Daraxonrasib Improves OS Across Subgroups in Previously Treated mPDAC

Daraxonrasib (Rasonque) improved overall survival (OS) compared with investigator’s choice of standard-of-care chemotherapy across RAS genotype subgroups, preselected chemotherapy regimens, and prior treatment settings in patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC), according to data from a subgroup analysis from the phase 3 RASolute 302 trial (NCT06625320) presented at the 2026 ESMO Congress.¹

In the overall population, the analysis showed the OS hazard ratio (HR) was 0.42 (95% CI, 0.32-0.55) with daraxonrasib (n = 248) vs chemotherapy (n = 252). By KRAS genotype subgroup, the OS HRs were 0.49 (95% CI, 0.33-0.74) for patients with KRAS G12D mutations (daraxonrasib, n = 95; chemotherapy, n = 121); 0.32 (95% CI, 0.19-0.54) for those with KRAS G12V mutations (n = 102; n = 76); 0.61 (95% CI, 0.29-1.30) for those with KRAS G12R mutations (n = 30; n = 31); 0.29 (95% CI, 0.08-1.06) for those with other KRAS mutations (n = 11; n = 14), including 0.37 (95% CI, 0.09-1.44) for Q61 mutations (n = 11; n = 11); and 0.43 (95% CI, 0.09-1.98) for patients with no identified KRAS mutation (n = 9; n = 7).

In the primary analysis of RASolute 302, daraxonrasib produced a median OS of 13.2 months (95% CI, 10.0-not estimable) vs 6.7 months (95% CI, 5.8-8.0) with chemotherapy (HR, 0.40; 95% CI, 0.30-0.53; P = 4.6 × 10⁻¹¹).² Those data supported the FDA approval of daraxonrasib in August 2026 for adult patients with mPDAC who have received at least 1 prior systemic therapy or are not candidates for multi-agent systemic therapy.³

"Consistent OS improvement across key patient subgroup reinforces daraxonrasib as a new standard of care for previously treated mPDAC," said Zev A. Wainberg, MD, a professor of medicine at the David Geffen School of Medicine at UCLA, co-director of the UCLA GI Oncology Program, and medical director of the UCLA Pancreas Cancer Center, where he also serves as director of the Early Phase Clinical Research Program at the Jonsson Comprehensive Cancer Center.

How was RASolute 302 designed?

The global, randomized, open-label trial enrolled adult patients with mPDAC who had received 1 prior fluoropyrimidine- or gemcitabine-based regimen in the metastatic setting, had an ECOG performance status of 0 or 1, and had documented tumor RAS mutational status per local testing.¹

Patients were randomly assigned to receive oral daraxonrasib at 300 mg once daily or investigator’s choice of chemotherapy, which was selected before randomization. Randomization was stratified by ECOG performance status, metastatic disease at diagnosis, liver metastases at baseline, and tumor RAS mutational status.

The dual primary end points were OS and progression-free survival (PFS) per blinded independent central review (BICR) in the KRAS G12–mutant population. Key secondary end points included OS and PFS in the overall population; objective response rate (ORR) per BICR in the KRAS G12–mutant and overall populations.

Baseline characteristics revealed that patients had a median age of 66 years (range, 30-88) in the daraxonrasib arm vs 65 years (range, 36-86) in the chemotherapy arm, and 70% of patients in each arm had liver metastases at baseline. KRAS G12D (43.2%), G12V (35.6%), and G12R (12.2%) mutations were the most common alterations; Q61 mutations (4.4%), G13 mutations (0.6%), other G12 mutations (0.8%), and no identified RAS mutation (3.2%) were also reported.

What was the OS benefit of daraxonrasib across chemotherapy regimens and prior treatment settings?

The OS benefit was maintained regardless of the preselected chemotherapy regimen. The OS HR was 0.45 (95% CI, 0.32-0.65) among patients for whom gemcitabine plus nab-paclitaxel (Abraxane) was preselected (daraxonrasib, n = 140; chemotherapy, n = 141); 0.46 (95% CI, 0.23-0.95) for the pooled modified modified FOLFIRINOX (mFOLFIRINOX; leucovorin, fluourouacil, irinotecan, and oxaliplatin)/neoadjuvant fluorouracil and oxaliplatin group (n = 30; n = 30); and 0.32 (95% CI, 0.18-0.58) for nanoliposomal irinotecan (Onivyde) plus 5-fluoruracil/leucovorin (n = 78; n = 81).

By disease setting of prior treatment, the OS HR was 0.36 (95% CI, 0.17-0.75) for patients who were diagnosed with metastatic disease less than 6 months after their last dose of neoadjuvant or adjuvant therapy (n = 42; n = 34). Among patients who received 1 prior line of therapy for metastatic disease, the OS HR was 0.43 (95% CI, 0.32-0.58; n = 206; n = 218).

What did the PFS and response analyses show?

Per BICR, the PFS HR in the overall population was 0.55 (95% CI, 0.43-0.70), with HRs of 0.48 (95% CI, 0.33-0.69) in the KRAS G12D–mutated subgroup, 0.54 (95% CI, 0.33-0.87) in the G12V subgroup, and 0.80 (95% CI, 0.41-1.56) in the G12R subgroup; HRs exceeded 1 in the other KRAS mutation (1.29; 95% CI, 0.47-3.51) and no identified RAS mutation (1.92; 95% CI, 0.39-9.52) subgroups. Per investigator assessment, the PFS HRs were 0.48 (95% CI, 0.38-0.61) overall and ranged from 0.43 (95% CI, 0.30-0.62) in the KRAS G12D–mutated subgroup to 0.73 (95% CI, 0.38-1.39) in the G12R subgroup.

The ORR per BICR was 32% with daraxonrasib vs 11% with chemotherapy at baseline. By genotype, BICR-assessed ORRs were 24% vs 9% in the KRAS G12D–mutated subgroup and 50% vs 15% in the G12V subgroup. In the G12R subgroup, the BICR-assessed ORR was 7% with daraxonrasib vs 14% with chemotherapy, whereas the investigator-assessed ORR was 10% vs 3%. Investigator-assessed ORRs in the overall population were 24% vs 8%.

References

1. Wainberg ZA, Wolpin BM, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): additional subgroup analyses from the phase 3 RASolute 302 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA82.
2. Wolpin B, Wainberg Z, Hendifar A, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. Presented at: 2026 ASCO Annual Meeting; May 29-June 2,2026; Chicago, IL.
3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. October 23, 2026. Accessed October 23, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery