Daraxonrasib Emerges as a Promising Contender in Metastatic Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers, with a 5-year survival rate of approximately 3% in metastatic disease and limited treatment options dominated by cytotoxic chemotherapies like FOLFIRINOX and gemcitabine/nab-paclitaxel (GnP). Revolution Medicines’ daraxonrasib (RMC-6236), a groundbreaking RAS(ON) multi-selective tri-complex inhibitor, is poised to address this unmet need. Targeting over 90% of PDAC cases driven by RAS mutations (e.g., KRAS G12D, G12V) [1], daraxonrasib has shown promising early data in first-line (1L) and second-line or later (2L+) metastatic PDAC, as detailed in the company’s September 10, 2025, investor presentation [1]. Here, we analyze the latest clinical results of daraxonrasib, compare monotherapy and combination approaches, and explore their implications for patients, the broader RAS-targeted oncology landscape, and the pivotal RASolute 303 Phase 3 trial.

First-Line Monotherapy: Strong Efficacy with Favorable Tolerability

In a cohort of 38 treatment-naïve patients with RAS-mutant mPDAC (data cutoff: July 28, 2025), daraxonrasib monotherapy at 300 mg daily demonstrated an objective response rate (ORR) of 47% (18/38, per RECIST v1.1) and a disease control rate (DCR) of 89% (34/38), with a median follow-up of 9.3 months [1]. These results significantly outperform historical 1L chemotherapy benchmarks, such as GnP (ORR 23% in MPACT [3]; 30–43% in later real-world reports [4]; DCR 62–76% [3–8]) and FOLFIRINOX (ORR 32% in PRODIGE 4 [2]; DCR 62–70% [2, 5–8]), positioning daraxonrasib as a potential chemotherapy-sparing option.

The safety profile is encouraging, with 35% (14/40) of patients experiencing Grade ≥3 treatment-related adverse events (TRAEs), primarily rash (8%), diarrhea (10%), and stomatitis/mucositis (8%) [1]. Dose modifications occurred in 63% of patients, with 10% discontinuations and a mean dose intensity of 85% [1]. Compared to chemotherapy’s ~70% Grade ≥3 TRAE rate and ~25% discontinuations [5], daraxonrasib monotherapy offers a more tolerable option, potentially improving quality of life for patients with this aggressive disease. Progression-free survival (PFS) and overall survival (OS) data remain immature, with most patients still on treatment, signaling potential for durable responses.

First-Line Combination with GnP: Enhanced Efficacy, Higher Toxicity

In a parallel 1L mPDAC cohort (N=31, efficacy-evaluable; data cutoff: July 28, 2025), daraxonrasib (200 mg daily) combined with GnP (1000 mg/m² gemcitabine, 125 mg/m² nab-paclitaxel, Days 1 and 15) achieved an ORR of 55% (17/31) and a DCR of 90% (28/31), with a median follow-up of 6.9 months [1]. These metrics exceed historical benchmarks [2–8], suggesting additive benefits from combining RAS inhibition with chemotherapy.

The combination’s safety profile reflects additive toxicities, with 58% (23/40) of patients experiencing Grade ≥3 TRAEs, including anemia (23%), neutropenia (15%), and rash/diarrhea/fatigue (13% each) [1]. Daraxonrasib-related TRAEs (e.g., rash, diarrhea) align with monotherapy, while hematologic toxicities (e.g., anemia, neutropenia) are consistent with GnP’s known effects [1]. Dose reductions occurred in 23% (daraxonrasib) and 43% (GnP), with discontinuations at 5% and 8%, respectively [1]. Daraxonrasib maintained an 81% dose intensity, compared to GnP’s 63%, indicating better tolerability for the targeted agent [1]. While the 58% Grade ≥3 TRAE rate approaches chemotherapy’s ~70% [5], low discontinuation rates suggest patients can sustain treatment, critical in PDAC’s aggressive setting. PFS and OS data are immature, awaiting longer follow-up.

Comparing Monotherapy and Combination Therapy

The monotherapy and combination results highlight a trade-off between efficacy and tolerability. Monotherapy achieves a robust ORR of 47% and DCR of 89%, closely approaching the combination’s 55% ORR and 90% DCR, despite using a higher daraxonrasib dose (300 mg vs. 200 mg) [1]. The combination’s 8% higher ORR suggests deeper tumor responses, as evidenced by the waterfall plots, likely due to GnP’s cytotoxic effects complementing RAS inhibition [1]. However, Grade ≥3 TRAEs rise from 35% (monotherapy) to 58% (combination), driven by GnP-related hematologic AEs (e.g., anemia 23%, neutropenia 15%) [1]. Monotherapy’s comparable discontinuation rates (10% vs. 5–8%) and higher dose intensity (85% vs. 81% for daraxonrasib, 63% for GnP) underscore its tolerability advantage, particularly for patients intolerant to chemotherapy [1]. The upcoming RASolute 303 Phase 3 trial, comparing both approaches to GnP alone, will clarify whether the combination’s efficacy justifies its toxicity or if monotherapy can suffice as a less toxic standard of care [1].

Second-Line and Beyond: A Benchmark for Success

In 2L+ mPDAC (N=83, data cutoff: June 30, 2025), daraxonrasib monotherapy (300 mg daily) delivered an ORR of 29–35% (any RAS mutation/KRAS G12X), DCR of 92–95%, median PFS of 8.1–8.5 months, and median OS of 13.1–15.6 months, with a 16.7-month follow-up [1]. These outcomes significantly exceed 2L+ chemotherapy standards (e.g., 5-FU/nal-IRI: ORR 8%, mPFS 3.1 months, mOS 6.1 months in NAPOLI-1 [9]). The safety profile mirrors 1L monotherapy, with 34% Grade ≥3 TRAEs, no discontinuations, and an 86% dose intensity [1], reinforcing daraxonrasib’s consistency across treatment lines.

Looking Ahead: RASolute 303 trial

The RASolute 303 Phase 3 trial (anticipated start Q4 2025) will randomize approximately 900 first-line metastatic PDAC patients with RAS mutations

Arms:

1. Daraxonrasib monotherapy (300 mg QD) [ADD: Reference Slide 16 for monotherapy ORR/DCR waterfall].
2. Daraxonrasib (200 mg QD) + GnP (gemcitabine 1000 mg/m² + nab-paclitaxel 125 mg/m², Days 1 and 15 of a 28-day cycle for up to 6 months), followed by daraxonrasib maintenance (300 mg QD) [ADD: Reference Slide 22 for combo ORR/DCR waterfall; Slide 27 for schedule/rationale].
3. GnP alone (standard dosing: Days 1, 8, 15 of a 28-day cycle) [ADD: Optional reference to historical benchmark slides, e.g., Slide 7–8].

Endpoints:

• Primary: progression-free survival (PFS) and overall survival (OS) [ADD: Slide 27 if trial schema is shown].
• Secondary: objective response rate (ORR), duration of response (DOR), and safety [ADD: Slide 24 for safety table].

The combination arm was designed to optimize efficacy while limiting chemotherapy-related toxicity, leveraging a Day 1/15 schedule to reduce hematologic and neurotoxic adverse events [ADD: Slide 27 rationale graphic]. This approach allows continuous RAS suppression while maintaining tolerability, informed by prior 2L PDAC experience [ADD: Slide 35 if 2L PDAC data shown].

The trial will determine whether daraxonrasib monotherapy’s favorable safety profile can achieve comparable clinical benefit to the combination, potentially establishing a new standard of care in first-line RAS-mutant PDAC.

Competitive Landscape

Daraxonrasib’s pan-RAS activity targets ~92% of PDAC cases with RAS mutations (e.g., KRAS G12D, G12V, G12R) [1], giving it a significant advantage over KRAS G12C-specific inhibitors like sotorasib (Lumakras) and adagrasib (Krazati), which address only ~1–2% of PDAC cases [1, 16, 17]. In 1L mPDAC, daraxonrasib monotherapy achieves a 47% ORR and 89% DCR, while the combination with GnP reaches a 55% ORR and 90% DCR [1]. In contrast, sotorasib in 2L+ mPDAC (N=38, CodeBreaK 100) reported a 21.1% ORR, 84.2% DCR, median PFS of 4.0 months, and median OS of 6.9 months [16]. Adagrasib in 2L+ mPDAC (N=21, KRYSTAL-1) showed a 33.3% ORR, 81% DCR, median PFS of 5.4 months, and median OS of 8.0 months [17]. While adagrasib’s 1L data with chemotherapy suggest an ORR of ~30–40% and mPFS of ~6–7 months [1], daraxonrasib’s superior ORR and DCR in 1L, and longer PFS/OS in 2L+, highlight its broader applicability and efficacy. Safety profiles are comparable, with daraxonrasib’s 35% Grade ≥3 TRAEs (monotherapy) and 58% (combination) [1] aligning with sotorasib and adagrasib’s ~20–30% Grade ≥3 TRAEs [16, 17], all lower than chemotherapy’s ~70% [5]. The ongoing RASolute 303 and 302 Phase 3 trials [1], compared to sotorasib and adagrasib’s earlier-stage PDAC data [16, 17], position daraxonrasib as a frontrunner. Its potential in other RAS-driven cancers, such as non-small cell lung cancer (NSCLC), where early data show a 38% ORR in 2L+ [1], further bolsters its promise.

Conclusion

Daraxonrasib represents a significant advance for mPDAC, with 1L monotherapy (ORR 47%, DCR 89%) and combination therapy (ORR 55%, DCR 90%) surpassing current chemotherapy standards [1–8]. Monotherapy’s favorable tolerability (35% Grade ≥3 TRAEs) contrasts with the combination’s higher toxicity (58% Grade ≥3 TRAEs), posing a critical question for RASolute 303: can monotherapy’s efficacy suffice without chemotherapy’s burden? While challenges remain, including competition from other RAS inhibitors and the need for mature survival data, daraxonrasib’s early results position it as a transformative option for patients with this devastating disease.

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Disclaimer: Daraxonrasib is an investigational agent and has not been approved by the FDA or any regulatory authority. The clinical data discussed are preliminary and may change as trials mature. This article is intended for informational purposes only and does not constitute medical or investment advice. Readers should consult peer-reviewed literature and regulatory sources for verification.