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Advancing candidates designed to address resistance mechanisms in multiple cancers
Our portfolio of novel agents targets multiple resistance mechanisms by leveraging our specialized expertise in the following areas:
PRC2 INHIBITOR PROGRAM: ORIC-944
The dysregulation of PRC2 methyltransferase activity can lead to tumorigenesis in a wide range of cancers including prostate cancer, breast cancer, and hematological malignancies. PRC2 is composed of two druggable subunits: EED and EZH2. Several companies are developing EZH2 inhibitors; however, the pharmacologic properties of these compounds result in high doses that achieve only partial target inhibition in the clinic. Additionally, preclinical studies suggest drug resistance to EZH2 inhibitors may develop via EZH1 bypass compensation or acquired mutations in EZH2. Allosteric inhibition of EED impacts the assembly, stabilization, and activation of PRC2, and may have benefits over EZH2-mediated inhibition of PRC2. ORIC-944 is a potent and selective allosteric inhibitor of PRC2 via the EED subunit that was designed to have superior drug properties over EZH2 inhibitors and is efficacious in androgen-insensitive and enzalutamide-resistant prostate cancer models in preclinical studies. We filed and cleared an IND with the FDA for ORIC-944 in the fourth quarter of 2021.
In January 2024, we reported initial data from the Phase 1b trial of ORIC-944 as a single agent in patients with advanced prostate cancer, demonstrating potential best-in-class drug properties, including clinical half-life consistent with a preclinical prediction of greater than 10 hours, robust target engagement, and a favorable safety profile. In May 2025, we reported Phase 1b combination data from the dose exploration cohort of ORIC-944 in combination with apalutamide and with darolutamide in 17 patients with mCRPC. In November 2025, we announced the completion of the dose exploration portion of the Phase 1b trial and the selection of provisional recommended Phase 2 doses (RP2Ds) of ORIC-944 to be tested in combination with the approved doses of darolutamide and apalutamide in the dose optimization portion of the Phase 1b trial: 400 mg and 600 mg once daily of ORIC-944 in combination with 600 mg twice daily of darolutamide; and 600 mg, 800 mg and 1,200 mg once daily of ORIC-944 in combination with 240 mg once daily of apalutamide. Also, in November 2025, we reported Phase 1b dose exploration data in 20 patients with mCRPC, which included the 17 patients reported in May 2025, who were treated with ORIC-944 in combination with 240 mg once daily of apalutamide or with 600 mg twice daily of darolutamide. Circulating tumor DNA (ctDNA) was assessed for 17 patients with mCRPC who had available ctDNA samples and evidence of ctDNA at baseline prior to study entry. The November 2025 data set (cutoff date of September 22, 2025) demonstrated PSA responses and ctDNA reductions across all ORIC-944 dose levels and at comparable rates in combination with apalutamide or with darolutamide. Broad and deep PSA responses were demonstrated, with 55% of patients achieving a PSA50 response rate (confirmed in 40%), and 20% of patients achieving a PSA90 response rate (all confirmed). Rapid and deep ctDNA responses were observed in patients across a breadth of AR mutations and other gene alterations, with 76% of patients achieving >50% ctDNA reduction, and 59% of patients achieving ctDNA clearance, which is greater than clearance rates observed in precedent trials with standard of care agents in comparable mCRPC patient populations. Both combination regimens demonstrated a safety profile compatible with long-term dosing, with the vast majority of treatment-related adverse events (TRAEs) Grade 1 or 2 in severity and consistent with PRC2 and AR inhibition. Only one patient experienced a Grade 3 TRAE, and there were no Grade 4 or Grade 5 AEs attributed to ORIC-944, apalutamide or darolutamide. We are now enrolling the dose optimization portion of the study, evaluating ORIC-944 in combination with AR inhibitors darolutamide and apalutamide. We expect to report dose optimization data in the first quarter of 2026, and we expect to initiate our first global Phase 3 registrational trial for ORIC-944 in mCRPC in the first half of 2026.
- Two druggable subunits:
– EED: responsible for histone binding; target of ORIC-944
– EZH2: responsible for histone methylation; target of first-generation inhibitors - Dysregulation of PRC2 linked to several cancers
– Decreased expression of target genes associated with poor prognosis in prostate cancer - First-generation inhibitors, designed to inhibit EZH2, have demonstrated promising clinical activity and chemoresistance
– Approved for epithelioid sarcoma and follicular lymphoma
– Limited progress made for treatment of prostate cancer
therapeutic potential in prostate cancer, among other indications
BRAIN PENETRANT EGFR/HER2 INHIBITOR PROGRAM: Enozertinib (ORIC-114)
The ErbB receptor tyrosine kinase family is involved in key cellular functions, including cell growth and survival. EGFR and HER2 exon 20 insertion mutations are observed across multiple solid tumors, including NSCLC, breast, gastrointestinal, bladder and other cancers. EGFR exon 20 insertion mutations are observed in approximately 2.1% of all patients with NSCLC and these patients have a worse prognosis than patients with NSCLC driven by other EGFR mutations. HER2 exon 20 insertion mutations are observed in approximately 1.5% of all patients with NSCLC and atypical EGFR mutations are observed in approximately 2.9% of all patients with NSCLC. Approximately one-third of patients with exon 20 insertion mutations develop brain metastases, which contributes to poor prognosis.
Enozertinib is a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations. Enozertinib has demonstrated greater brain exposure in preclinical studies compared to certain other compounds being developed against exon 20 mutations and has shown strong anti-tumor activity in an EGFR-driven intracranial lung cancer model. Enozertinib has also demonstrated strong anti-tumor activity in both a subcutaneous and intracranial HER2-positive breast cancer model. In the fourth quarter of 2021, we filed a CTA for enozertinib in South Korea, which was cleared in the first quarter of 2022. We also filed and cleared an IND with the FDA for enozertinib in the third quarter of 2022. We are enrolling a Phase 1b trial of enozertinib as a single-agent in patients with advanced solid tumors with EGFR and HER2 exon 20 alterations, atypical EGFR mutations or HER2 amplifications, and this trial allows patients with CNS metastases that are either treated or untreated but asymptomatic. We reported initial Phase 1b data from this trial at the ESMO Congress in October 2023, which demonstrated both systemic and intracranial activity in a heavily pre-treated patient population across multiple dose levels. Additionally, we are enrolling enozertinib in combination with subcutaneous amivantamab in patients with NSCLC with EGFR exon 20 mutations, and this trial also allows patients with CNS metastases that are either treated or untreated but asymptomatic.
of EGFR/HER2 driven cancers, including in patients with active brain metastases