Behind the FDA Approval: Daraxonrasib Delivers in Pancreatic Cancer

Months ahead of the target action date, the FDA recently approved the pan-RAS inhibitor daraxonrasib (Rasonque) for patients with metastatic pancreatic adenocarcinoma who have received at least 1 prior systemic therapy or who are not candidates for multiagent systemic therapy.¹

In an interview with Targeted Oncology^TM, Shubham Pant, MD, MBBS, discussed the significance of the approval for the field of pancreatic cancer. Pant is a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, TX.

Targeted Oncology: What pathways and mutations does daraxonrasib target, and what is their significance in pancreatic cancer?

Shubham Pant, MD: Daraxonrasib is a pan-RAS inhibitor. That means it targets all RAS, and KRAS mutations are in 90% of patients with pancreatic cancer. It essentially targets almost all patients with pancreatic cancer, and it binds to the RAS(ON) protein. It is a "molecular glue" that attaches to a chaperone protein, cyclophilin A, and RAS(ON) protein to form a tri-complex that leads to steric hindrance and cancer cell death.

The RASolute 302 trial² supported the FDA approval of daraxonrasib. Please discuss the significance of the study findings and their overall meaning to the pancreatic cancer paradigm.

For 30 to 40 years in pancreatic cancer, have had multiple negative clinical trials, and the positive trials have been very few and far between. These included FOLFIRINOX versus gemcitabine (NCT00112658), gemcitabine plus nab-paclitaxel versus gemcitabine alone, and NALIRIFOX vs gemcitabine/nab-paclitaxel (NCT04083235). We have not really had a lot of options for our patients; just a few chemotherapy options. But now the RASolute 302 trial opens up the door with a targeted therapy for our patients.

And historically, the trial have yielded overall survival benefits in terms of weeks or [at best] a couple months. But for the RASolute 302 trial, which was in patients with metastatic pancreatic cancer who had progressed on frontline therapy, daraxonrasib almost doubled overall survival at a median of 13.2 months vs 6.7 months with investigator’s choice of chemotherapy.

What do oncologists in the clinic need to know about dosing and toxicity management with daraxonrasib?

The dosing is 300 mg once daily. The main side effects are rash, stomatitis, diarrhea, nausea, and paronychia. The are prophylactic measures that can be taken for managing these side effects. We start patients on doxycycline when they start daraxonrasib. We also give them hydrocortisone cream for their face. We can give them [pramosone] cream for their body, and if they have stomatitis, we give mouthwashes, such as magic mouthwash or dexamethasone mouthwashes.

If patients are having intolerable side effects, however, then the recommendation is to hold the daraxonrasib, and the toxicities tend to normally go away in 1 to 2 weeks. The maximum I've seen is mostly 2 weeks, and the patients feel better and can restart at that dose or at a dose reduction.

What’s next for research with daraxonrasib?

I am very excited about the next steps with daraxonrasib. There's a trial called RASolute 303 (NCT07491445) in patients with treatment-naive metastatic pancreatic cancer that is comparing daraxonrasib alone or combined with gemcitabine plus nab-paclitaxel vs gemcitabine/nab-paclitaxel alone in the frontline setting. We also have RASolute 304 (NCT07252232), which is evaluating daraxonrasib vs standard observation in patients with resected pancreatic ductal adenocarcinoma who have completed neoadjuvant and/or adjuvant chemotherapy. So those are 2 trials assessing daraxonrasib in earlier treatment settings.

Can you please discuss the overall state of RAS-directed treatment in pancreatic cancer?

There are a lot of RAS-directed agents beyond daraxonrasib coming down the pike, including other RAS(ON) inhibitors and pan-RAS inhibitors. There’s also these allele-specific KRAS G12D inhibitors, and there are multiple trials which are ongoing to test these in combination with chemotherapy or with other novel agents like daraxonrasib.

There is a lot of ongoing activity and a lot of great data coming out with RAS-directed treatment for patients with pancreatic cancer. Hopefully, we should soon have a number of options for these patients.

REFERENCES

1. FDA Approves First in Class Targeted Therapy for Metastatic Pancreatic Cancer. Published online August 26, 2026. Accessed August 28, 2026. https://tinyurl.com/457vwtek

2. Wolpin BM, Wainberg ZA, Hendifar AE, 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 44, 2026 (suppl 17; abstr LBA5)