Background
Phase 3, international, open-label RCT; N=500; previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC); 91.8% with KRAS G12 mutations. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active GTP-bound state of mutant and wild-type RAS.
Results
Interventions and follow up: Arm A: Daraxonrasib, oral, once daily (n=248)
Arm B: Investigator's-choice chemotherapy (n=252)
Primary endpoints: OS and PFS in the KRAS G12 population (dual primary)
mFollow up: NR
Results: OS (G12 population): 13.2 vs 6.6 mo; HR 0.40; P<.001
OS (overall population): 13.2 vs 6.7 mo; HR 0.40; P<.001
PFS (G12 population): 7.3 vs 3.5 mo; HR 0.45; P<.001
PFS (overall population): 7.2 vs 3.6 mo; HR 0.49; P<.001
Arm B: Investigator's-choice chemotherapy (n=252)
Primary endpoints: OS and PFS in the KRAS G12 population (dual primary)
mFollow up: NR
Results: OS (G12 population): 13.2 vs 6.6 mo; HR 0.40; P<.001
OS (overall population): 13.2 vs 6.7 mo; HR 0.40; P<.001
PFS (G12 population): 7.3 vs 3.5 mo; HR 0.45; P<.001
PFS (overall population): 7.2 vs 3.6 mo; HR 0.49; P<.001
Adverse events
Grade ≥3 (any): 61.8% vs 69.6%
Any-grade AEs: 100% (daraxonrasib) vs 97.7% (chemo)
Treatment-related discontinuation: 1.2% vs 11.2%
Any-grade AEs: 100% (daraxonrasib) vs 97.7% (chemo)
Treatment-related discontinuation: 1.2% vs 11.2%
Conclusions
In previously treated mPDAC, daraxonrasib roughly doubled overall survival versus chemotherapy (13.2 vs 6.6 mo; HR 0.40) with far fewer treatment discontinuations. It is the first RAS(ON) inhibitor to extend survival in pancreatic cancer, with consistent benefit in KRAS G12 and overall populations.
Key Limitations
Open-label design (no placebo) with investigator's-choice chemotherapy comparator. Benefit driven by the KRAS G12-mutant subgroup (91.8% of enrollees); limited data in non-G12 RAS alterations. OS still maturing; long-term durability and CNS activity not yet characterized.
Clinical Context
First targeted RAS(ON) inhibitor to improve survival in mPDAC, where second-line chemotherapy yields median OS <7 mo. FDA granted Breakthrough Therapy and Orphan Drug designations and a ‘safe-to-proceed’ expanded-access protocol (April 2026); daraxonrasib was selected for the FDA Commissioner's National Priority Voucher pilot, with an NDA planned. Not yet FDA-approved as of June 2026. Presented at the 2026 ASCO Annual Meeting.