2026 ASCO Conference Coverage

Daraxonrasib Improves OS, PFS vs Chemotherapy in Second-Line Metastatic Pancreatic Adenocarcinoma

Anthony Calabro, MA

Key Highlights

  • Daraxonrasib met dual primary endpoints of overall survival and progression-free survival by blinded independent central review in the RAS G12-mutant population.
  • Median overall survival was 13.2 months with daraxonrasib vs 6.7 months with chemotherapy in the RAS G12 population.
  • Grade ≥3 treatment-related adverse events occurred less often with daraxonrasib than with chemotherapy.
  • The study authors stated that the findings support daraxonrasib as a new standard of care for second-line metastatic pancreatic adenocarcinoma.

Daraxonrasib improved overall survival (OS) and progression-free survival (PFS) compared with standard-of-care cytotoxic chemotherapy in patients with previously treated metastatic pancreatic adenocarcinoma, according to the primary and final analyses of the phase 3 RASolute 302 study, presented at the 2026 American Society of Clinical Oncology Annual Meeting plenary session and published as an abstract in the Journal of Clinical Oncology.

“Daraxonrasib demonstrated unprecedented improvements in OS and PFS vs chemotherapy in patients with second-line metastatic pancreatic adenocarcinoma,” the researchers concluded in their study.

The study evaluated daraxonrasib, an oral RAS(ON) multi-selective tri-complex inhibitor targeting the active, GTP-bound state of mutant and wild-type RAS. The investigators noted that available second-line therapies for metastatic pancreatic adenocarcinoma offer limited clinical benefit, with reported median PFS of 3 to 4 months and median OS of 6 to 7 months.

RASolute 302 was a global, randomized, open-label phase 3 trial enrolling patients with second-line metastatic pancreatic adenocarcinoma and ECOG performance status 0 or 1. Patients were randomly assigned 1:1 to receive daraxonrasib 300 mg orally once daily or the investigator’s choice of standard-of-care cytotoxic chemotherapy.

The dual primary endpoints were OS and PFS, as assessed by blinded independent central review, in the RAS G12-mutant population. Key secondary endpoints included OS and PFS by blinded independent central review in the overall population, as well as objective response rate in both the RAS G12 and overall populations.

Study Findings

A total of 500 patients were randomized, with 248 receiving daraxonrasib and 252 receiving chemotherapy. Baseline characteristics were balanced between treatment arms. On the February 10, 2026, data cutoff, with a median follow-up of 8.5 months, all primary and key secondary endpoints were met.

In the RAS G12 population, median OS was 13.2 months with daraxonrasib vs 6.7 months with chemotherapy (HR, 0.40; 95% CI, 0.30-0.54; P < .0001). Median PFS was 7.3 months vs 3.5 months, respectively (HR, 0.45; 95% CI, 0.34-0.59; P < .0001). Objective response rates were 33.2% with daraxonrasib and 11.8% with chemotherapy.

In the overall population, median OS was 13.2 months with daraxonrasib vs 6.7 months with chemotherapy (HR, 0.40; 95% CI, 0.30-0.53; P < .0001). Median PFS was 7.2 months vs 3.6 months, respectively (HR, 0.49; 95% CI, 0.38-0.64; P < .0001). Objective response rates were 31.6% with daraxonrasib and 11.2% with chemotherapy.

Grade ≥3 treatment-related adverse events occurred in 43.6% of patients receiving daraxonrasib and 57.5% receiving chemotherapy. The most common grade ≥3 treatment-related adverse events were rash and stomatitis with daraxonrasib and decreased neutrophil count and anemia with chemotherapy. Treatment-related serious adverse events occurred in 10.8% and 18.7% of patients, respectively.

Clinical Implications

According to the study authors, daraxonrasib demonstrated clinically meaningful improvements in OS and PFS compared with chemotherapy in patients with second-line metastatic pancreatic adenocarcinoma, including those with or without an identified tumor RAS mutation.

Expert Commentary

"Duraxonrasib, in the RASolute 302 study, met the primary endpoint and all key secondary endpoints in patients with previously treated metastatic pancreatic cancer, including improvements in overall survival, progression-free survival, response rate, and patient reported outcomes," Brian Wolpin, MD, MPH, Dana-Farber Cancer Institute, told the Oncology Learning Network. "It demonstrated a manageable safety profile and this drug, we hope, will provide a new standard of care for patients with previously treated metastatic pancreatic cancer."

References

1. Wolpin BM, Wainberg ZA, 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. J Clin Oncol. 2026;44(suppl 17). doi:10.1200/JCO.2026.44.17_suppl.LBA5

2. Daraxonrasib improves survival outcomes in previously treated metastatic pancreatic cancer. Oncology Learning Network. Published May 31, 2026. Accessed June 2, 2026. https://www.hmpgloballearningnetwork.com/site/onc/videos/second-line-daraxonrasib-improves-survival-outcomes-metastatic-pancreatic-ductal