Why This Study Matters
RAS mutations drive more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases, a cancer with historically limited targeted-therapy options and poor outcomes. Daraxonrasib, an oral RAS(ON) multi-selective tri-complex inhibitor, showed encouraging monotherapy activity in previously treated RAS-mutant metastatic PDAC: in the second-line population treated at 300 mg daily in the phase 1/2 trial, the earlier primary report cited in this analysis found a median progression-free survival of 8.1 months and median overall survival of 15.6 months. That activity was since corroborated by the randomized phase 3 RASolute 302 trial. As with virtually all targeted therapies, however, durable benefit is ultimately limited by acquired resistance. This study is the first comprehensive genomic and preclinical characterization of how tumors escape daraxonrasib monotherapy, and it directly informs which combination strategies are worth pursuing next.
Study Design
Investigators profiled paired circulating tumor DNA (ctDNA) — collected at pretreatment baseline and at end of treatment, at the time of disease progression — from 44 patients with RAS-mutant metastatic PDAC. All patients had been treated with daraxonrasib monotherapy (160-300 mg daily) as second-or-later-line therapy in the single-arm phase 1/2 trial (NCT05379985), and each had achieved a complete response, partial response, or stable disease with progression-free survival greater than 3 months before eventually progressing. Targeted sequencing covered more than 800 genes. A separate comparator subset of 13 patients treated at lower doses (≤120 mg daily) during the trial's dose-escalation phase was also analyzed. The genomic findings were corroborated in preclinical models — xenograft, syngeneic, and in vitro resistant cell lines — used to functionally test candidate resistance mechanisms and combination strategies.
Patient Population
The primary analysis cohort comprised 44 patients with RAS-mutant metastatic PDAC who had progressed on second-or-later-line daraxonrasib monotherapy at 160-300 mg daily. TP53 co-mutations were the most common baseline co-alteration, present in 31 of 44 patients (70%), consistent with the expected frequency in KRAS-mutant PDAC. A comparator group of 13 patients treated at ≤120 mg daily during dose escalation was analyzed separately to assess dose-resistance relationships.
Key Findings
Acquired KRAS amplification copy number at progression varied widely, ranging from 2.21 to 28.36 copies. Higher daraxonrasib doses (160-300 mg daily) were associated with a numerically higher rate of acquired RAS pathway alterations than lower doses (≤120 mg daily) — 59% versus 31% — though this difference did not reach statistical significance (P = 0.11).
These results reinforce that RAS/MAPK pathway-dependent cancers are oncogene-addicted and that the evolution of therapeutic resistance often selects for reactivation of driver oncogene signaling.
— Discussion, Aronchik, Kar, Zhuang, et al., Nature Medicine, 2026
Subgroup Analyses
The clearest subgroup signal in this study involved pretreatment TP53 mutation status and its association with acquired KRAS amplification at progression:
| Pretreatment TP53 Status | Acquired KRAS Amplification at Progression | Statistic |
|---|---|---|
| Oncogenic TP53 mutation present (n=32) | 15 of 32 (47%) | P = 0.03 (two-sided Fisher's exact test) |
| Wild-type TP53 (n=12) | 1 of 12 (8%) |
No significant associations were found between acquired KRAS amplification at progression and pretreatment co-alterations in SMAD4, CDKN2A, ARID1A, or CHEK2; the source reports these occurred at frequencies near the expected baseline prevalence in PDAC without providing exact comparative statistics for this analysis.
Safety Profile
Not specified in this source. This article is a genomic and preclinical resistance-mechanism analysis nested within the phase 1/2 trial — it does not report new adverse-event data. Daraxonrasib monotherapy safety findings were published in the earlier primary phase 1/2 report and further characterized in the phase 3 RASolute 302 trial, neither of which is the source for this article. The only tolerability statement present in this source is qualitative: the investigational RAS(ON) inhibitor doublet of daraxonrasib plus zoldonrasib (under clinical evaluation, NCT06040541) is described as having been "well tolerated" in early evaluation, without specific adverse-event rates given.
Interpretation and Broader Context
The genomic picture that emerges is one of pathway reactivation rather than on-target drug escape: resistance converged overwhelmingly on RAS pathway hyperactivation (KRAS amplification, RAF/MAPK alterations, RTK upregulation, PI3K/mTOR alterations) rather than on the secondary KRAS mutations that limit mutant-selective KRAS G12C(OFF) inhibitors. That distinction is clinically actionable: the authors nominate two combination strategies for further evaluation in PDAC — pairing daraxonrasib with RTK-directed biologics such as trastuzumab deruxtecan or amivantamab, and intensifying RAS pathway blockade with a RAS(ON) inhibitor doublet (daraxonrasib plus the mutant-selective inhibitor zoldonrasib), already under clinical evaluation in NCT06040541. Combinations with DNA damage response inhibitors and with chemotherapy — the latter being explored in the frontline RASolute 303 trial (NCT07491445) — are also flagged as active areas of investigation.
The authors are explicit about the study's boundaries: candidate genomic resistance drivers were identifiable in roughly 60% of patients, implying that a substantial share of tumors that relapse on daraxonrasib may do so through nongenomic mechanisms not captured by ctDNA sequencing of a fixed 800-gene panel. They call for larger cohorts with paired tumor biopsies — potentially drawing on the larger RASolute 302 trial population — to validate these findings and to distinguish acquired resistance alterations from those that may have pre-existed at baseline.
This first comprehensive resistance analysis of the RAS(ON) inhibitor daraxonrasib in pancreatic cancer found that tumors escape treatment primarily through RAS pathway reactivation — most often KRAS amplification — rather than through the secondary resistance mutations seen with older KRAS G12C(OFF) inhibitors, and identified pretreatment TP53 mutation as a marker of amplification risk. That mechanistic clarity points toward two testable next steps: pairing daraxonrasib with RTK-directed biologics, or intensifying RAS blockade with the daraxonrasib-zoldonrasib doublet already in early clinical testing. But with a genomic driver identifiable in only about 60% of progressing tumors, a meaningful share of resistance remains unexplained and will require larger, biopsy-paired studies to resolve.