impacted your potential development strategy for this inhibitor?

Michael, it's Jacob. I can take that one. Yes. So obviously, we, like many others took note of that recent coast data from AZ. It's the first randomized large data set for CD73 as a target. And obviously, that PFS hazard ratio of 0.44 was quite impressive. So from our perspective, it's great to see that validation of the target. Obviously, we've presented a lot of preclinical data that we -- some of which we review today, but basically showing a potential best-in-class profile for this molecule compared to all the classes that you would think of. So compared to the antibodies, compared to the small molecule CD73 inhibitors, compared to the adenosine receptor antagonists. So we clearly think we have a differentiated profile of ORIC-533 versus those. That said, for the immediate near term, we aren't planning to go launch into big I/O combo studies. It doesn't mean we're taking that off the table in terms of the medium or longer term, the immediate near-term focus is really on the single-agent development strategy that we came up with last year. So as a means of differentiating from the rest of the field, not only by the preclinical profile that I just walked through, but also in terms of clinical plans. Last year, we established a collaboration with an outside KOL who is the world's leading expert in 1 particular tumor type, which we have not disclosed yet for competitive reasons. And in those patient-derived models, saw compelling preclinical evidence for single-agent activity of a CD73 inhibitor in that tumor type. So that's what we have said. Starting Q4 this year, we expect to enroll the first patient for ORIC-533 in that undisclosed tumor type. We will also reveal in Q4 this year, what that undisclosed tumor type is. But I think that lets just call the question of efficacy really quickly with ORIC-533. One of the things you've seen with both our prostate update and previously the Abraxane update for ORIC-101 is just obviously the longer time lines to see signal in a combo regimen. And I think for that reason, from a corporate perspective, we're more focused for 533 on a single agent strategy here for the near term. That said, like I said, we are very open in the medium term to doing bigger I/O combo studies, but I would say that those are things that probably a large pharma partner with a PD-1 or PD-L1 of their own might be better suited to do. Thankfully, right now, we're one of the only unencumbered CD73 programs out there. So I think that helps to hopefully put us in the driver seat for those discussions.

Our next question will come from the line of Yigal Nochomovitz from Citi.

This is Carly on for Yigal. We have 2 questions. First, can you talk about how many more patients you believe you need to enroll before making a go, no-go decision and the expected timing for that? And then secondly, in addition to extending time on treatment, providing a meaningful benefit to patients, would you eventually expect to see RECIST responses with the GR blockade mechanism.

Thanks, Carly. Pratik, take this.

Sure. So in terms of how many more patients, so our interim is going to be conducted when we had approximately 30 patients enrolled to the expansion cohort, and those patients need to have sufficient follow-up. So we expect to reach this milestone in the first half of 2022. And then with that, we'll expect to update this study in next year as well in 2022. In terms of RECIST responses, I think, again, what we're looking at here is a mechanism that results in disease stabilization and prolonged time on treatment and deferred progression. So we wouldn't necessarily expect just as with PSA to see RECIST responses either.

And the next question will come from the line of Kevin DeGeeter from Oppenheimer.

Just maybe 2 for us on 101 and then maybe a follow-up. I think you mentioned, Pratik, that adding 6 months with enza plus 101 would be a clinically relevant threshold. Could you point anything in the literature to help us understand how that might translate for this GR moderate-to-high population in terms of PFS, the ultimate registrational endpoint. And then I guess for the 2 patients that you call out that stayed on drug beyond that threshold, one, I guess, 7 to 11 months, were those GR high patients, moderate patients? Just do we have GR scores for those 2?

To answer your second question, first, I think it's actually on the slide, the GR scores. So 1 was -- the GR score was 160 for the patient that's at 11 months. And then the one that's a little past 7 had almost -- got the high score 298 out of a possible 300. So they were GR high. All of the ones in red in that slide are GR high. And right now, we're using the cutoff of an H-score greater than 100 -- greater than or equal to 100, but we'll also refine that as we go through our expansion cohort.

And Kevin, just on that point, as it so happens, those 6 GR moderate to high that are on that slide, the lowest score was 160. So it was 160 and higher as it so happened in that group.

And then in terms of PFS. So yes, so you're asking what a 6-month time on enzalutamide would translate into in terms of. So I think actually would translate roughly to about a 6-month time to radiographic progression-free survival. So that's the interval we'd be looking for.

Great. And then just as we think about the slide you highlighted today with regard to potential development of 114 in HER2-positive breast cancer. Just -- How do you think about the landscape there, given some of the data we saw at ESMO from certain other HER2 amplifying agents and kind of just sort of how do you think about the clinical thresholds for these Exon 20 patients against a backdrop of improvement for certain other segments of the HER2 population.

So in terms of the HER2 population, I think, obviously, the showstopper was being HER2 data in second-line breast cancer. And so our feeling there is that small molecule inhibitors of HER2 like ORIC-114, still have great potential, and we're still very excited about our potential there over and above our interest in the EGFR space with 114. Several ways to pursue development. One is combination. Obviously, there's a lot of work done not with in HER2 yet, although there are ongoing studies of combinations of antibodies and small molecules demonstrating better outcomes than using either modality alone. Second, as you know, breast cancer has a high rate of CNS involvement brain metastases. And so HER2 studies were done and at least the ones that have seen that are being planned exclude patients with active brain mets. And as we have said all along, one of the most exciting aspects of 114 is its potential for high CNS activity. And so that makes a combination all the more compelling. And then finally, just second line after in HER2. These patients who get in HER2 second line and potentially eventually first line, once they progress, which will still unfortunately happen, second-line therapies will be needed and ORIC-114 could be well positioned there as well.

And our last question will come from the line of Colleen Kusy from Baird.

So the 2 longest duration patients that look like received radiation therapy. What triggered the radiation therapy? Did you see anything notable after? And would you expect to use radiation in additional patients?

Triggered it was pain. So it's usually a bone met that is causing pain. So that's what triggers the radiation. It's pretty routine.

Got it. And then the time to start on enza, the median, I think, was 20 months, but there was a pretty wide range. So was there any difference in those that progress more rapidly on enza?

No. We'll obviously redo that analysis once we have more data, but there wasn't an apparent sort of difference in outcomes. An important aspect was that we were, as part of the eligibility screening out patients who progressed on enza within the first 3 months of starting on enza, to try to screen out the ones who never had or developed any kind of response to enzalutamide. But beyond that, as you said, there is still a big spread in terms of time on enzalutamide. And to date, we haven't seen that correlate with any of the outcome measures.

Thank you. And that will conclude our Q&A segment for today. And with that, this will conclude our program for today. Thank you for participating. You may all disconnect.