Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor that targets the active, GTP-bound forms of KRAS, HRAS and NRAS, with affinity for mutant and wild-type variants. It showed encouraging efficacy as monotherapy at clinically active dose levels in a phase 1/2 clinical trial of previously treated, RAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC), supporting confirmatory evaluation in a randomized phase 3 trial.
To define mechanisms of acquired resistance to daraxonrasib, investigators analyzed paired pretreatment and end-of-treatment circulating tumor DNA (ctDNA) from patients treated on the phase 1/2 study, using a targeted sequencing panel covering more than 800 genes. The analysis focused on treatment-emergent genomic alterations that could explain loss of benefit from daraxonrasib monotherapy.
The resistance analysis used ctDNA pairs from 44 patients enrolled in the phase 1/2 trial. Sequencing was targeted to a large cancer-focused gene set to capture treatment-emergent changes across oncogenic pathways. Findings reported are derived from this paired ctDNA cohort and subsequent mechanistic corroboration in preclinical models, as described in the source report.
Treatment-emergent genomic alterations affecting the RAS signaling pathway were observed in more than half of patients (26 of 44; 59%). The most notable and frequent alteration was amplification of mutant KRAS, detected in one-third of patients (16 of 44; 36%). Additional acquired alterations mapped to other signaling axes: receptor tyrosine kinase (RTK) alterations in 4 of 44 patients (9%), MAPK pathway alterations in 11 of 44 (25%) and PI3K pathway alterations in 4 of 44 (9%).
These results indicate that diverse genomic events converge on reactivation or reinforcement of RAS pathway signaling as a common route to acquired resistance against daraxonrasib monotherapy in PDAC.
A salient clinical observation was the absence of acquired secondary KRAS point mutations in this cohort. This pattern contrasts with resistance profiles reported for mutant-selective KRAS G12C(OFF) inhibitors, where secondary KRAS mutations have been implicated in emergent resistance. The lack of secondary KRAS mutations in daraxonrasib-treated patients suggests different evolutionary routes to resistance when a RAS(ON) multi-selective inhibitor is used.
To corroborate the clinical ctDNA findings, the investigators examined human and murine preclinical models of PDAC. They identified or mechanistically established concordant resistance mechanisms, including mutant KRAS amplification, MYC amplification and upregulation of RTKs. These preclinical data supported the interpretation that many acquired genomic events observed in patients are functionally relevant and drive reactivation of RAS effector signaling despite daraxonrasib exposure.
Based on the clinical and preclinical resistance mechanisms, several combination therapy strategies were evaluated or proposed in preclinical models. Notably, daraxonrasib combined with agents targeting the DNA damage response, with inhibitors of RTKs, or with the mutant-selective RAS(ON) G12D inhibitor zoldonrasib delayed or averted resistance in model systems. These combinations were selected to address the specific mechanisms identified (for example, KRAS amplification, RTK upregulation or downstream pathway reactivation) and to produce deeper or more durable pathway suppression than daraxonrasib monotherapy.
The reported preclinical results indicate that mechanistic, genomics-informed combinations may mitigate common routes of acquired resistance and provide a rationale for exploring such regimens in clinical development.
The study’s integrated approach—sequencing of paired ctDNA from patients and mechanistic validation in preclinical models—shows that most daraxonrasib resistance mechanisms operate via reactivation of RAS pathway signaling. The frequent occurrence of mutant KRAS amplification and alterations in RTK, MAPK and PI3K pathways point to vulnerabilities that can be targeted in combination with RAS(ON) inhibition.
These findings provide a framework to prioritize combinations for further clinical testing in PDAC, guided by the specific genomic alterations that emerge on therapy. Details on individual patient outcomes, timing of emergent alterations, and the full experimental data from preclinical combination studies were reported in the source article but are not reproduced in this summary beyond the overarching findings and concepts described above.
Collectively, the clinical sequencing and preclinical validation reported in the source article support continued investigation of daraxonrasib-based combinations to overcome or prevent acquired resistance in RAS-driven PDAC.