Revolution Medicines begins dosing its RAS(ON) doublet in G12D pancreatic cancer

On 5 October 2026, Revolution Medicines began treating patients in RASolute 309, a global, randomized Phase 3 trial of its RAS(ON) multi-selective inhibitor daraxonrasib (RASONQUE) combined with zoldonrasib, an investigational RAS(ON) G12D-selective inhibitor, as first-line treatment for metastatic RAS G12D pancreatic adenocarcinoma ^[1]. The trial is registered as NCT07805954, is recruiting toward 400 patients, and pits the doublet against gemcitabine plus nab-paclitaxel, with progression-free survival and overall survival as primary endpoints ^[2]. Its start date was 28 August 2026 and primary completion is targeted for March 2029 ^[2].

The comparator choice is the signal. By testing the doublet against gemcitabine and nab-paclitaxel rather than against daraxonrasib alone, Revolution Medicines is reading its own doublet as a regimen that should clear first-line chemotherapy outright in the G12D subset, not merely add incremental benefit to a monotherapy already approved later in the disease ^[2].

Why it matters

The move into Phase 3 rests on earlier data. In previously treated RAS G12D pancreatic cancer, zoldonrasib plus daraxonrasib showed what the company called compelling preliminary antitumor activity and a manageable safety and tolerability profile, and those findings supported initiating RASolute 309 ^[3].

RASolute 309 is one of several overlapping first-line bets. Revolution Medicines is also advancing daraxonrasib in first-line metastatic and adjuvant PDAC through RASolute 303 and 304, and zoldonrasib with chemotherapy through RASolute 305 ^[3]. The company is building a RAS(ON) franchise across the treatment line, and 309 tests whether two of its assets combine better than either alone.

Who is exposed, who gained

Tango Therapeutics gains indirectly. Its vopimetostat (a PRMT5 inhibitor) plus daraxonrasib combination reported a 92% objective response rate and a 90% six-month PFS rate in MTAP-deleted, RAS-mutant pancreatic cancer, and the company is working toward a registrational plan with Revolution Medicines for that combination ^[5]. Every new daraxonrasib trial deepens the backbone Tango is building on.

Competitors are circling daraxonrasib's resistance window. Erasca is advancing ERAS-0015, a pan-RAS molecular glue, which showed a 57% unconfirmed objective response rate at 8 weeks in second-line-plus KRAS G12X PDAC, with a first-line PDAC Phase 3 planned to start in 2027 ^[7].

What to watch next

The hard catalyst is distant: RASolute 309's primary completion is set for March 2029 ^[2].

What Prognyx could not verify

Prognyx could not confirm the full body of the 5 October release beyond its dosing-start announcement, and no SEC filing in the retrieved set documents the dosing event itself ^[1]. Veru's statement that median time to progression on daraxonrasib was 7.2 months is company-reported in a promotional context and is not confirmed by Revolution Medicines or a trial registry ^[6].

The now-what

Three moves are on the table for operators in this space. First, read the chemo comparator as a declaration: Revolution Medicines is positioning the doublet to displace first-line chemotherapy in G12D disease, so anyone holding a competing first-line asset is now measured against a two-drug RAS(ON) regimen, not a single agent. Second, post-daraxonrasib resistance is already a defined commercial opening that Veru and others are planning around; second-line G12D strategy belongs on the roadmap now. Third, partnering onto the daraxonrasib backbone, the route Tango took, is a validated path for RAS-pathway combination assets.

Verdict: low near-term threat, long fuse. The competitive signal is real, but the data that resolves it sits roughly three years out at a March 2029 primary completion; the window to position second-line and combination assets against a RAS(ON) backbone is now.