Targeting Advanced Pancreatic Ductal Adenocarcinoma: A Practical Overview

Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, with a five-year overall survival rate below 10%. While the introduction of multi-agent chemotherapy regimens has improved outcomes marginally, most patients with advanced disease continue to have limited therapeutic options. Molecular profiling has uncovered actionable genomic alterations in select subgroups of PDAC, yet the clinical impact of targeted therapies remains modest. This review aims to provide a clinically oriented synthesis of emerging molecular targets in PDAC, their therapeutic relevance, and practical considerations for biomarker testing, including current FDA and EMA indications. Methods: A narrative review was conducted using data from PubMed, Embase, Scopus, and international guidelines (NCCN, ESMO, ASCO). The selection focused on evidence published between 2020 and 2025, highlighting molecularly defined PDAC subsets and the current status of targeted therapies. Results: Actionable genomic alterations in PDAC include KRAS G12C mutations, BRCA1/2 and PALB2-associated homologous recombination deficiency, MSI-H/dMMR status, and rare gene fusions involving NTRK, RET, and NRG1. While only a minority of patients are eligible for targeted treatments, early-phase trials and real-world data have shown promising results in these subgroups. Testing molecular profiling is increasingly standard in advanced PDAC. Conclusions: Despite the rarity of targetable mutations, systematic molecular profiling is critical in advanced PDAC to guide off-label therapy or clinical trial enrollment. A practical framework for identifying and acting on molecular targets is essential to bridge the gap between precision oncology and clinical management.

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, with a five-year overall survival (OS) rate of less than 10% [1]. Although it accounts for only 3% of all cancers, PDAC is projected to become the second leading cause of cancer-related death by 2030 in Western countries, due to rising incidence and persistently poor outcomes [2,3].

Epidemiological projections indicate that PDAC cases will continue to rise over the next two decades, driven by aging populations, increasing obesity, diabetes, and tobacco exposure [4]. Despite progress in systemic therapy, treatment for advanced PDAC remains largely palliative. First-line regimens such as FOLFIRINOX or gemcitabine combined with nab-paclitaxel offer only modest benefits, with the median OS rarely exceeding 11 months [5].

Even among patients with actionable molecular alterations, such as germline BRCA mutations or KRAS G12C, targeted therapies have shown limited and short-lived responses, often hindered by primary or acquired resistance mechanisms [6,7,8].

Several biological features contribute to PDAC’s poor therapeutic response. The tumor microenvironment (TME) is highly desmoplastic and immunosuppressive, forming both a physical barrier to drug delivery and a biochemical shield against immune attack [9,10]. Dense fibrosis, poor vascularization, and abundant cancer-associated fibroblasts interfere with chemotherapy efficacy and immune cell infiltration [11]. In addition, frequent KRAS mutations promote an immune-excluded phenotype and further reinforce immune resistance [12,13].

Given the increasing global burden of PDAC and the limitations of current treatments, there is an urgent need for more effective therapeutic strategies. This review aims to provide a practical and updated overview of molecularly targeted approaches in PDAC, focusing not only on current evidence, but also on their clinical applicability.

Specifically, we aim to assist clinicians in deciding when and how to conduct molecular testing, identify actionable biomarkers, and understand how these markers may inform the use of approved drugs, off-label options, or trial enrollment. In doing so, we hope to bridge the gap between molecular oncology and everyday clinical practice.

2. Materials and Methods

This narrative review was conducted to provide a clinically relevant and up-to-date synthesis of targeted therapy strategies in PDAC, with an emphasis on molecular subgroups and corresponding therapeutic implications.

A comprehensive and focused literature search was carried out using PubMed/MEDLINE, Embase, and Scopus, as well as the official websites of international regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The search strategy combined terms such as “pancreatic cancer,” “targeted therapy,” “KRAS,” “BRCA,” “PALB2,” “MSI,” “NTRK,” “RET,” “NRG1,” and “HER2.”

No language restrictions or publication year limits were applied during the initial search. However, we prioritized studies published between 2020 and 2025, to ensure the inclusion of recent clinical trials, updated guideline recommendations, and emerging therapeutic data. Sources were selected based on clinical relevance, methodological quality, and their contribution to the practical management of PDAC.

High-impact publications were prioritized, including pivotal trials, systematic reviews, real-world evidence, and official guidance from leading oncology societies, namely the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) [14,15,16].

No new data were generated or analyzed for this manuscript, and therefore no institutional review board (IRB) approval or patient informed consent was required. No proprietary databases, analytical tools, or commercial software were used.

The aim of this review was not only to summarize key molecular findings, but to interpret their real-world clinical impact, helping oncologists determine when and how to test, and how to act on actionable mutations, even when therapy options may lie outside of standard indications or require trial enrollment.

3. Results

3.1. Targeting KRAS: From G12C Inhibitors to Pan-RAS and Beyond

Mutations in KRAS are the predominant oncogenic drivers in PDAC, present in approximately 90% of cases [17]. The most frequent variants include G12D (~45%), G12V (~25%), and G12R (~15%), followed by rarer mutations such as G12C (1–2%), G13D, Q61H, and A146T [18].

Among these, KRAS G12C stands out as the only variant currently amenable to direct pharmacologic targeting, thanks to the presence of a cysteine residue at codon 12 that allows covalent inhibitor binding [19]. This mutation retains intrinsic GTPase activity and cycles between its active (GTP-bound) and inactive (GDP-bound) forms, making it suitable for selective inhibition by small molecules that bind the GDP-bound state [7,8].

Two first-generation KRAS G12C inhibitors, sotorasib and adagrasib, have shown preliminary efficacy in PDAC. In the CodeBreaK100 trial, sotorasib demonstrated an objective response rate (ORR) of 21%, with a median progression-free survival (PFS) of 4.0 months and a median OS of 6.9 months in 38 previously treated patients with advanced PDAC [7]. Adagrasib, tested in the KRYSTAL-1 trial, yielded an ORR of 33.3%, with median PFS of 5.4 months and OS of 8.0 months in a similar population [8].

Newer KRAS G12C inhibitors are under investigation, aiming to overcome resistance mechanisms and improve potency. Olomorasib (BAY-293) and glecirasib (JDQ443) are structurally distinct from first-generation inhibitors and show enhanced pharmacokinetics and intracellular retention [20,21]. In the LOXO-RAS-20001 trial, olomorasib achieved an ORR of 46% and a median PFS of 6.4 months in a cohort of 24 PDAC patients [22]. Glecirasib also demonstrated encouraging results in the KontRASt-01 study, with an ORR of 22% and disease control rate exceeding 70% in KRAS^G12C-mutant tumors [21].

For the majority of patients with non-G12C KRAS mutations, targeting remains more complex. These mutations typically lack a cysteine at codon 12 and favor the GTP-bound active form, rendering them resistant to current covalent inhibitors. New strategies are emerging, such as MRTX1133—a non-covalent, allosteric inhibitor targeting KRAS G12D. It binds a pocket adjacent to the Switch II region and has demonstrated potent tumor regression in PDAC mouse models [23].

Efforts to develop pan-RAS or pan-KRAS inhibitors have also gained momentum. RMC-6236, a trivalent RAS(ON) inhibitor, blocks the active GTP-bound form of mutant RAS by forming a ternary complex with cyclophilin A, sterically inhibiting downstream signaling. In a recent phase I trial, RMC-6236 achieved a median PFS of 7.6 months in second-line and 4.2 months in later-line settings among RAS-mutant PDAC patients [24]. RMC-6291, a next-generation GTP-bound selective inhibitor of KRAS G12C, is now in early clinical development [25].

Beyond enzymatic inhibition, KRAS degradation strategies are also being explored. These include PROTAC-based platforms such as RP03707, which recruit E3 ubiquitin ligases to selectively degrade mutant KRAS proteins. Preclinical models have shown over 90% degradation of KRAS G12D and superior antitumor efficacy compared to inhibitors alone [26,27].

Current clinical guidelines recommend comprehensive molecular profiling in all patients with advanced PDAC, preferably using next-generation sequencing (NGS) [14,15,16]. While the NCCN 2025 and ESMO 2023 guidelines recommend testing for common somatic mutations such as KRAS to identify actionable alterations, the ASCO 2020 guidelines do not currently include KRAS in their molecular testing recommendations [14,15,16].

As of mid-2025, no KRAS inhibitors are FDA- or EMA-approved for PDAC, although both sotorasib and adagrasib are approved for KRAS G12C-mutant non-small cell lung cancer (NSCLC). The signals of activity observed in pancreatic cancer support ongoing research and may pave the way toward future tumor-agnostic approvals.

3.2. Homologous Recombination Deficiency: The Role of BRCA and PALB2

Homologous recombination deficiency (HRD) has emerged as a biologically and clinically significant vulnerability in PDAC, affecting approximately 10–15% of patients [28]. This defect results from mutations in genes involved in the homologous recombination repair (HRR) pathway, such as BRCA1, BRCA2, PALB2, ATM, CHEK2, and RAD51C/D [29,30]. Loss of function in these genes compromises DNA double-strand break repair and sensitizes tumor cells to DNA-damaging agents [28].

In PDAC, germline mutations in BRCA2 are the most prevalent, found in 5–7% of cases, followed by BRCA1 (1–2%) and PALB2 (~1%) [31,32,33,34,35]. Alterations in other HRR genes like ATM and CHEK2 are less frequent and currently lack consistent therapeutic validation [36].

Only germline BRCA1/2 mutations are recognized as predictive biomarkers for PARP inhibitor (PARPi) therapy in PDAC [6]. Although somatic mutations in these genes may also confer sensitivity, they are not yet considered actionable outside clinical trials [37].

From a therapeutic standpoint, BRCA1/2- and PALB2-mutated PDAC often shows improved responses to platinum-based chemotherapy, particularly regimens like FOLFIRINOX or cisplatin–gemcitabine [35,38]. This platinum sensitivity likely reflects the underlying DNA repair defect. Retrospective data and translational studies have reported prolonged disease control and higher response rates in this subgroup [39,40].

For patients with germline BRCA1/2 mutations who do not progress after at least 16 weeks of platinum-based therapy, maintenance treatment with olaparib is recommended. This is supported by the POLO trial, which showed a significant PFS benefit (7.4 vs. 3.8 months; HR 0.53; p = 0.004), although no statistically significant OS improvement was observed, likely due to treatment crossover [6].

Real-world evidence further supports the role of PARPi beyond strict maintenance use. In a cohort of 114 metastatic PDAC patients with germline BRCA mutations, exposure to olaparib at any point was associated with an OS benefit (HR 0.57; p = 0.02) [41]. Notably, the benefit appeared less pronounced in patients who closely matched the POLO criteria, suggesting broader utility in selected real-life cases.

For PALB2 mutations, available evidence is more limited but encouraging. Preclinical and retrospective clinical data suggest sensitivity to both platinum agents and PARP inhibitors [35]. However, no current regulatory approvals exist for PARPi use in this context, and their role remains investigational [42,43,44].

The current guidelines support germline testing for BRCA1 and BRCA2 in all patients with PDAC, regardless of age or family history, with NCCN 2025 strongly recommending universal testing (Category 1), ESMO 2023 supporting it for patients eligible for systemic therapy, and ASCO 2020 endorsing testing where treatment implications exist [14,15,16]. The NCCN also recommends including PALB2 in germline panels (Category 2A), while PALB2 is recognized by ESMO as biologically relevant, although routine PARP inhibitor use is not recommended outside of clinical trials [14,15]. For patients with germline BRCA1/2 mutations, platinum-based first-line chemotherapy is standard, followed by olaparib maintenance in non-progressive disease, consistent across all three guidelines [14,15,16].

In summary, germline mutations in BRCA1, BRCA2, and PALB2 define a distinct therapeutic subset of PDAC patients who may derive benefits from targeted approaches. Routine germline testing should be performed early, to ensure timely access to platinum-based regimens and potential maintenance strategies with PARP inhibitors—especially for patients not eligible for clinical trials.

3.3. NTRK and RET Gene Fusions

Gene fusions involving NTRK (Neurotrophic Tropomyosin Receptor Kinase) and RET (Rearranged during Transfection) are oncogenic alterations that promote tumor growth by activating pathways such as RAS/MAPK and PI3K/AKT [42,43]. These fusions are considered actionable and tumor-agnostic, meaning they can predict responses to targeted therapies across multiple cancer types, regardless of histologic origin.

In unselected PDAC, these fusions are exceedingly rare, with NTRK fusions occurring in less than 1% and RET fusions in approximately 0.2–0.3% of cases [44,45]. However, their prevalence increases significantly in KRAS wild-type PDAC, where NTRK fusions have been observed in up to 4–6% and RET fusions in around 2% of patients [46,47].

Clinical evidence supporting the targeting of these fusions in PDAC is limited but encouraging. Larotrectinib, a selective TRK inhibitor, has demonstrated high efficacy in NTRK fusion-positive solid tumors. In pooled analyses from trials such as LOXO-TRK-14001 and NAVIGATE, ORRs exceeded 75%, with some responses lasting over 35 months [48,49]. Although only a few PDAC patients were included, at least one partial response was observed, suggesting a potential benefit in this setting.

Entrectinib, another TRK inhibitor with central nervous system penetration, was evaluated in the STARTRK-2 trial and yielded an ORR of 57% and median duration of response (DoR) of 10.4 months across tumor types [50]. Again, although only two patients with pancreatic cancer were enrolled, one experienced a durable response.

For RET fusions, the LIBRETTO-001 trial investigated selpercatinib in patients with RET fusion-positive tumors. Among 11 PDAC patients, the ORR was 55%, with durations of response ranging from 2.5 months to over three years [51]. These results suggest that, while uncommon, RET fusions in PDAC may define a responsive molecular subgroup.

Clinical guidelines support testing for these alterations in specific contexts. The NCCN 2025 guidelines support extended molecular profiling for all patients with locally advanced or metastatic pancreatic cancer, including assessment of fusions such as NTRK, RET, NRG1, and others, preferably using RNA-based next-generation sequencing due to its superior sensitivity for gene rearrangements [15]. The ESMO 2023 guidelines suggest considering these fusions primarily in KRAS wild-type tumors or when no other actionable alterations are identified [14].

From a regulatory standpoint, larotrectinib and entrectinib are approved by both the FDA and EMA for NTRK fusion-positive solid tumors, regardless of tumor type. Selpercatinib is FDA-approved for RET fusion-positive solid tumors, including PDAC, while EMA approval currently applies only to RET fusion-positive lung and thyroid cancers [25,26,51].

Although these fusions are rare, their identification is clinically meaningful. In KRAS wild-type PDAC—a molecular subset often lacking standard treatment options—detection of NTRK or RET fusions may open the door to effective targeted therapies or enrollment in clinical trials.

3.4. NRG1 Fusions: Emerging Opportunities in Targeting PDAC

Neuregulin 1 (NRG1) gene fusions are rare but increasingly recognized oncogenic drivers across multiple solid tumors, including PDAC [52]. NRG1 encodes a ligand that activates HER3, leading to HER2-HER3 heterodimerization and downstream signaling through the PI3K-AKT-mTOR and MAPK pathways, ultimately promoting tumor growth and survival [52,53].

In unselected PDAC populations, NRG1 fusions are extremely uncommon, occurring in fewer than 1% of cases. However, their prevalence increases in KRAS wild-type tumors, where studies have reported rates of approximately 0.5–1% [54]. These tumors typically lack other known driver mutations and may be biologically dependent on HER2/HER3 signaling, making them attractive candidates for targeted inhibition.

Detection of NRG1 fusions can be technically challenging, as they are best identified through RNA-based next-generation sequencing, which is more sensitive for gene rearrangements than DNA-based assays [55].

The most promising therapeutic candidate to date is zenocutuzumab (MCLA-128), a bispecific monoclonal antibody that targets both HER2 and HER3. Zenocutuzumab simultaneously blocks the NRG1-HER3 interaction and HER2-HER3 dimerization, while also inducing antibody-dependent cellular cytotoxicity (ADCC) [56].

The eNRGy trial, a phase 2 basket study, assessed zenocutuzumab in patients with NRG1 fusion-positive solid tumors, including a predefined PDAC subgroup [57]. Among 36 evaluable patients with PDAC—all of whom were KRAS wild-type—the trial reported an objective ORR of 42%, with a median DoR of 7.4 months and PFS of 9.2 months. Notably, 77% of patients experienced a ≥50% reduction in CA19-9, a commonly used biomarker in PDAC. Treatment was well tolerated, with mostly grade 1–2 adverse events [57].

Despite these encouraging findings, zenocutuzumab remains investigational. It is not yet approved by the FDA or EMA, although early access programs and clinical trials are ongoing in the United States and Europe.

The potential clinical relevance of NRG1 fusions is acknowledged by NCCN 2025, which includes it among actionable gene fusions to be assessed via RNA-based NGS in advanced PDAC. ESMO 2023 also highlights NRG1 as a rare but targetable alteration, particularly in KRAS wild-type tumors or in the absence of other actionable mutations [14,15]. ASCO 2020 does not specifically address NRG1 fusions [16]. Testing for these fusions is not yet mandated, but is strongly encouraged when broader NGS panels are used. Clinical trial enrollment is advised for eligible patients.

In summary, NRG1 fusions represent an emerging and biologically distinct therapeutic target in PDAC. While their rarity limits population-wide impact, identifying NRG1 fusions can meaningfully alter treatment options for select patients, especially those without KRAS or other driver mutations.

3.5. Immunotherapy Beyond the Immune Desert?

Despite the success of immune checkpoint inhibitors (ICIs) in several solid tumors, PDAC remains largely refractory to immunotherapy. This resistance is not due to a lack of clinical trials, but rather to the intrinsic immunobiology of the tumor.

PDAC is often considered a prototypical “cold” tumor, characterized by a dense, desmoplastic tumor microenvironment (TME) that is both physically and functionally immunosuppressive [9,10]. The extracellular matrix is enriched with collagen, hyaluronic acid, and cancer-associated fibroblasts, which act as a barrier to drug delivery and T cell infiltration [11]. The immune milieu is dominated by M2 macrophages, regulatory T cells, myeloid-derived suppressor cells, and immature dendritic cells, all of which contribute to immune evasion [9,10,12].

On a molecular level, frequent KRAS mutations, along with alterations in TP53 and SMAD4, drive a non-inflamed, immune-excluded phenotype, limiting T cell activation and infiltration [12,13]. Low tumor mutational burden (TMB) and low PD-L1 expression further reduce neoantigen presentation and responsiveness to checkpoint blockade [12].

The main exception to this pattern is the small subset of PDAC cases that are mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H). These account for approximately 1–2% of cases and tend to harbor a higher neoantigen load, making them more responsive to immunotherapy [12].

In the KEYNOTE-158 trial, pembrolizumab achieved an ORR of 18.2% in 22 MSI-H PDAC patients, with a median OS of 13.4 months [58]. Real-world European data from the AGEO group reported an even higher ORR of 48.4% and PFS of 12.4 months [59]. A systematic review and meta-analysis including 21 studies and 937 patients treated with ICIs for metastatic PDAC confirmed that clinical benefit is almost exclusively seen in MSI-H/dMMR tumors, with a mean PFS of 10.7 months and ORR of 36.1% in this subgroup [9].

Outside of this niche, ICIs have shown limited activity in unselected PDAC populations. Several early-phase trials have explored combinations to overcome immune resistance, pairing ICIs with chemotherapy, radiotherapy, TGF-β inhibitors like galunisertib [60], CXCR4 antagonists such as BL-8040 [61], and dual checkpoint inhibitors (e.g., anti-PD-1 plus anti-CTLA-4). Some responses have been observed—for example, the COMBAT trial reported an ORR of 32% using BL-8040 with pembrolizumab and chemotherapy [61]—but these remain the exception rather than the rule.

Vaccination strategies have also been tested. GVAX and CRS-207, sometimes combined with ICIs, have produced mixed results [62]. More recently, personalized mRNA neoantigen vaccines have shown promise. In a phase I trial, 16 patients with resected PDAC received a neoantigen-specific mRNA vaccine (autogene cevumeran) along with atezolizumab and mFOLFIRINOX. Eight patients developed robust CD8⁺ T cell responses, and responders had significantly prolonged disease-free survival, with some T cell responses persisting beyond two years [13].

Despite promising signals, immunotherapy remains limited to a small subset of PDAC patients. All major guidelines—NCCN 2025, ESMO 2023, and ASCO 2020—recommend universal testing for MSI-H or dMMR, with pembrolizumab considered a valid treatment option in second or later lines for patients with MSI-H/dMMR-positive tumors [14,15,16].

Both the FDA and EMA have granted tissue-agnostic approval for pembrolizumab in MSI-H/dMMR solid tumors, reinforcing the importance of molecular screening in all advanced PDAC cases.

4. Discussion

Despite significant advances in molecular oncology, PDAC remains one of the most therapeutically challenging malignancies. The integration of NGS and molecular profiling into clinical practice has unveiled several potentially actionable genomic alterations, yet only a small fraction of patients derive meaningful benefit from targeted therapies.

Among these alterations, KRAS mutations remain the most common, present in over 90% of PDAC cases [14]. While KRAS G12C inhibitors such as sotorasib and adagrasib have shown modest efficacy in early-phase trials—ORRs of 21–33% and a median OS of around 7–8 months [17,18]—most KRAS mutations, including G12D and G12V, remain undruggable. Ongoing efforts with novel agents like MRTX1133, pan-RAS inhibitors, and PROTAC-based degraders may expand therapeutic options in the future [21,22,23,24,25,26,27].

For patients with homologous recombination deficiency (HRD), particularly those with germline BRCA1, BRCA2, or PALB2 mutations, platinum-based chemotherapy remains the recommended first-line approach [30,33,34,35]. The POLO trial demonstrated that maintenance olaparib after platinum response improves PFS in germline BRCA-mutated patients, although the OS benefit was not statistically significant [6]. Real-world data suggest broader benefits of PARP inhibition, even beyond strict maintenance settings [41].

Immunotherapy has yet to transform the treatment landscape in PDAC. Outside the MSI-H/dMMR subgroup, which represents 1–2% of cases and can benefit from pembrolizumab, most patients show minimal response to immune checkpoint blockade [12,57,59]. Efforts to remodel the tumor microenvironment through combination strategies (e.g., CXCR4 blockade, vaccination, TGF-β inhibition) are ongoing, but the results remain preliminary [60,61,62,63].

Rare gene fusions—such as NTRK, RET, and NRG1—offer promising but limited opportunities. These alterations are enriched in KRAS wild-type PDAC and are associated with responses to tumor-agnostic therapies like larotrectinib, entrectinib, selpercatinib, and investigational agents such as zenocutuzumab [47,48,49,50,51,52,57]. However, their low prevalence and limited access to molecular testing still pose barriers to widespread clinical impact.

Practical implementation remains a major challenge. Despite guideline recommendations for broad molecular testing, many patients are still not sequenced early enough to benefit from trial enrollment or off-label use. In

Table 1. Comparative table summarizing ASCO (2020), ESMO (2024), and NCCN (2025) recommendations on molecular biomarker testing in PDAC, including related therapeutic indications.

	ASCO (2020)	ESMO (2023)	NCCN (2025)
KRAS mutation	Not discussed in ASCO 2020.	Recommended as part of broad NGS panel in advanced PDAC.	Testing recommended for all advanced PDAC patients; specify mutation (e.g., G12C) to assess clinical trial eligibility.
BRCA1/2 (germline)	Strong recommendation for germline BRCA1/2 testing; PARP inhibitors considered after platinum.	Germline testing recommended for all; olaparib approved for gBRCA-mutated PDAC.	Universal germline testing advised. Olaparib indicated as maintenance after platinum response in gBRCA-mutated patients.
PALB2	Mentioned; no formal therapeutic recommendation.	Testing advised. No formal approval for PARP inhibitors; some retrospective support.	Germline testing recommended. Platinum sensitivity supported; PARP inhibitors not currently approved.
MSI-H/dMMR	Testing recommended in all advanced PDAC cases; pembrolizumab valid in positive cases.	Recommended in all PDAC. ICIs supported in MSI-H/dMMR tumors.	Universal testing recommended. Pembrolizumab an option for MSI-H/dMMR tumors.
NTRK fusion	Supported for tumor-agnostic use; testing suggested as part of extended molecular workup.	Advised in KRAS wild-type or NGS testing; larotrectinib/entrectinib approved.	Recommended in KRAS wild-type PDAC or when no standard options are available. Larotrectinib/entrectinib are tumor-agnostic options.
RET fusion	Not discussed in ASCO 2020.	Recommended in extended NGS; more relevant in KRAS wild-type PDAC.	Testing optional but advised in KRAS wild-type tumors. Selpercatinib may be considered off-label.
NRG1 fusion	Not discussed in ASCO 2020.	Testing recommended in NGS, especially for KRAS wild-type tumors.	Testing suggested in KRAS wild-type PDAC; clinical trial enrollment strongly encouraged.
HER2 (ERBB2)	Not discussed in ASCO 2020.	HER2 testing advised in selected cases; relevance mainly in KRAS wild-type or rare histology.	Testing recommended in KRAS wild-type or atypical tumors. Consider trial enrollment for HER2-targeted therapy.

, we summarized current testing recommendations from NCCN, ESMO, and ASCO.

Table 2. FDA and EMA approvals for targeted therapies discussed in this review.

Drug	Target	FDA Approval	EMA Approval
Sotorasib	KRAS G12C	Yes (NSCLC, 2021)	Yes (NSCLC, 2022)
Adagrasib	KRAS G12C	Yes (NSCLC, 2022)	Yes (NSCLC, 2023)
Olomorasib	KRAS G12C	No	No
Glecirasib	KRAS G12C	No	No
Zenocutuzumab	NRG1 fusion	No (investigational)	No
Larotrectinib	NTRK fusion	Yes (tumor-agnostic, 2018)	Yes (tumor-agnostic, 2019)
Entrectinib	NTRK fusion	Yes (tumor-agnostic, 2019)	Yes (tumor-agnostic, 2020)
Selpercatinib	RET fusion	Yes (solid tumors incl. PDAC, 2022)	Yes (lung and thyroid cancer, not PDAC)
Pembrolizumab	MSI-H/dMMR	Yes (tumor-agnostic, 2017)	Yes (tumor-agnostic, 2020)
Olaparib	gBRCA1/2	Yes (PDAC, maintenance, 2019)	Yes (PDAC, maintenance, 2020)

outlines which agents have FDA and/or EMA approval—most notably, only a few (e.g., pembrolizumab and olaparib) are formally approved in PDAC.

Given the aggressive biology of PDAC and the narrow therapeutic window, early and comprehensive molecular profiling is essential. This includes KRAS typing, germline BRCA1/2 and PALB2 testing, and fusion analysis for NTRK, RET, and NRG1, especially in KRAS wild-type tumors. Where standard therapies fail or are unavailable, these molecular markers may offer one of the few viable therapeutic paths—whether through off-label use or clinical trials.

However, obtaining adequate tissue for such analyses can be challenging due to the dense stromal reaction, necrosis, and low tumor cellularity typical of PDAC, particularly in small biopsy samples [63]. EUS-guided fine needle biopsy, especially with 19G needles, has shown good performance in acquiring sufficient core tissue for next-generation sequencing and enabling precision oncology approaches [64,65]. Greater investment is needed to ensure that advances in precision oncology translate into real-world benefit. This means not only broader access to testing and drugs, but also clearer regulatory guidance for agents that show promising activity in early-phase data but remain unapproved in PDAC.