Current landscape of RAS-targeted therapy for pancreatic cancer

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AbstractPancreatic ductal adenocarcinoma (PDAC) continues to carry a poor prognosis, and only incremental gains in systemic therapy have been made over the past decade. Because activating KRAS mutations are present in more than 90% of PDAC and serve as the inciting oncogenic driver, RAS has long been a coveted but elusive therapeutic target, historically deemed “undruggable.” Allele-specific KRASG12C inhibitors provided the first proof of concept, but G12C mutations account for only about 1% of PDAC, in which G12D, G12V, and G12R predominate. Recent advances in the structural and biochemical understanding of RAS have yielded a rapidly expanding therapeutic landscape, broadly comprising non-G12C allele-specific inhibitors, pan-RAS and pan-KRAS inhibitors, and proteolysis-targeting chimeras. This progress is exemplified by the phase III RASolute-302 trial, in which the RAS(ON) multi-selective tri-complex inhibitor daraxonrasib nearly doubled overall survival versus chemotherapy in previously treated metastatic PDAC (13.2 vs 6.7 months), positioning it as the first broadly applicable RAS-targeted therapy in this disease. Here we review the biology of RAS, the mechanistic rationale and clinical data behind emerging RAS-directed agents, and the central challenges ahead: targeting different KRAS subtypes, managing distinct toxicities, and overcoming the genetic and non-genetic resistance mechanisms that will require rational combination strategies to translate these gains into durable benefit.

targeting ras and kras g12c cc by

RAS proteins are binary molecular switches and GTPases with diverse biological functions. They cycle between an inactive guanosine diphosphate (GDP)-bound OFF state and an active guanosine triphosphate (GTP)-bound ON state.10 In PDAC, RAS mutations most commonly occur at codons 12, 13, and 61, causing a conformational change that disrupts GTPase-activating protein (GAP)-mediated GTP hydrolysis, thus favoring its GTP-bound ON state.7 Activated RAS subsequently engages downstream effector pathways, including mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling, to promote cell proliferation. Although its mechanism is well known, the lack of drug-binding pockets in the RAS protein, its high affinity for GTP (making GTP-competitive inhibitors ineffective), and frequent cycling between the ON and OFF states elude drug targeting.11,12 The first breakthrough in direct RAS targeting came with KRASG12C inhibitors. Notably, the KRASG12C mutant protein has a relatively accessible GDP-bound OFF state.11,13 Discovery of the switch II effector and drug-binding pocket in mutated KRAS led to the development of compounds that can bind to the cysteine residue of KRASG12C while sparing wild-type RAS proteins lacking these residues, locking KRASG12C in its inactive OFF state (Figure 1A).14 The FDA approvals of the KRASG12C inhibitors sotorasib and adagrasib in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) marked a watershed in RAS-targeted drug development.14–17 Now, second-generation KRASG12C inhibitors are undergoing investigation.15–23 While sotorasib and adagrasib have some activity in PDAC,24,25 they are not FDA-approved for this indication. KRASG12C mutations occur in approximately 1% of PDAC,7 so novel RAS-targeting strategies extending beyond this allele offer greater clinical relevance.

novel therapeutic approaches to targeting ras cc by

KRAS G12D is the most common variant in PDAC, accounting for approximately 40% of KRAS mutations.7,13 Aspartate substitution of glycine causes KRAS to be persistently activated by decreasing GTP hydrolysis.26 In contrast to KRASG12C, the KRASG12D protein is a poor nucleophile and a more challenging target for OFF state inhibitors like sotorasib and adagrasib, which rely on forming covalent bonds in the switch II pocket. Similarly, KRASG12V, the second most common mutation in PDAC,7,13 replaces glycine with valine, a bulky amino acid that causes conformational rigidity, including in the effector-binding switch regions, suppressing GTP hydrolysis and locking the protein in the ON state.13 Without accessible binding sites, targeting these mutant subtypes has posed significant challenges for drug development and necessitated a strategy for inhibiting the activated ON state. With better understanding of the biochemical and structural properties of RAS proteins, recent years have seen the emergence of a variety of novel RAS-targeted therapies that can be broadly categorized into three primary approaches: (1) non-KRASG12C allele-specific KRAS inhibitors, (2) pan-RAS inhibitors, including isoform-specific inhibitors, and (3) protein degraders like proteolysis targeting chimeras (PROTACs).

allele-specific kras inhibitors cc by

Allele-specific inhibitors are also being developed against non-G12C KRAS variants that are more prevalent in PDAC, including KRASG12D and KRASG12V (Table 1). Agents targeting KRASG12D have followed similar design strategies as those targeting KRASG12C. In the absence of a reactive cysteine, MRTX1133 emerged as the first selective KRASG12D inhibitor, binding noncovalently to the switch II pocket and stabilizing the mutant protein in its GDP-bound OFF state.39 Unfortunately, despite preclinical efficacy, its clinical phase I/II trial was terminated early due to variable, suboptimal pharmacokinetics. Zoldonrasib (RMC-9805) is a KRASG12D-selective inhibitor that employs the same tri-complex molecular-glue mechanism as daraxonrasib.40 Preliminary phase I results demonstrated an ORR of 30% and a DCR of 80% among 40 evaluable patients with KRASG12D-mutated PDAC treated with zoldonrasib across two dose levels.27 Of all patients with KRASG12D-mutated solid tumors treated with zoldonrasib, the most common treatment-related adverse effects were nausea (27%), diarrhea (20%), vomiting (15%), and rash (10%), all of which were Grade 1 or 2 in severity.27 Although survival data are not available, these findings are promising and are consistent with the expectation that higher target selectivity leads to less toxicity. Recent phase I data for the KRASG12D inhibitor INCB161734 demonstrated ORRs of 23% at 600 mg (N = 22) and 34% at 1200 mg (N = 29), with corresponding DCRs of 73% and 86%. The most common adverse events were nausea (58%), diarrhea (51%), vomiting (46%), and fatigue (18%), which were mostly Grade 1 to 2.28 Unlike MRTX1133 and zoldonrasib, INCB161734 binds the switch II pocket of both the GDP- and GTP-bound forms of KRASG12D.41 Two KRASG12V inhibitors are currently in development; however, conventional small-molecule approaches have been limited because valine is not amenable to covalent targeting or favorable polar noncovalent interactions.38 Utilizing a similar strategy as daraxonrasib and zoldonrasib, RMC-5127 forms a tri-complex between the ON state of KRAS G12V and CypA, disrupting effector binding and signal transduction through steric occlusion.38 RMC-5127 is currently investigated in a phase I clinical trial (NCT07349537). Another KRASG12V inhibitor, QTX3544, acts on both the ON and OFF states of KRAS in biochemical and cellular assays42 and being investigated in a phase I trial (NCT06715124).37 Other allele-specific KRAS inhibitors are listed in Table 2. Another relatively common mutation occurs at codon 61, and approximately 5% of PDAC have KRASQ61H mutations, which impair intrinsic GTPase activity53 and are associated with worse prognosis compared to other subtypes.54 Recently, some evidence suggests that tumors with KRASQ61H mutations may be less sensitive to pan-RAS inhibition like daraxonrasib, and KRASQ61H-specific inhibitors are in preclinical development.55 In addition, tumors with KRASG12R present other unique challenges, which are described below.

pan-(k)ras inhibitors cc by

Experience with KRASG12C inhibitors show that acquired resistance often develops within KRASG12C or secondary KRAS sites.56,57 Pan-RAS inhibitors may reduce opportunities for such resistance by targeting multiple RAS mutational subtypes. Currently, all pan-RAS inhibitors are tri-complex-forming agents that act as ON state molecular glues while many pan-KRAS inhibitors target the switch II pocket (Table 2). As previously described, daraxonrasib (or RMC-6236) is now the first FDA-approved pan-RAS inhibitor for PDAC. Daraxonrasib is a RAS(ON) tri-complex inhibitor that binds to mutant and wild-type RAS and occupies both switch pockets to inhibit effector binding (Figure 1B).8 For patients with any KRASG12 substitution in the RASolute-302 trial, daraxonrasib had similar mOS (13.2 months) and mPFS (7.3 months) compared to the overall population (13.2 and 7.2 months, respectively), which included those whose tumors had mutations in KRAS, NRAS, or HRAS at codon 12, 13, or 61 (G12, G13, or Q61), or wild-type RAS.9 These findings suggest that daraxonrasib may be active across less common RAS subtypes, although interpretation is limited because fewer than 10% of enrolled patients had tumors without a RASG12 mutation. Nevertheless, daraxonrasib is now the first RAS-targeted therapy with broad applicability in PDAC. Other pan-RAS inhibitors currently under investigation include ERAS-001543 and AN9025,44 which utilize a similar tri-complex ON inhibitor strategy (Table 1). Phase I clinical trials for these agents are ongoing. Although grade ≥3 treatment-related adverse events were less frequent with daraxonrasib than with chemotherapy in RASolute-302 (43.6% vs 57.5%), clinically meaningful toxicity remained common.9 The most frequent treatment-related adverse events were rash (85.5%), diarrhea (58.1%), stomatitis (53.1%), nausea (46.5%), and vomiting (36.9%).9 Skin toxicity is an expected on-target effect of RAS pathway inhibition, with acneiform and maculopapular rashes occurring frequently.58,59 To mitigate dermatologic toxicity, current guidelines recommend administration of topical corticosteroids, emollient creams, broad spectrum sunscreen, and prophylactic oral antibiotics (ie, doxycycline or minocycline) with daraxonrasib. Temporary treatment interruption may be necessary to allow rash improvement, and dose reduction may be warranted for recurrent or intolerable toxicity. Rash that persists or worsens despite initial supportive measures should prompt dermatologic consultation and consideration of additional therapy. Trials of novel treatments for skin toxicity specific to RAS inhibition are also under development. Pan-KRAS inhibitors spare NRAS and HRAS and employ distinct mechanisms that may reduce skin toxicity relative to pan-RAS inhibition. LY4066434 binds GDP-bound KRAS and stabilizes its inactive OFF state,60 whereas BBO-11818 noncovalently engages the switch II pocket of both GDP- and GTP-bound KRAS mutants, inducing conformational changes that prevent effector binding.46 Phase I trials of these and other pan-KRAS inhibitors are ongoing, with clinical data not yet available (Table 1).

protacs cc by

Given the longstanding challenges of developing direct small-molecule RAS inhibitors, alternative strategies may circumvent the need for sustained inhibitory binding. PROTACs recruit an E3 ubiquitin ligase to KRAS through a ternary complex, promoting proteasomal degradation of mutant KRAS (Figure 1C).61 Because degradation does not depend on a single nucleotide-bound conformation, PROTACs may target both the ON and OFF states of KRAS. Setidegrasib (ASP3082) is a first-in-class KRASG12D-targeted PROTAC. In a phase I trial, setidegrasib demonstrated antitumor activity in NSCLC and PDAC. Among 21 patients with metastatic PDAC, the ORR was 24% (95% CI, 8-47), median PFS was 3.0 months (95% CI, 1.4-6.9), and median OS was 10.3 months (95% CI, 4.2-13.0).62 Setidegrasib is currently being evaluated in the frontline treatment of metastatic PDAC (NCT07409272). ARV-806, another KRASG12D-targeted PROTAC,63 is being investigated in a phase I/II trial (NCT07023731). These agents are summarized in Table 3. Figure 2 shows a summary of (K)RAS targeted agents in development.

targeting kras g12r cc by

Many emerging RAS-targeted therapies exclude KRASG12R, which accounts for approximately 20% of PDAC and is associated with less nodal involvement, fewer distant recurrences, and improved survival.7,13,65,66 KRASG12R disrupts switch II-dependent effector signaling, particularly PI3K activation, and exhibits reduced migratory and EMT potential.65,67,68 Consequently, switch II pocket inhibitors may be ineffective, whereas tri-complex agents such as daraxonrasib may retain activity.

lessons in acquired resistance from kras g12c inhibitors cc by

Many challenges remain despite the recent plethora of RAS-targeted therapies for PDAC, and some lessons may be learned from prior experiences with KRASG12C-targeted agents in NSCLC and CRC. The development of resistance mechanisms to RAS-targeted therapy could be a major limitation to achieving durable responses and improving patient outcomes. With KRASG12C inhibition, acquired resistance across tumor types is mediated by secondary mutations in the target KRAS protein including amplification of KRASG12C, activation of alternative pathways through other receptors or downstream proteins, or phenotypic transformation.56 For example, bypass pathway activation included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN.56 Similarly, patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib developed polyclonal and convergent resistance through RAS pathway reactivation, including PIK3CA and KRAS mutations and KRASG12C amplification, as well as bypass signaling through MYC, MET, EGFR, and CDK6 alterations.69

emerging patterns of resistance to daraxonrasib monotherapy cc by

Because daraxonrasib will be widely available for the treatment of PDAC, work to understand mechanisms of resistance to this agent has already been undertaken. One study evaluated circulating tumor DNA (ctDNA) collected from patients with PDAC who received daraxonrasib monotherapy. Genomic mechanisms of resistance were found in more than half of patients, with the most common alteration being KRAS amplification (36%). Unlike KRASG12C inhibition, no acquired oncogenic secondary KRAS mutations were observed, likely due to the broad RAS inhibitory activity of daraxonrasib. Other acquired alterations were frequently observed in RAF, MYC, PI3K pathway genes, as well as upregulation of receptor tyrosine kinases (RTKs).70–72 Paired pretreatment and end-of-treatment tissue or ctDNA analyses from 40 patients treated with daraxonrasib identified 18 recurrent alterations associated with resistance.73 These included KRAS Y64 and Y71 mutations that impair tri-complex formation or favor RAS–RAF signaling, PPIA alterations affecting CypA, and RAF pathway alterations, including BRAF, that promote ERK signaling and reduce tri-complex engagement.

primary resistance to ras inhibition cc by

Primary resistance to RAS inhibition may arise from preexisting tumor features or co-mutations that confer KRAS independence. Mechanisms include epithelial-mesenchymal transition, YAP activation, and KEAP1 alterations.74 Preclinical models of KRASG12D-mutant PDAC have identified epithelial-mesenchymal transition and PI3K–AKT–mTOR signaling as baseline features associated with resistance to MRTX1133.69 In KRASG12C-mutant NSCLC, KEAP1 co-mutations are poor prognostic markers and may also confer resistance to KRAS-targeted therapy. However, other studies could not confirm it as a predictive marker for sotorasib response.75 In both PDAC and CRC, TP53 and PIK3CA have been implicated as possible drivers of KRASG12C inhibitor resistance, but post-hoc analyses from CodeBreaK and the KRYSTAL-1 trials could not confirm these co-mutations as predictive markers of treatment response either.75 As of now, genomic markers of KRAS inhibitor response have not been identified and is an area of active investigation. Further, emerging evidence points to cell identity changes as a distinct resistance axis that may contribute to both acquired and intrinsic drug resistance. Changes in cell identity, such as mucinous differentiation, shifts from alveolar type 2 to type 1 cells, or lineage switching from adenocarcinoma to squamous cell carcinoma, have been shown to contribute to resistance.74 Mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state in preclinical models of PDAC.69 This may reflect differential dependence on KRAS-driven survival signaling, with classical-state tumors having greater capacity to activate alternative survival pathways.

overcoming resistance and combination therapy cc by

Primary and acquired resistance remain important limitations of RAS inhibitor monotherapy, prompting active investigation of combination strategies.76 One approach, already being investigated in ongoing clinical trials, is to combine (K)RAS inhibition with chemotherapy. Preclinical data demonstrate that combining KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models.69 PDAC also comprises a spectrum of classical and basal epithelial states, with basal-state dominance associated with chemotherapy resistance. Preclinical studies of the KRASG12D-selective inhibitor MRTX1133 demonstrated preferential activity against basal-state cells and treatment-associated enrichment of the classical state, providing a rationale for combining RAS inhibition with chemotherapy. Accordingly, daraxonrasib is being evaluated with standard chemotherapy in the frontline RASolute-303 trial (NCT07491445).76 Other KRAS inhibitors, particularly KRASG12D-specific inhibitors, INCB161734 (NCT07522073) and zoldonrasib (RASolute-305; NCT07621718), are also being investigated in the first-line setting in combination with chemotherapy. Overcoming resistance mechanisms involves enhancing the efficacy of drugs targeting mutant KRAS, developing broad-spectrum inhibitors, and combining therapies targeting multiple pathways.77 Additionally, biomarker-selected combinations targeting co-occurring alterations are also under investigation. In MTAP-deleted, RAS-mutant PDAC, daraxonrasib is being evaluated with vopimetostat, an MTA-cooperative PRMT5 inhibitor (NCT06922591; NCT07492680).78,79 Preliminary phase I/II data demonstrated a 92% ORR (11/12 evaluable patients), 100% DCR, and 90% 6-month PFS rate, although these findings are based on a small, nonrandomized cohort reported by Tango Pharmaceuticals in a press release. RAS also plays a role in upregulating homologous recombination and non-homologous end joining, critical pathways for DNA damage repair,80 which may be exploited for patients with BRCA alterations. Preclinical studies show that KRASG12D blockade suppresses homologous recombination, which sensitizes PDAC cells to poly(ADP-ribose) polymerase (PARP) inhibition.81 Preclinical data suggest that this combination may induce synthetic lethality irrespective of BRCA mutation status and delay emergence of therapeutic resistance, supporting its evaluation in clinical studies.80,81 Targeting upstream of RAS to attenuate RTK-driven feedback reactivation, such as SHP2 inhibition, has shown synergy with KRASG12C inhibition in preclinical models and is being evaluated in combination trials.77 More prominently, the treatment of KRASG12C-mutant CRC now includes a KRASG12C inhibitor with EGFR co-inhibition.82 In CRC, overactivation of KRAS signaling suppresses RTK (ie, EGFR) expression via a negative feedback loop, but KRAS and ERK inhibition promotes rebound EGFR expression and formation of drug-resistant RAF dimers,83 the latter similarly to acquired resistance to daraxonrasib. Thus, KRAS inhibitors in combination with EGFR antibodies for PDAC is also being investigated.37 Inhibiting KRAS also disrupts protein homeostasis, but reactivation of MAPK or AKT can restore it, aiding tumor cell survival,74 suggesting that co-targeting these downstream nodes may delay the emergence of resistance. Already, combination of KRASG12C inhibitors and MEK or RAF inhibitors show modest activity in NSCLC and CRC.84 However, in PDAC, combination with a pan-RAS inhibitor likely presents greater toxicity than with an allele-specific KRAS inhibitor. Allele-specific KRAS inhibitors are vulnerable to resistance through development of secondary mutations in KRAS, resulting in activation of bypass pathways. Combining the G12D-selective inhibitor zoldonrasib with a multi-selective RAS inhibitor daraxonrasib is therefore intended to deepen RAS pathway suppression and produce more durable responses than either agent alone. In a phase I trial of patients with metastatic PDAC, the combination of zoldonrasib and daraxonrasib resulted in an ORR of 50% in the second line setting and 47% in the third line setting, with DCR exceeding 90%. Median PFS was 9.6 months (95% CI: 7.1-NE) and 7.6 months (95% CI: 4.6-10.5), respectively. While OS data remain immature, 6-month OS were 89% and 82%, respectively.85 These findings provide the rationale for evaluating this doublet in the upcoming phase III RASolute-309 trial. Other combination approaches being considered includes integrating immunotherapy into KRAS inhibitor combinations, with evolving evidence that KRAS blockade may remodel the immunosuppressive tumor microenvironment of PDAC in ways that enhance responsiveness to checkpoint inhibition.76 Already, the KRASG12D inhibitor HRS-4642 was combined with adebrelimab, an anti-PD-L1 antibody, in a phase I trial with 48 patients, demonstrating an ORR of 41.9%, DCR of 83.7%, mPFS of 5.6 months, and mOS was not reached. The most common adverse events were elevated lipase (16.7%), gamma-glutamyl transpeptidase (12.5%), and blood cholesterol (8.3%).86

(k)ras inhibition in the non-metastatic setting cc by

As novel therapies prove effective in the metastatic setting, they are increasingly being investigated earlier in the disease course, where they may improve outcomes and offer a greater chance of cure. Daraxonrasib is being investigated in the adjuvant setting to evaluate recurrence outcomes for patients whose tumors were resected and who have completed adjuvant chemotherapy (RASolute-304; NCT07252232). In addition, a novel KRAS-targeted vaccine has recently been evaluated in patients with minimal residual disease following curative-intent therapy, as indicated by detectable ctDNA or persistently elevated tumor marker levels. ELI-002 2P is a lymph-node-targeted vaccine comprised of amphiphile (Amph)-modified KRASG12D and KRASG12R long peptides as well as Amph-modified Toll-like receptor 9 (TLR9) agonistic CpG-7909 DNA (Figure 1D). The Amph vaccines are larger than other peptides and contain modifications that allow “hitchhiking” onto endogenous albumin. Thus, the vaccine can better accumulate in lymph nodes and enter antigen-presenting cells, promoting an antitumor immune response. Of 25 participants with mutated KRAS in the phase 1 AMPLIFY-201 trial investigating ELI-002, 20 had PDAC and the other 5 had CRC. T cell and tumor biomarker responses were both observed in 84% of participants (21/25), and biomarker clearance was observed in 24% (6/25) of patients. The median recurrence-free survival was 16.3 months and correlated with T cell response and reduction in tumor marker levels.87 Beyond its potential to reduce recurrence in the adjuvant setting, (K)RAS-targeted therapy may also have a role as neoadjuvant treatment, where effective tumor downstaging could render initially unresectable PDAC amenable to curative resection. Conversion to resectability has been associated with improved survival in PDAC,88,89 underscoring the need for more effective neoadjuvant regimens. For patients with locally advanced disease or tumors that cannot be downstaged with standard chemotherapy, (K)RAS-targeted agents in combination with chemotherapy or dual KRAS pathway suppression may expand surgical candidacy and potentially improve clinical outcomes. These neoadjuvant trials are currently in development.

future directions cc by

The clinical validation of KRAS inhibition in PDAC represents a landmark achievement following decades of failed attempts to drug this target. While KRAS targeting has opened a new frontier for the treatment of PDAC, the field is in its infancy, and many questions remain to be answered. In the now widening landscape of KRAS-targeted therapies, most agents are still in early phase trials, and which compound will ultimately emerge as the best-in-class will require maturation of survival data and safety profiles that are not yet available. However, it appears that tri-complex molecular glues so far may demonstrate enhanced efficacy compared to switch II pocket inhibitors in this disease. Management of potential toxicities distinct from those of chemotherapy will also require clinician experience. In addition, resistance mechanisms may still limit the impact of KRAS inhibition in patients with PDAC, with heterogeneous genetic and non-genetic mechanisms of resistance co-evolving under therapeutic pressure. Addressing this complexity will require combination regimens rationally designed to preempt multiple resistance nodes simultaneously, deeper molecular characterization of tumors at baseline and at progression, and clinical trial designs capable of detecting activity in genomically stratified patient populations. As (K)RAS-targeted therapies enter the PDAC armamentarium across disease stages, the field must now confront a question it has rarely had the luxury of asking: how best to sequence effective options. For now, chemotherapy remains the standard front-line therapy, with daraxonrasib now approved as second line therapy. This is unlikely to hold. (K)RAS-targeted therapy will almost certainly migrate into the front-line setting, whether alone or combined with chemotherapy or dual RAS pathway targeted therapy, giving rise to other pressing concerns. For patients who progress on (K)RAS-targeted therapy, chemotherapy will likely remain the most established subsequent treatment, although emerging approaches may permit rational sequencing of targeted agents. Tumors progressing after an allele-specific KRAS inhibitor may retain sensitivity to a multi-selective RAS inhibitor, whereas pan-KRAS-directed PROTAC degraders may offer another potential salvage strategy. Similarly, resistance mediated by alterations that disrupt tri-complex formation may remain susceptible to agents that inhibit or degrade RAS through alternative mechanisms. Serial molecular profiling during treatment and at progression will therefore be increasingly important for defining resistance mechanisms and guiding subsequent therapies, including combinations targeting activated bypass pathways. Before progression, (K)RAS-targeted agents may also have a role as maintenance therapy, potentially reducing cumulative chemotherapy exposure. Moreover, in a disease that has historically been resistant to immunotherapy, RAS inhibition may remodel the tumor microenvironment in ways that enhance the activity of immunotherapeutic approaches, including vaccines and adoptive cell therapies. For PDAC, a disease that carries a dismal prognosis where standard treatment offered little beyond cytotoxic chemotherapy, the advent of (K)RAS-targeted therapy represents an important shift. Direct pharmacologic targeting of the primary oncogenic driver in PDAC has only now become feasible, and growing evidence suggests that (K)RAS-targeted therapies can deliver meaningful improvements in survival and response rates. Moving forward, translating this potential into consistent and durable clinical benefit will be critical. Although important uncertainties remain, the emergence of (K)RAS-targeted therapies marks the beginning of a new therapeutic era in PDAC.