STIFEL 2026 HEALTHCARE CONFERENCE - ORIC PHARMACEUTICALS INC

Explicit Guidance:

• Himalayas I (PRC-2 inhibitor): Top-line data expected in the first half of 2028.
• Inozertinib (EGFR atypical): Phase III study expected to commence in the first half of 2025.
• Inozertinib (EGFR exon 20): Additional data expected in mid-2027; Phase III initiation contingent on data review.
• Program Update: Commitment to provide a second-half program update (timing within H2 2025/2026 depending on calendar reference), which may include insights on the Himalayas I trial status, a potential second Phase III study in prostate cancer, or incremental data from existing cohorts.
• Control Arm Benchmark: Pfizer's Phase III control arm (enzalutamide/docetaxel) expected to yield a progression-free survival (PFS) of 5 to 8 months; 50-50 split assumption yields ~6.75 months durability.
• Safety/Dosage Context: Pfizer's regimen noted to be reduced from 1250mg BID (fasted) to 875mg (fed state) to mitigate toxicity.

Business-Segment Outlook:

• Prostate Cancer (RIN-Z):
  • Mechanism: Conviction in PRC-2 inhibition combined with AR inhibitors; preclinical and clinical data suggest superior safety/tolerability compared to competitors.
  • Differentiation: Targeting safety profile as key commercial driver (similar to darolutamide in current market); potential to capture market share via reduced fatigue, diarrhea, and drug-drug interactions (no BBB crossing).
  • Market View: Physicians indicate >70% prescription likelihood based on safety differentiation assuming equivalent efficacy.
  • Next Study Potential: Considering Phase III expansion into metastatic castration-sensitive prostate cancer (CSPC) or earlier post-ARi populations if MevPRO-1 outcomes are positive; currently focusing on post-abiraterone metastatic CRPC.
• Lung Cancer (Inozertinib):
  • Atypical Mutations: Phase III design targets "untreated brain mets" with high CNS activity (70% CNS response in ~60% of patients with baseline mets). Control arm: Osimertinib or Afatinib (neither approved/ideal for atypicals).
  • Exon 20: Three-prong approach (monotherapy, chemo combo, Amivantamib combo) to be reviewed mid-2027 for potential Phase III initiation.
  • CNS Penetration: High brain penetrability is a core differentiator, addressing unmet need in patients with brain metastases (who often lack options and face treatment discontinuation).

Market and Competitive Outlook:

• Competitor (Pfizer MevPRO-1):
  • Timeline Shift: Primary completion date shifted from mid-2026 to Q3/Q4 2026, then to February 2027 (Q1 2027) due to slower-than-expected event accumulation in the treatment arm.
  • Data Validation: Recent ASCO 2025 data (80-patient randomized) showed 14.3-month PFS benefit vs. ~6-month control; validates the PRC-2 mechanism.
  • PSA Confounder: Pfizer data suggests PSA levels may not correlate with clinical benefit (PRC-2 mechanism increases KLK3 expression/PSA), but PFS remains robust (9-month single-agent data).
• Competitor (J&J Riptac):
  • New Mechanism: T-cell engager data at ESMO is viewed as "exciting" but early; long-term durability and safety profiles remain unknown.
  • Coexistence: White space exists for multiple therapies (T-cell engagers, PRC-2 inhibitors) in the massive prostate cancer market.
• EGFR Landscape:
  • Atypical Segment: Significant unmet need; competitors (Afatinib, Osimertinib) show low efficacy, poor tolerability, or exclusion of brain met patients.
  • CNS Activity: Inozertinib's brain penetration is a critical differentiator against first-generation EGFR inhibitors, driving longer PFS and commercial opportunity.

Macro / Industry Outlook:

• Regulatory Endpoints: Emphasis that PFS (not PSA) is the regulatory endpoint for approval; PSA responses can be misleading with epigenetic mechanisms.
• Clinical Trial Operations: Phase 3 blinding to PSA levels expected to reduce early discontinuation rates compared to Phase 1 unblinded studies, where "PSA not budging" often leads to dropout.
• Patient Demographics: Market focused on elderly men (65-70+) requiring long-term therapy (4-5 years), making safety and tolerability paramount for market penetration.
• Economic/Supply: No specific macro FX or rate impacts mentioned; focus remains on clinical execution and competitor readouts.

Strategic Initiatives:

• Himalayas I: Already initiated Phase III in H1 2025 (metastatic CRPC, post-abiraterone).
• Inozertinib Phase III: Enrollment planned for H1 2025 in EGFR atypical population.
• Inozertinib Exon 20 Strategy: Continuing monotherapy, chemo, and amivantamib combination studies through mid-2027 to determine Phase III eligibility.
• M&A/Partnerships: No specific M&A or partnership guidance provided; focus is on internal Phase III execution.
• Capacity/Capex: Not explicitly quantified, but implies increased operational focus on managing two simultaneous Phase III programs.

Risks and Headwinds to Outlook:

• Pfizer Outcome Uncertainty: While "big miss" considered low probability due to biological validation, potential for "small miss" (regimen-related issues or safety discontinuation) remains.
• Safety Profile: Potential for off-target toxicity (on-target toxics) as seen with Pfizer's higher starting doses; differentiation depends on RIN-Z maintaining a superior safety profile.
• Data Interpretation: Risk that Pfizer's delayed readout might not provide granular color on safety vs. biology, limiting Auric's ability to adjust Phase III strategies immediately.
• Competitor Acceleration: New mechanisms (e.g., J&J T-cell engagers) could shift the competitive landscape or standard of care before Auric's top-line data.
• Patient Recruitment: While CNS enrichment is a natural outcome, prospectively managing CNS met populations in Phase III to ensure statistical power remains a consideration.

Management Tone on the Future:

• Confidence: High confidence in the PRC-2 mechanism and the "totality of data" supporting a move to Phase III ahead of Pfizer's readout.
• Stance on Delays: Viewing Pfizer's delay as a signal of "less events occurring" rather than failure; expects Pfizer to proceed with the study despite timing shifts.
• Differentiation: Strong belief that safety/tolerability will drive commercial success (comparable to darolutamide's market leadership), citing independent market research (>70% physician preference).
• Hedges: Acknowledges the "small miss" scenario for Pfizer is possible but attributes it to regimen/safety rather than biology.

Miscellaneous:

• PSA Biomarker: Clarified that PRC-2 inhibitors may paradoxically increase PSA (due to KLK3 upregulation) without compromising PFS, contrasting with typical AR inhibitors.
• Trial Design Specifics: Inozertinib Phase III (300+ patients) randomized vs. Osimertinib/Afatinib; allows both treated and untreated brain mets (not exclusive to untreated).
• Market Size: Prostate cancer described as "huge" and "underserved"; Atypical lung cancer estimated at ~3% of lung cancer cases (larger than ROS1/RET).