Advancing candidates designed to address resistance mechanisms in multiple cancers

PRC2 INHIBITOR PROGRAM: Rinzimetostat (ORIC-944)

The dysregulation of PRC2 methyltransferase activity is found in a wide range of cancers including prostate cancer, lung cancer, colorectal 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 may 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, thus allosteric inhibition of PRC2 via EED may have benefits over EZH2-mediated inhibition of PRC2. Rinzimetostat 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 receptor pathway inhibitor (ARPI) -sensitive and -resistant prostate cancer models in preclinical studies. We filed and cleared an IND with the FDA for rinzimetostat in 2021.

In 2024, we reported initial data from the Phase 1b trial of rinzimetostat as a single agent in patients with advanced prostate cancer, demonstrating potential best-in-class drug properties, including long clinical half-life, robust target engagement, and a favorable safety profile.

In May 2025, we reported Phase 1b combination data from the dose exploration cohort of rinzimetostat in combination with apalutamide or with darolutamide in 17 patients with metastatic castration-resistant prostate cancer (mCRPC).

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 rinzimetostat in combination with apalutamide or with darolutamide. The November 2025 data set demonstrated PSA responses and ctDNA reductions across all rinzimetostat 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). 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 rinzimetostat, apalutamide or darolutamide.

Also 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 rinzimetostat to be tested in combination with darolutamide and apalutamide in the dose optimization portion of the Phase 1b trial. We are now enrolling the dose optimization portion of the study and expect to report data in the first quarter of 2026. We expect to initiate our first global Phase 3 registrational trial for rinzimetostat in mCRPC in the first half of 2026.

PRC2 Function

PRC2 Background

• Two druggable subunits:
  – EED: responsible for histone binding; target of rinzimetostat
  – 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

Brain-penetrant EGFR inhibitor program: Enozertinib (ORIC-114)

The ErbB receptor tyrosine kinase family is involved in key cellular functions, including cell growth and survival. Epidermal Growth Factor Receptor (EGFR) mutations are observed across multiple solid tumors, including NSCLC, breast, gastrointestinal, bladder and other cancers. EGFR exon 20 and EGFR P-loop and alpha C-helix compressing (PACC) mutations are collectively observed in approximately 5% of all patients with NSCLC in the US. Approximately 30% of patients with EGFR mutant NSCLC have known CNS disease at diagnosis, and approximately 50% develop brain metastases over the course of their disease, with the brain often the first site of progression, which contributes to poor prognosis.

Enozertinib is a brain-penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR with high potency against exon 20 and PACC 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.

The CTA for enozertinib in South Korea 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.

Enozertinib is being evaluated in Phase 1b trials in EGFR exon 20 and EGFR PACC mutated NSCLC. The trials allow enrollment of patients with CNS metastases that are either treated or untreated but asymptomatic. We reported initial Phase 1b data with enozertinib as a monotherapy in patients with EGFR exon 20 mutations at the 2023 ESMO Congress, which demonstrated both systemic and intracranial activity in a heavily pre-treated patient population across multiple dose levels. We reported additional Phase 1b data at the 2025 ESMO Asia Congress in treatment-naïve and in previously treated NSCLC patients with EGFR exon 20 and EGFR PACC mutations. Enozertinib achieved highly competitive systemic response rates as well as profound antitumor activity in the CNS. Enozertinib also demonstrated a well-tolerated safety profile, with no significant off-target toxicity and manageable on-target toxicity, resulting in a low rate of discontinuations. Based on these data, 80 mg once daily oral enozertinib has been selected as the monotherapy dose for potential Phase 3 development. Dosing and follow-up continues in NSCLC patients with exon 20 mutations, including as a monotherapy, in combination with amivantamab and hyaluronidase-lpuj subcutaneous injection (SC amivantamab) and in combination with chemotherapy, as well as in NSCLC patients with EGFR PACC mutations as a monotherapy.

EGFR exon 20 Cancer with brain metastases