Phase III international randomized trial | RASolute 302 Trial Investigators | n = 500 | Previously treated metastatic PDAC | New England Journal of Medicine 2026 **O’Reilly et al.** Eileen M. O’Reilly, Zev A. Wainberg, Brian M. Wolpin Published in New England Journal of Medicine, 2026 Enrollment: 2024–2025 [PubMed Link](https://pubmed.ncbi.nlm.nih.gov/42223072/) --- ### Essential Takeaway RASolute 302 demonstrated significant improvements in overall survival, progression-free survival, objective response, and patient-reported outcomes with daraxonrasib compared with investigator’s-choice chemotherapy in previously treated metastatic pancreatic ductal adenocarcinoma. The trial is potentially practice-changing because it showed that direct inhibition of active RAS signaling can produce clinically meaningful benefit in a disease where RAS alterations are present in the vast majority of tumors. --- ### Clinical Question Does daraxonrasib improve survival compared with standard chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma? --- ### Population - Previously treated metastatic pancreatic ductal adenocarcinoma - Prior progression after one prior fluoropyrimidine- or gemcitabine-based regimen - ECOG 0–1 - Measurable disease by RECIST 1.1 - Documented RAS mutational status - No prior RAS-targeted therapy Most patients had RAS G12 mutations. - Overall population: 500 patients - RAS G12 population: 459 patients - RAS G12 mutations: 91.8% --- ### Study Design #### Arm 1 — Daraxonrasib - Daraxonrasib - 300 mg orally once daily - Continued until progression, unacceptable toxicity, or withdrawal #### Arm 2 — Investigator’s-Choice Chemotherapy Chemotherapy options included: - gemcitabine + nab-paclitaxel - modified FOLFIRINOX - FOLFOX - liposomal irinotecan + 5-FU/leucovorin Crossover was not permitted. --- ### Endpoints #### Primary Endpoints Dual primary endpoints in the **RAS G12 population**: - Overall survival - Progression-free survival by blinded independent central review #### Secondary Endpoints - Overall survival in the overall population - Progression-free survival in the overall population - Objective response - Patient-reported pain deterioration - Patient-reported global health status / quality-of-life deterioration - Safety --- ### Key Results #### Overall Survival Major improvement with daraxonrasib: | Population | Daraxonrasib | Chemotherapy | HR | |---|---:|---:|---:| | RAS G12 | 13.2 mo | 6.6 mo | 0.40 | | Overall population | 13.2 mo | 6.7 mo | 0.40 | Daraxonrasib reduced the risk of death by approximately 60%. --- #### Progression-Free Survival Substantial improvement with daraxonrasib: | Population | Daraxonrasib | Chemotherapy | HR | |---|---:|---:|---:| | RAS G12 | 7.3 mo | 3.5 mo | 0.45 | | Overall population | 7.2 mo | 3.6 mo | 0.49 | --- #### Objective Response | Population | Daraxonrasib | Chemotherapy | |---|---:|---:| | RAS G12 | 33.2% | 11.8% | | Overall population | 31.6% | 11.2% | Response rate was roughly three-fold higher with daraxonrasib. --- #### Patient-Reported Outcomes Daraxonrasib delayed deterioration in both pain and global health status / quality of life. Pain deterioration: - RAS G12: 9.0 vs 3.7 months - Overall population: 9.2 vs 3.8 months Global health status / quality-of-life deterioration: - RAS G12: 5.6 vs 2.4 months - Overall population: 5.7 vs 2.6 months --- ### Toxicity Daraxonrasib had a distinct toxicity profile, dominated by dermatologic and gastrointestinal adverse events. Common treatment-related adverse events included: - rash - diarrhea - stomatitis - nausea - vomiting Grade 3 or higher adverse events: | Toxicity Endpoint | Daraxonrasib | Chemotherapy | |---|---:|---:| | Any grade ≥3 adverse event | 61.8% | 69.6% | | Grade ≥3 treatment-related adverse event | 43.6% | 57.5% | | Serious treatment-related adverse event | 10.8% | 18.7% | | Treatment-related discontinuation | 1.2% | 11.2% | Despite nearly universal adverse events, treatment-related discontinuation was uncommon with daraxonrasib. --- ### Additional Findings #### RAS Biology Became Clinically Actionable Daraxonrasib targets the active GTP-bound RAS(ON) state and has activity across mutant and wild-type RAS, including G12, G13, and Q61 variants. This is important because oncogenic RAS alterations are present in more than 90% of pancreatic ductal adenocarcinomas, with most involving KRAS codon 12. #### Benefit Extended Beyond Traditional Chemotherapy Benchmarks The chemotherapy arm performed as expected for previously treated metastatic PDAC, with median OS around 6–7 months and median PFS around 3–4 months. Daraxonrasib substantially exceeded these benchmarks. #### Quality-of-Life Signal Patient-reported pain and global health status outcomes favored daraxonrasib, supporting that the survival benefit was not achieved at the expense of worse patient experience. --- ### Interpretation RASolute 302 is potentially one of the most important modern metastatic PDAC trials because it demonstrated a large survival benefit from direct pharmacologic RAS pathway inhibition. The trial supports active RAS inhibition as a clinically meaningful strategy in previously treated metastatic PDAC and may redefine second-line systemic therapy for patients with appropriate molecular profiles. The magnitude of benefit is notable: - OS approximately doubled - PFS approximately doubled - Objective response improved substantially - Patient-reported deterioration was delayed - Treatment discontinuation was lower than with chemotherapy --- ### Important Limitations #### Open-Label Design The trial was open label, which may affect adverse-event reporting, treatment decisions, and patient-reported outcomes. #### Investigator’s-Choice Control Arm The control arm included multiple chemotherapy regimens, reflecting real-world practice but introducing heterogeneity. #### Chemotherapy Non-Initiation A larger proportion of patients assigned to chemotherapy never started protocol therapy. #### Short Follow-Up The reported analysis was based on the first interim analysis, with median follow-up of 8.5 months. #### Limited Non-G12 Data More than 90% of patients had RAS G12 mutations. Outcomes in RAS G13, Q61, or RAS wild-type tumors should be interpreted cautiously. --- ### Practice Impact RASolute 302 may establish daraxonrasib as a preferred therapy for previously treated metastatic PDAC with RAS pathway dependence, especially RAS G12-mutant disease. For HPB surgeons, the trial matters because it may change expectations for patients with recurrent or metastatic PDAC after surgery and reinforces the importance of molecular testing in pancreatic cancer. Potential practice implications: - RAS testing becomes more clinically relevant - Effective later-line therapy may extend disease control after recurrence - Systemic therapy options for metastatic PDAC may shift away from purely cytotoxic sequencing - The boundary between “targetable” and “non-targetable” PDAC may change