Nicholas Hornstein, Assistant Professor at Northwell Health, shared Sawyer Bawek’s, Junior Chief Fellow at Cleveland Clinic, post on LinkedIn:
“This one is special. This is the hottest paper of 2026 and potentially in the history of pancreatic cancer. Let’s dive in.
For decades, pancreatic cancer has been where good ideas go to die. We have optimized chemotherapy. We have sequenced chemotherapy. We have celebrated modest gains. But the central driver of PDAC has always been sitting there in plain sight:
RAS.
More than 90% of pancreatic cancers have oncogenic RAS mutations, and until recently, we had essentially nothing direct to do about it.
Daraxonrasib is an oral RAS(ON) multiselective inhibitor targeting the active GTP-bound state of mutant and wild-type RAS. And in RASolute 302, it delivered. Quick hits:
Phase 3 international randomized trial 500 patients with previously treated mPDAC Daraxonrasib vs investigator’s choice chemotherapy
RAS G12 population: 91.8% of patients had RAS G12 mutations
- OS in RAS G12 population
13.2 vs 6.6 months
HR 0.40
P<0.001 - OS in overall population
13.2 vs 6.7 months
HR 0.40
P<0.001 - PFS in RAS G12 population
7.3 vs 3.5 months
HR 0.45
P<0.001 - PFS in overall population
7.2 vs 3.6 months
HR 0.49
P<0.001
12-month OS
Overall population: 53.2% vs 17.3%
Toxicity matters, but this was not just more efficacy for more toxicity
- Grade ≥3 AEs: 61.8% vs 69.6%
- TRAEs leading to discontinuation: 1.2% vs 11.2%
This is the kind of survival curve we almost never get to see in pancreatic cancer.
This validates RAS(ON) inhibition in the most RAS-addicted major cancer. It takes a target we have talked about for decades and turns it into a clinically meaningful survival benefit in a randomized phase 3 trial. The next questions come fast: 1L combinations, maintenance, perioperative disease, sequencing, resistance, toxicity management, and whether this becomes a new backbone.
RAS is here, and it couldn’t have come sooner.”
Title: Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer
Authors: Eileen M. O’Reilly, Zev A. Wainberg, Andrew E. Hendifar, Mitesh J. Borad, Filippo Pietrantonio, Shubham Pant, Pascal Hammel, Chiara Cremolini, Gulam A. Manji, Paul E. Oberstein, Ignacio Garrido-Laguna, Christoph Springfeld, Nilofer S. Azad, Makoto Ueno, Stephen Y. Chui, Ying Zhang, Hina Patel, Yeonju Lee, Zeena Salman, Brian M. Wolpin
Read the Full Article.
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