Two Onc Docs, hosted by Samantha A. Armstrong, MD, and Karine Tawagi, MD, is a podcast dedicated to providing current and future oncologists and hematologists with the knowledge they need to ace their boards and deliver quality patient care. Dr Armstrong is a hematologist/oncologist and assistant professor of clinical medicine at Indiana University Health in Indianapolis. Dr Tawagi is a hematologist/oncologist and assistant professor of clinical medicine at the University of Illinois in Chicago.

In this episode, OncLive On Air® partnered with Two Onc Docs to provide a comprehensive review of data from the phase 3 RASolute 302 trial (NCT06625320), a landmark study presented at the 2026 ASCO Annual Meeting that has established daraxonrasib (RMC-6236) as the new standard of care (SOC) for the second-line treatment of patients with metastatic pancreatic adenocarcinoma.

The discussion began by highlighting the historical context of second-line treatment, where standard chemotherapy options like FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) or gemcitabine-based regimens typically yielded a median overall survival (OS) of only approximately 6 to 7 months. Although RAS mutations drive approximately 90% of pancreatic cancers, they were historically considered undruggable. Daraxonrasib addresses this challenge with its mechanism of action of an oral, RAS(ON), multi-selective, tri-complex inhibitor that targets the active GTP-bound state of both mutant and wild-type RAS, covering variants at codons G12, G13, and Q61.

The RASolute 302 trial was an international, open-label study that randomly assigned patients with progression after 1 prior line of therapy to receive either daaxonrasib or investigator’s choice of chemotherapy. In the RAS G12–mutated subpopulation of patients, daraxonrasib generated a higher median OS compared with chemotherapy. Similar benefits were observed with daraxonrasib in the overall population, where the median progression-free survival nearly doubled.

Drs Armstrong and Tawagi emphasized that the toxicities associated with daraxonrasib are highly clinically relevant and distinct from the myelosuppression seen with chemotherapy. Key adverse effects (AEs) include dermatologic events, diarrhea, and stomatitis. Management of these AEs is critical; the hosts recommended the use of prophylactic oral antibiotics and topical corticosteroids to manage rash, alongside standard oral care for mucositis. Despite being associated with these AEs, daraxonrasib was better tolerated than chemotherapy, with a low treatment discontinuation rate due to AEs.

Daraxonrasib is currently accessible in the US through an Expanded Access Program and is undergoing accelerated review for full FDA approval. The experts noted that the agent is being further investigated in the frontline setting through the phase 3 RASolute 303 trial (NCT07491445) and in the adjuvant setting via the phase 3 RASolute-304 trial (NCT07252232), potentially expanding the agent's effect across the continuum of pancreatic cancer care.