RASolute 302
Daraxonrasib versus chemotherapy in previously treated metastatic pancreatic ductal adenocarcinoma. Phase 3, open-label, randomized.
Trial design
RASolute 302 was a phase 3, international, open-label, randomized trial conducted at 59 sites in six countries. Enrollment ran from October 16, 2024 to November 7, 2025. Patients were randomly assigned 1:1. Crossover to the other group was not permitted. An independent data monitoring committee oversaw safety.
Treatment arms
Key eligibility
- Age: at least 18 years
- Disease: histologically or cytologically confirmed mPDAC with measurable disease per RECIST v1.1
- Prior therapy: progression after one prior line of fluoropyrimidine- or gemcitabine-based therapy for metastatic disease (or progression less than 6 months after neoadjuvant/adjuvant therapy)
- Performance status: ECOG 0 or 1
- RAS status: documented tumor RAS mutational status by local testing (KRAS, NRAS, or HRAS at codon 12, 13, or 61, or no RAS mutation identified)
- Key exclusions: known CNS metastases; prior RAS-targeted therapy
Stratification factors
- ECOG performance status (0 vs 1)
- Metastatic disease at initial diagnosis (yes vs no)
- Liver metastases at baseline (yes vs no)
- Tumor RAS mutational status (RAS G12D/V vs other RAS G12 vs RAS G13 or Q61 or no RAS mutation identified)
Endpoints
Overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) per RECIST v1.1, in the RAS G12 population.
Key secondaryOS and PFS in the overall population; objective response rate (ORR) in the RAS G12 and overall populations; patient-reported time to deterioration (TTD) in pain and in global health status/quality of life, in both populations.
Additional secondaryTime to response and safety. Adverse events graded per NCI CTCAE v5.0.
The overall population included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified. The RAS G12 population (459 patients, 91.8%) comprised those with RAS G12 mutations.
Overall survival
| Population | Events, n (%) | Median OS, mo (95% CI) | HR (95% CI) | P value |
|---|---|---|---|---|
| RAS G12 · Daraxonrasib (n=228) | 72 (32) | 13.2 (10.0–NE) | 0.40 (0.30–0.54) |
P<0.001 5.9×10⁻¹⁰ |
| RAS G12 · Chemotherapy (n=231) | 127 (55) | 6.6 (5.4–8.2) | ||
| Overall · Daraxonrasib (n=248) | 79 (32) | 13.2 (10.0–NE) | 0.40 (0.30–0.53) |
P<0.001 4.6×10⁻¹¹ |
| Overall · Chemotherapy (n=252) | 141 (56) | 6.7 (5.8–8.0) |
NE = not estimable. HR by stratified Cox model.
RAS G12 12-month OS: 53.3% vs 18.7%.
Progression-free survival (BICR)
| Population | Events, n (%) | Median PFS, mo (95% CI) | HR (95% CI) | P value |
|---|---|---|---|---|
| RAS G12 · Daraxonrasib (n=228) | 112 (49) | 7.3 (6.3–8.1) | 0.45 (0.34–0.59) |
P<0.001 3.2×10⁻⁹ |
| RAS G12 · Chemotherapy (n=231) | 121 (52) | 3.5 (2.9–3.8) | ||
| Overall · Daraxonrasib (n=248) | 127 (51) | 7.2 (5.7–7.5) | 0.49 (0.38–0.64) |
P<0.001 5.2×10⁻⁸ |
| Overall · Chemotherapy (n=252) | 130 (52) | 3.6 (2.9–4.2) |
6-month PFS (RAS G12): 58.7% vs 31.7%. 6-month PFS (overall): 56.0% vs 32.9%.
Objective response (confirmed, BICR)
95% CI 27.0–39.9
95% CI 7.8–16.8
95% CI 25.8–38.0
95% CI 7.5–15.9
Both comparisons P<0.0001. Median time to response was 1.9 months in both groups. ORR denominators are patients with measurable disease at baseline per BICR (RAS G12: daraxonrasib 237, chemotherapy 221; overall: 248 and 252). Duration of response and tumor-shrinkage (waterfall) data were not reported in the available sources.
Overall survival subgroups (overall population)
Hazard ratios and 95% CIs by unstratified Cox model. The unstratified “Overall” HR is 0.42 (0.32 to 0.55); the headline stratified HR is 0.40 (0.30 to 0.53). Events shown as daraxonrasib / chemotherapy. Point size is not scaled here; n’s appear on every row.
Patient-reported time to deterioration (overall population)
| Measure | Daraxonrasib, mo | Chemotherapy, mo | HR (95% CI) | P value |
|---|---|---|---|---|
| Pain (EORTC QLQ-PAN26) | 9.2 | 3.8 | 0.51 (0.37–0.71) | P<0.001 |
| Global health status / QoL (QLQ-C30) | 5.7 | 2.6 | 0.60 (0.46–0.79) | P<0.001 |
RAS G12 pain medians were 9.0 vs 3.7 months; GHS/QoL 5.6 vs 2.4 months.
Safety overview
| Event | Daraxonrasib (n=241) | Chemotherapy (n=214) |
|---|---|---|
| Median time on treatment, mo | 6.2 | 1.5–3.2* |
| Any TEAE (all-cause), n (%) | 241 (100) | 209 (97.7) |
| Grade ≥3 TEAE (all-cause), n (%) | 149 (61.8) | 149 (69.6) |
| Any TRAE, n (%) | 236 (97.9) | 200 (93.5) |
| Grade ≥3 TRAE, n (%) | 105 (43.6) | 123 (57.5) |
| Serious TRAE, n (%) | 26 (10.8) | 40 (18.7) |
| TRAE leading to dose reduction, n (%) | 87 (36.1) | 123 (57.5) |
| TRAE leading to dose interruption, n (%) | 135 (56.0) | 118 (55.1) |
| TRAE leading to discontinuation, n (%) | 3 (1.2) | 24 (11.2) |
| Grade 5 (fatal) TRAE, n (%) | 1 (0.4) | 0 |
*Chemotherapy median time on treatment is reported as a range across the four component regimens. One daraxonrasib patient died of treatment-related pneumonitis (the single grade 5 TRAE). Median dose intensity: 93.1% daraxonrasib vs 65.3 to 95.0% across chemotherapy regimens.
Treatment-related adverse events (any grade) in ≥20% of either arm
Any-grade incidence with grade ≥3 in parentheses. Threshold: any-grade incidence at least 20% in either arm. Grade ≥3 bars overlay the any-grade bar. Several terms are grouped composites (for example, rash, stomatitis, neutropenia, thrombocytopenia, and peripheral neuropathy).
Most common events by arm
Rash 85.5%, diarrhea 58.1%, stomatitis 53.1%, nausea 46.5%, vomiting 36.9%. Mostly low-grade dermatologic and gastrointestinal events; grade ≥3 rash 13.7% and stomatitis 12.0% were the only grade ≥3 TRAEs at 10% or higher. No grade 4 TRAEs except as noted; one grade 5.
Fatigue 44.4%, anemia 39.7%, nausea 39.3%, neutropenia 38.3%, diarrhea 37.9%, thrombocytopenia 33.2%, peripheral neuropathy 25.2%. Grade ≥3 TRAEs at 10% or higher: neutropenia 27.6% and anemia 16.4%.
