Prior Regimen Did Not Affect Daraxonrasib Benefit in Pretreated Pancreatic Cancer

One of the first practical questions to follow the approval of daraxonrasib (Rasonque) in previously treated metastatic pancreatic cancer is whether its benefit depends on what a patient received first. Zev A. Wainberg, MD, professor of medicine at the University of California, Los Angeles (UCLA), and co-director of the UCLA Gastrointestinal Oncology Program, answered it directly after presenting additional subgroup analyses of the phase 3 RASolute 302 trial (NCT06625320) at the 2026 European Society for Medical Oncology (ESMO) Congress: it does not.¹

Wainberg made the point on 2 axes. The first is the prior line itself. Whatever a patient received in the first-line setting, he said, does not matter much in terms of how much benefit they go on to derive from the RAS(ON) multi-selective inhibitor. Patients enrolled in RASolute 302 had received 1 prior fluoropyrimidine- or gemcitabine-based regimen for metastatic disease, and in the subgroup analyses the overall survival (OS) advantage held both for the 424 patients treated with 1 prior line for metastatic disease (HR, 0.43; 95% CI, 0.32-0.58) and for the 76 patients whose metastatic disease was diagnosed within 6 months of neoadjuvant or adjuvant therapy (HR, 0.36; 95% CI, 0.17-0.75).

The second axis is the comparator. RASolute 302 randomly assigned patients to daraxonrasib or investigator's choice of chemotherapy. Daraxonrasib outperformed each control regimen, with OS HRs of 0.45 (95% CI, 0.32-0.65) against gemcitabine plus nab-paclitaxel, 0.46 (95% CI, 0.23-0.95) against leucovorin, fluorouracil, irinotecan, and oxaliplatin (modified FOLFIRINOX) or leucovorin, fluorouracil, and oxaliplatin (FOLFOX), and 0.32 (95% CI, 0.18-0.58) against nal-IRI with fluorouracil and leucovorin.

For clinicians, the practical consequence is that the second-line decision does not need to be reverse-engineered from the first-line choice. The primary results of RASolute 302 were published in The New England Journal of Medicine, and the FDA approved daraxonrasib for metastatic pancreatic adenocarcinoma on August 26, 2026.^2,3

Transcript:

CancerNetwork: As a second-line option, how should daraxonrasib be sequenced after FOLFIRINOX vs gemcitabine and nab-paclitaxel? Does the first-line regimen affect benefit?

The first line—whatever you get in first line doesn't much matter in terms of benefit. And neither did, in this study, what chemotherapy was selected as the second-line choice. So regardless of whether you selected [gemcitabine plus nab-paclitaxel], [FOLFOX], [FOLFIRINOX], or [Nal-IRI with fluorouracil and leucovorin], daraxonrasib outperformed them. I think that what [a patient was treated with] before doesn't much matter in terms of how much benefit you're going to get from this drug, as far as we can tell.

References

1. Wainberg ZA, Wolpin BM, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): additional subgroup analyses from the phase 3 RASolute 302 study. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA82.
2. O'Reilly EM, Wainberg ZA, Hendifar AE, et al; RASolute 302 Trial Investigators. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. 2026;395(4):325-337. doi:10.1056/NEJMoa2605555
3. FDA approves first in class targeted therapy for metastatic pancreatic cancer. News release. FDA. August 26, 2026. Accessed October 28, 2026. https://tinyurl.com/4dt6cwnv