Abstract LB337: Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC)

Abstract Background: mPDAC is a challenging, RAS-driven disease with 5-y survival of ∼3%. Standard 1L chemotherapy has substantial toxicity and limited benefit (ORR: 23-43%; PFS at 6 mo: 40%-50%; mOS: 8.5-11.7 months). Oncogenic RAS mutations occur in >90% of cases. Daraxonrasib is a potent, oral, RAS(ON) multi-selective inhibitor targeting GTP-bound mutant (incl. G12, G13, and Q61 mutations) and WT RAS. In a phase 1/2 study (NCT05379985), second-line daraxonrasib demonstrated manageable safety and encouraging early efficacy in pts with RAS-mutant mPDAC. Here, we present the safety and efficacy of daraxonrasib as 1L therapy for pts with RAS-mutant mPDAC (NCT05379985). Methods: Pts with RAS-mutant mPDAC received 1L daraxonrasib 300 mg QD and were evaluated for safety, tolerability, antitumor activity, and ctDNA response per treated and evaluable pts. Results: As of Dec 1, 2025 (median follow-up: 13.7 mo), 40 pts received daraxonrasib. All-grade TRAEsa (≥20%) were rash (88%), diarrhea (63%), stomatitis/mucositis (63%), nausea (53%), vomiting (50%), fatigue (35%), and paronychia (20%). Grade ≥3 TRAEs (≥10%) were rash, diarrhea, and stomatitis/mucositis (10% each). No Grade 4/5 TRAEs occurred. TRAEs led to dose modifications in 70% of pts and discontinuation in 1 (3%) pt. The mean relative dose intensity was 84%. Antitumor and ctDNA responses to daraxonrasib treatment are shown in the table. Conclusions: Daraxonrasib monotherapy in 1L mPDAC showed manageable safety, consistent with prior studies, and compelling preliminary efficacy supporting the initiation of a global 3-arm phase 3 study (RASolute 303) of daraxonrasib with or without chemotherapy in 1L mPDAC. Citation Format: Eileen M. O'Reilly, Brian Wolpin, Shubham Pant, Joel Randolph Hecht, Jennifer Valerin, Dae Won Kim, Nilofer Azad, Kyaw Aung, Lin Tao, Sumit Kar, Hina Patel, Rashmi Vora, Aparna Hegde, Alexander Spira, Alexander Starodub, Benjamin Herzberg, Ignacio Garrido-Laguna. Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB337.