Daraxonrasib (RMC-6236) and zoldonrasib (RMC-9805), investigational RAS(ON) inhibitors, have shown promising results in early-phase clinical trials for patients with RAS-mutated pancreatic ductal adenocarcinoma (PDAC). These findings, presented at recent oncology symposia, suggest potential new treatment avenues for this challenging cancer. Daraxonrasib targets multiple RAS variants, while zoldonrasib selectively inhibits KRAS G12D, a common mutation in PDAC.
Daraxonrasib Demonstrates Broad RAS Inhibition
Updated findings from a phase 1 study (NCT05379985) of daraxonrasib, presented at the 2025 Genitourinary Cancers Symposium, revealed antitumor activity and a manageable safety profile in patients with RAS-mutated PDAC. The study evaluated daraxonrasib in patients with advanced solid tumors harboring KRAS G12X mutations who had previously received standard therapy.
At the recommended phase 2 dose (RP2D) of 300 mg in the second line, patients with KRAS G12X-mutated disease (n = 22) experienced a median progression-free survival (PFS) of 8.8 months (95% CI, 8.5-NE). Those with RAS-mutated disease (n = 37) had a median PFS of 8.5 months (95% CI, 5.9-NE). The overall response rates (ORR) were 36% and 27% in the KRAS G12X- and RAS-mutated subgroups, respectively, with disease control rates (DCR) of 91% and 95%.
Notably, a greater than 50% decrease in RAS VAF from baseline was observed in 93% of patients with KRAS G12X mutations (n = 56/60) and 90% of those with RAS mutations (n = 66/73).
"Daraxonrasib is the first investigational targeted agent designed to directly inhibit all major forms of oncogenic RAS(ON), the common drivers of PDAC," said lead study author Ignacio Garrido-Laguna, MD, PhD, MBA, from the University of Utah School of Medicine and Huntsman Cancer Institute.
Safety Profile of Daraxonrasib
Treatment-related adverse events (TRAEs) were observed in 98% and 96% of patients in the 160-mg-to-300-mg group vs the 300-mg group, respectively. Grade 3 or higher TRAEs occurred in 29% and 34% of patients in these respective groups. The most common TRAEs included rash (91%), diarrhea (48%), and nausea (43%).
Zoldonrasib Shows Promise in KRAS G12D-Mutated PDAC
Data presented at the 2025 Gastrointestinal Cancers Symposium from an ongoing phase 1 trial (NCT06040541) showed that zoldonrasib (RMC-9805) was well tolerated and demonstrated preliminary antitumor activity in patients with KRAS G12D-mutated PDAC. Zoldonrasib is an orally bioavailable, tri-complex, covalent RAS(ON) inhibitor selective for KRAS G12D.
Among patients with PDAC who received zoldonrasib at 1200 mg daily (n = 60), the most common treatment-related AEs (TRAEs) included nausea (27%), diarrhea (20%), and vomiting (15%). No grade 4/5 TRAEs or serious AEs were reported.
Clinical Activity of Zoldonrasib
Among response-evaluable patients with KRAS G12D-mutated PDAC who received zoldonrasib at 1200 mg daily (n = 40), the overall response rate was 30%, and the disease control rate was 80%. Marked reductions in KRAS G12D VAF in ctDNA from pretreatment levels were observed among 28 evaluable patients with PDAC who received zoldonrasib at 1200 mg daily; 86% experienced a KRAS G12D VAF decrease of greater than 50%, and 39% achieved a 100% decrease.
Ongoing and Future Studies
The RASolute 302 study (NCT06625320), a global randomized phase 3 clinical trial, is currently underway to evaluate daraxonrasib as a second-line treatment vs chemotherapy in patients with previously treated metastatic PDAC. This trial will enroll approximately 460 patients and assess PFS and OS among patients with KRAS G12X mutations. Further development of zoldonrasib, both as a single agent and in combination with other therapies like daraxonrasib, is also being explored. These agents represent a potential shift in the treatment paradigm for RAS-mutated pancreatic cancers.
