For years, treatment for metastatic pancreatic cancer has relied on highly toxic chemotherapy regimens that offer survival gains typically measured in months. Most patients diagnosed with advanced disease do not survive beyond a year.

That math — and the treatment strategy — is now starting to change. KRAS, the mutation driving more than 90% of pancreatic tumors and long considered undruggable, has become the focal point for two emerging therapeutic strategies: inhibition and degradation.

In April, drugmaker Revolution Medicines reported that its oral KRAS inhibitor, daraxonrasib, nearly doubled median survival in patients with previously treated metastatic pancreatic ductal adenocarcinoma. In the phase 3 RASolute 302 trial, patients receiving daraxonrasib lived a median of 13.2 months vs 6.7 months with investigator’s choice of chemotherapy. The benefit held across patients with a range of KRAS mutations.

Weeks earlier, a separate KRAS-directed program reached its own milestone. Setidegrasib (ASP3082), a first-in-class KRAS G12D-targeted protein degrader, became the first KRAS-directed degrader to advance toward a phase 3 trial. Phase 1 data, published in late March, showed the drug produced tumor responses in 24% of heavily pretreated patients with metastatic pancreatic cancer and reported a median overall survival of 10.3 months.

The emergence of two mechanistically distinct RAS-directed strategies may mark an inflection point for pancreatic cancer, especially in the second-line setting where objective response rates to second-line chemotherapy have historically been low, with median overall survival often ranging from 5 to 7 months.

“I can’t remember the last time I saw such a leap forward in pancreatic cancer,” said Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare in Murray, Utah.

These promising options also raise an important question for oncologists: which strategy to use, for which patient, and when.

A Tale of Two Strategies

KRAS belongs to a family of three closely related RAS proteins that act as molecular switches, relaying growth signals from cell surface receptors to MAPK and other pathways that regulate cell division and survival. In healthy cells, the switch toggles between active and inactive states: KRAS turns on, then off, allowing the signal to pulse, then quiet.

Cancer-associated mutations disrupt this control mechanism, leaving the switch stuck on. Downstream signaling never quiets, and cells proliferate.

In pancreatic ductal adenocarcinoma, more than 90% of tumors harbor a KRAS mutation. The disease is dominated by G12D, G12V, and G12R variants, rather than G12C, which is the target of the first approved KRAS inhibitors — sotorasib and adagrasib. These agents, approved for certain lung and colorectal cancers, inhibit KRAS G12C by locking the mutant protein in its inactive state. Still, no KRAS-targeted therapy has been approved for pancreatic cancer.

“G12C is the easy one — the light switch is off,” Lewis explained. “The much larger problem is that the vast majority of pancreatic cancer has a KRAS mutation where the light switch is stuck on.”

That’s where the latest drugs come in.

Daraxonrasib does not try to turn the switch off. Instead, the oral drug binds the chaperone protein cyclophilin A, and the resulting complex binds the active form of RAS, blocking downstream signaling. Daraxonrasib does not discriminate by mutation type. It can target a broad range of RAS variants in their active state, including wild-type RAS.

“If the light switch is stuck on, let’s just cut the wires that run to the light,” Lewis said. “It is an incredibly effective, but also less selective approach.”

Setidegrasib takes a different path. Rather than blocking the protein, it tags KRAS G12D for destruction by the cell’s own disposal machinery — the same system that clears damaged proteins under normal conditions. The drug then dissociates and binds another KRAS molecule, triggering a catalytic mechanism.

The trade-offs of the two drugs follow from the mechanism. Daraxonrasib casts a much wider net across KRAS-mutated disease, which covers most patients, but that broader reach comes with greater toxicity. Setidegrasib targets fewer patients — only the roughly 40% of patients whose tumors carry KRAS G12D mutations — but comes with fewer side effects.

It’s essentially a shotgun vs sniper approach, explained Wungki Park, MD, MS, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City and lead author of setidegrasib’s phase 1 study.

The shotgun approach for daraxonrasib “is not as clean. It will hit a lot,” while setidegrasib’s sniper approach will just target G12D, Park said.

LEGGI TUTTO https://www.medscape.com/viewarticle/reshaping-pancreatic-cancer-treatment-inside-kras-approach-2026a1000gza?ecd=wnl_tp10_daily_260525_MSCPEDIT_etid8370767&uac=286300CK&impID=8370767