Rinzimetostat Dose Optimization Data Update

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Rinzimetostat Dose Optimization Data Update Agenda Executive

Summary Preclinical Differentiation Clinical Program Update and Next Steps - Selection of Phase 3 Dose - Preliminary Profile of Phase 3 Dose - Next Steps and Registrational Strategy Commercial Potential for

Himalayas-1 and Beyond Q&A ORIC Participants Jacob Chacko, Chief Executive Officer Lori Friedman, Chief Scientific Officer Pratik Multani, Chief Medical Officer Matt Panuwat, Chief Business Officer

Dominic Piscitelli, Chief Financial Officer Keith Lui, SVP Commercial and Medical Affairs 3

Clinical Pipeline Focused on Advancement of Rinzimetostat and

Enozertinib Discovery / Clinical Phase 3 Program Indication IND Enabling Phase 1/2 Pivotal / Phase 3 Collaboration Initiations PRODUCT CANDIDATES Himalayas-1 Combination with darolutamide Expected in 1H 2026 Rinzimetostat Potential Prostate

Cancer Himalayas-2 (ORIC-944) in 2027 PRC2 inhibitor Combination with apalutamide 1L monotherapy NSCLC (1) 1L combination with SC amivantamab EGFR exon 20 1L combination with chemotherapy Enozertinib Potential

Redwood-1 (ORIC-114) in 2027 EGFR inhibitor NSCLC 1L monotherapy EGFR PACC Clinical-stage pipeline includes two potential best-in-class programs addressing large solid tumor market opportunities; Both programs approaching initiation of

registrational trials Note: PACC - P-loop and alpha C-helix compressing. Abiraterone refers to abiraterone acetate. (1) Clinical collaboration with Johnson & Johnson to evaluate enozertinib in combination with amivantamab and

hyaluronidase-lpuj subcutaneous injection (SC amivantamab) in patients with first-line NSCLC with EGFR exon 20 mutations. 5

Rinzimetostat Continues to Demonstrate Its Potential as a

Best-In-Disease New Therapeutic Option for Prostate Cancer PRC2 inhibitors have shown significant rPFS in mCRPC, comparing favorably to approved & emerging therapies Rinzimetostat is a next-generation PRC2 inhibitor designed to

have best-in-class drug properties Rinzimetostat 400 mg QD with darolutamide selected as provisional RP3D for first Phase 3 Highly competitive emerging efficacy profile (rPFS, PSA, ctDNA) supportive of durable clinical benefit

Highly differentiated, potential best-in-disease safety profile, with significantly lower frequency and severity of adverse events than competitor regimens, and conducive to long term dosing First Phase 3 trial in post-abiraterone

mCRPC expected to initiate in 1H26; additional trials under consideration Post-abiraterone mCRPC is a significant unmet need and commercial opportunity, representing a $3.5bn total addressable market annually in the US with lack of oral and

well-tolerated therapies Source: ORIC data on file. DRG 2025, Raval et al. J Clin Oncol (2025), Gebrael et al. J Clin Oncol (2025) and Schweizer et al. ASCO GU (2025). 6

PRC2 Inhibitors Are Associated with Significant Radiographic

Progression-Free Survival in Post-ARPI mCRPC, Comparing Favorably to Available Therapies Therapies for 1L+ mCRPC (Post-ARPI) Treatment Status 5-Month rPFS Median rPFS (months) 60% Enzalutamide (Xtandi ) Approved 6.2 65% 8.0 Cabazitaxel

(Jevtana ) Approved 75% 8.3 Docetaxel (Taxotere ) Approved Lutetium Lu 177 vipivotide 75% 9.3 Approved tetraxetan (Pluvicto ) 80% to 84% ~12 to 14 Mevrometostat + Enzalutamide Phase 3 Starting 84% to 85% Not mature Rinzimetostat +

Darolutamide Phase 3 PRC2 inhibitors in combination with an AR inhibitor have demonstrated much longer rPFS (key regulatory primary endpoint) than what has been reported with other approved and emerging therapies Source: Morris et al. Lancet (2024),

Petrylak et al. J Clin Oncol (2025), de Wit et al. N Engl J Med (2019), Schweizer et al. ASCO GU (2025), Schweizer et al. ASCO (2024), and Matsubara et al. ASCO GU (2026). Note: Androgen receptor pathway inhibitor (ARPI) represents abiraterone,

enzalutamide, apalutamide and darolutamide. Competitor rPFS percentages estimated from published data. All trademarks are the property of their respective registered owners. 7

Combination of Rinzimetostat + Darolutamide Compares Favorably to

Competitor PRC2 Combination and to AR Inhibitor Monotherapy In Post-Abiraterone mCRPC Rinzimetostat Dose Optimization Update (March 2026) Mevrometostat 1250 mg BID Rinzimetostat 400 mg QD Enzalutamide Fasted + Enzalutamide + Darolutamide 78% 92% 93%

3-Month rPFS 70% 86% 84% 4-Month rPFS 60% 80% 84% 5-Month rPFS 15% 34% 33% PSA50 Fatigue (43% / 3%) Diarrhea (78% / 17%) Fatigue (39% / 0%) Nausea (25% / 0%) Dysgeusia (59% / 0%) Diarrhea (22% / 0%)

Anemia (23% / 3%) Decreased appetite (59% / 0%) Nausea (22% / 0%) Diarrhea (18% / 0%) Fatigue (56% / 5%) Blood creatinine increased (17% / 0%) Decreased appetite (18% / 0%) ) Anemia

(49% / 5% Decreased appetite (11% / 0%) Dysgeusia (8% / 0%) Nausea (42% / 0%) Anemia (11% / 0%) SAFETY Alopecia (39% / 0%) AE cutoff of 10% (All Grade / Grade 3) Thrombocytopenia

(29% / 2%); 2% Gr 4 Neutropenia (22% / 7%); 2% Gr 4 Vomiting (22% / 0%) Arthralgia (22% / 0%) Rash (20% / 2%) AE cutoff of 20% Rinzimetostat + ARi safety profile compatible with long-term dosing, with

the majority of AEs Grade 1, and no Grade 4/5 events Source: ORIC data on file. Enzalutamide and mevrometostat + enzalutamide data from Schweizer et al. ASCO GU (2025) and Matsubara et al. ASCO (2025). AEs <30% estimated from Matsubara et al.

ASCO (2025). Note: Competitor rPFS percentages estimated from published data. PSA50 represents confirmed responses. Cross-trial comparison in previously treated mCRPC patients shown. Rinzimetostat + darolutamide efficacy data as of March 6, 2026,

and TRAE 8 data as of January 16, 2026. Enzalutamide AEs represent TEAE cutoff >30% across both mevrometostat 1250 mg BID + enzalutamide and enzalutamide monotherapy.

Rinzimetostat Has the Potential to Address Multiple Large Market

Opportunities in Prostate Cancer, with Several Development Opportunities in Other Solid Tumors Potential Rinzimetostat Commercial Opportunity (US Only) Future Development Opportunities 90,000 >$10 billion US Est. Annual US Incidence opportunity

80,000 mCRPC 70,000 37,000 (RLT, TCE, ADC Combo) 60,000 33,000 patients >$3.5 billion US NSCLC 50,000 45,000 (KRASi Combo) opportunity 40,000 CRC >$3.5 billion US 65,000 30,000 (KRASi Combo) opportunity 20,000 patients 20,000 Breast Cancer

220,000 10,000 (ERi Combo) 17,000 patients 0 mCRPC Post-Abiraterone mCRPC Post-AR Inhibitor mCSPC Rinzimetostat has the potential to address ~70,000 patients in the US with prostate cancer annually Source: DRG 2025, Swami et al. J Clin Oncol

(2025), Raval et al. J Clin Oncol (2025), Gebrael et al. J Clin Oncol (2025), SEER Cancer Stat Facts: Female Breast Cancer Subtypes, and ORIC data on file. Note: Addressable market assumes current price of ARPIs for illustrative purposes. RLT

- radioligand therapy; TCE - T-cell engager; ADC - antibody-drug conjugate. 9 Estimated Annual Incidence in the US

Preclinical Differentiation

Rinzimetostat: Next-Generation PRC2 Inhibitor Designed for

Best-in-Class Drug Properties Potential Best-in-Class PRC2 Inhibitor Landscape in Prostate Cancer CPI-1205 Tazemetostat Mevrometostat Rinzimetostat st st nd rd Key Features (1 gen) (1 gen) (2 gen) (3 gen) Superior potency vs. st 1 gen programs

across Cellular Potency Cellular Potency prostate cancer models Improved single agent and combination activity across In Vivo Activity In Vivo Activity prostate cancer models Strong Drug Strong Drug Higher and more consistent

Properties clinical exposures Properties (PK, solubility, no CYP autoinduction) Sustained target coverage Long Clinical Long Clinical and QD dosing Half-Life Half-Life (~20-hour half-life) Development Status Discontinued Discontinued

Phase 3 trials ongoing First Phase 3 initiation expected 1H 2026 Rinzimetostat is a potential best-in-class PRC2 inhibitor that addresses the limitations of earlier generation PRC2 inhibitors Source: Friedman et al. AACR (2024), Vaswani et al. J Med

Chem (2016), Motwani et al. and Bradley et al. AACR-EORTC-NCI (2019), Schweizer et al. ESMO (2022), Italiano et al. Lancet (2018), and Harb et al. TAT (2018). Note: Drug properties include absorption, CYP profile and metabolism, pharmacokinetic (PK)

and solubility profile. 11

Rinzimetostat Demonstrates Superior In Vitro Potency vs. First-Gen PRC2

Inhibitors In Vitro Potency in Prostate Cancer Cells LNCaP CWR22PC (AR-Positive Prostate Cancer Cells) (AR-Positive Prostate Cancer Cells) LNCaP (AR+ Cells) CWR22PC (AR+ Cells) 1.5 1.5 CPI-1205 CPI-1205 Tazemetostat Tazemetostat Mevrometostat

Mevrometostat Rinzimetostat Rinzimetostat 1.0 1.0 0.5 0.5 0.0 0.0 0.01 1 100 10000 0.01 1 100 10000 Concentration (nM) Concentration (nM) Rinzimetostat demonstrates potency in AR+ prostate cancer cell lines comparable to mevrometostat and superior

to tazemetostat and CPI-1205 Note: Head-to-head in vitro cell viability analysis with CellTiterGlo assay. 12 Cell Viability Cell Viability

PRC2 Epigenetic Dysregulation Plays a Key Mechanistic Role During the

Progressive Reprogramming of Prostate Cancers Treated with AR Inhibitors PRC2 Role in Prostate Cancer AR Dependent Prostate Cancer AR Independent Prostate Cancer Prostate cancer cells evade therapies by cellular reprogramming to an AR

independent state PRC2 inhibition can reverse or Castration sensitive Castration resistant Heterogeneous Lineage change prevent this process, such that prostate cancer cells regain or AR targeted therapies maintain AR dependency

Randomized data with PRC2 PRC2 inhibitors inhibitor + AR inhibitor Luminal cell state, reflects tissue of origin demonstrated significant PFS Pluripotent improvement Lineage Change Therapeutic potential of PRC2 inhibitors in prostate cancer is

maximized in combination with AR inhibitors Source: Mu et al. Science (2017), Dardenne et al. Cancer Cell (2016), Davies et al. Nat Cell Biol (2021), Nouruzi et al. Nat Commun (2022), Goel et al. Semin Cancer Bio (2022), and Schweizer et al. ASCO GU

Rinzimetostat Increases AR Signaling and Induces Luminal State to Drive

Synergy in Prostate Cancer Models Rinzimetostat Impact on AR Signaling Genes and Luminal Markers CRPC Model CSPC Model AR Signaling Genes Luminal Markers AR Signaling Genes Luminal Markers **** **** **** **** Rinzimetostat enhances AR signaling and

luminal markers to restore a cell state which has enhanced sensitivity to AR inhibition, providing strong mechanistic rationale for clinical combination Note: C4-2 CRPC xenograft tumors grown in intact mice (left), and LNCaP CSPC in vitro cells

treated for 14 days (right), were assessed by RNA-seq. Boxplots show average mean-centered expression of luminal markers (Daemen et al. AACR 2025) and AR signaling genes (Daemen et al. AACR 2024). Rinzimetostat vs. vehicle, weighted Stouffer test on

DESeq2 results using inversed log2 fold change standard errors as weights: ****, p<0.0001. 14 Mean-centered Signature Score Increasing Hormone Dependency Increasing Hormone Dependency

Rinzimetostat Remodels Chromatin to Block Transcription Factor Sites

that Drive Lineage Escape Rinzimetostat Impact on Accessibility to Lineage Escape Factors CRPC Model CSPC Model Less accessible More accessible Less accessible More accessible with rinzimetostat with rinzimetostat with rinzimetostat with

rinzimetostat Differential Enrichment of Transcription Factor Motifs Differential Enrichment of Transcription Factor Motifs Rinzimetostat reduces accessibility to lineage escape factors in both CRPC and CSPC Note: Comparison of transcription factor

motif accessibility based on ATAC-sequencing data in CRPC C4-2 intact xenografts (left) and CSPC LNCaP intact xenografts (right) treated with rinzimetostat + darolutamide vs. darolutamide. The accessibility change for every transcription factor

motif and its associated p-value are calculated using TOBIAS [Bentsen et al., Nat Comm (2020)]. Motifs that are significantly more accessible following combination treatment are shown in dark orange; more 15 accessible motifs with darolutamide

treatment are shown in blue. FOXA1:AR represents the FOXA1 motif juxtaposed to the AR half motif. -log10 (p-value) -log10 (p-value)

Rinzimetostat Increases Progression-Free Survival in Combination with

Darolutamide in Prostate Cancer Xenograft Tumors Progression-Free Survival in Prostate Cancer Xenografts CRPC Model CSPC Model 100 100 Rinzimetostat + Rinzimetostat + Darolutamide Darolutamide Mevrometostat + Mevrometostat + Darolutamide

Darolutamide Darolutamide Darolutamide 50 50 Vehicle Vehicle 0 0 0 10 20 30 40 10 20 30 40 Days Days Mevro + Rinzi + Mevro + Rinzi + Vehicle Daro Mevro Rinzi Vehicle Daro Mevro Rinzi Daro Daro Daro Daro Not Not Median PFS (days) 11 12.5 15.5 27 24.5

Median PFS (days) 18 25 21 19.5 28 Reached Reached Rinzimetostat combination with darolutamide improves progression-free survival in CRPC and CSPC settings in vivo Note: C4-2 CRPC model (left) grown in castrated mice and LNCaP CSPC (fast-growing

clone) model (right) grown in intact mice. Darolutamide 50 mg/kg BID, mevrometostat 100 mg/kg BID, and rinzimetostat 100 mg/kg QD. No drug-related tolerability issues. Progression event for either tumor volume >800 mm3 or morbidity. 16

Progression-Free Survival (%) Progression-Free Survival (%)