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A closer look at the investigational drug daraxonrasib
2026 Jul 29
Biotech Perspectives

Pancreatic cancer is, unfortunately, one of the most difficult cancer types to treat. While the reasons for this are many, a consistent issue has been the ability to appropriately and successfully target the causes of pancreatic cancer. One of these causes is the RAS protein, as around 90% of pancreatic tumours harbour mutations to the RAS family of genes. As a result, targeting the RAS protein is particularly important for patients with advanced pancreatic cancer; however, it has long been a maddening pursuit for researchers as it is remarkably difficult to drug. A new investigational drug, daraxonrasib, is drastically changing that pursuit, offering hopeful clinical evidence for pancreatic patients and caregivers.

Why has RAS been so difficult to target?

The RAS protein has a number of unique features that make it difficult to target, including:

  1. A smooth protein surface that lacks deep pockets for drug molecules to easily bind.
  2. A strong binding affinity to nucleotides that can out compete drug molecules for the binding site
  3. A constantly changing structure as it flips between its inactive (“OFF”) and active (“ON”) state.
  4. The existence of multiple isoforms (similar proteins from the same gene family) that impact the patient population differently.

Earlier generations of RAS inhibitors made important progress but were limited to specific mutations or by targeting RAS only in its inactive state.

: Drawing of four reasons, labelled 1-4, why the RAS protein is difficult to target. At the top is a title that reads “Why has RAS been so difficult to target?”. Reason 1 shows a fictitious drug sliding off of a RAS protein; text below it reads “1: Smooth protein surface that lacks deep pockets for a small-molecule drug to easily bind”. Reason 2 shows a fictitious drug unable to bind to RAS protein because a GTP nucleotide is blocking it; text below it reads “2: Strong binding affinity to nucleotides that can out small-molecule drugs for the binding site”. Reason 3 shows two RAS proteins, one in an “OFF” state with GDP bound, and one in an “ON” state with GTP bound; text below it reads “3: Constantly changing structure based on its inactive (“OFF”) and active (“ON”) state”. Reason 4 shows a collection of isoforms, labelled KRAS, HRAS, and NRAS; text below it reads “4: Multiple isoforms (similar proteins from the same gene family) that impact the patient population differently”.

What makes daraxonrasib different?

Instead of binding directly to RAS alone, daraxonrasib first binds to a widely expressed chaperone protein known as cyclophilin A. This complex creates a new binding surface that can act as a “molecular glue,” binding and inhibiting RAS in its active state. This is especially significant given that cancer-causing mutations result in RAS being stuck in the active state.

Another key difference from earlier-generation RAS inhibitors is that the new binding surface isn’t specific to mutations and isoforms. This allows daraxonrasib to target multiple RAS variations, overcoming the limitations of its predecessor.

Drawing demonstrating a series of 4 steps, labelled A-D with arrows between each step, demonstrating why the drug daraxonrasib differs from other RAS inhibitors. At the top is a title that reads “So what makes daraxonrasib different?”. Step A shows the drug daraxonrasib at the top, and a chaperone protein known as cyclophilin A. at the bottom; text below each reads “daraxonrasib” and “cyclophilin A.”. Step B shows daraxonrasib and cyclophilin A. bound together; text below it reads “daraxonrasib first binds with cyclophilin A. to create a new binding surface”. Step C shows the RAS protein in its active state; text below it reads “RAS, in its active state, attaches to the new binding surface and becomes inhibited”. Step D shows daraxonrasib and cyclophilin A., bound together, attached to a RAS protein with smaller representations of this binding in the background; text below it reads “The new binding surface can inhibit multiple RAS variations”.

How does the data look?

Based on how daraxonrasib binds to RAS proteins, we know it’s a promising option, in theory. But how does this early promise bear out in the data?

  • In the RASolute 302 trial studying daraxonrasib in a second-line setting as single-agent therapy (typically after receiving chemotherapy), daraxonrasib almost doubled the median overall survival compared to standard chemotherapy (13.2 months versus 6.7 months) and a 60% reduction in the risk of death (HR 0.40; P<0.0001)
  • In the RMC-6236-001 trial studying daraxonrasib in a first-line setting as single-agent therapy, early data reported an objective response rate of 47% (18/38) and a disease control rate of 89% (34/38). In the RMC-GI-102 trial that tested daraxonrasib combination in first-setting (daraxonrasib plus gemcitabine and nab-paclitaxel), the objective response rate was 58% (95% CI, 41%-73%), and the disease control rate was 90% (95% CI, 76%-97%) in treated patients. The 6-month progression-free survival rate reached 84% (95% CI, 68%-93%), and overall survival was reported to be 90% (95% CI, 76%-96%).

With strong, promising data and a novel mechanism of action, daraxonrasib has the potential to open new doors in treating other cancers, while simultaneously offering hope for patients with difficult-to-treat pancreatic cancer.

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