Current and emerging strategies to enhance chemotherapeutic efficacy in pancreatic ductal adenocarcinoma

Abstract

Background

Pancreatic cancer remains one of the most aggressive solid malignancies. The majority of patients present with locally advanced or metastatic disease, limiting treatment options to systemic chemotherapy. Conventional chemotherapy forms the backbone of the standard-of-care regimen and offers modest but significant survival benefits.

Main body

This review discusses currently established standard-of-care regimens and cutting edge clinical trials which aim to enhance chemotherapy efficacy in pancreatic cancer. Pancreatic cancer’s distinct pathological features—including its high metastatic potential, inherent chemoresistance, dense desmoplastic stroma, and profoundly immunosuppressive tumour microenvironment—underscore the rationale for the clinical development of chemosensitizing agents. As mechanisms of chemoresistance continue to be uncovered, new therapeutic avenues are emerging that aim to enhance the efficacy of chemotherapy. Emerging targets including KRAS, MTAP, EGFR, Claudin 18.2, and WEE1, which present unique vulnerabilities for rational combination therapies, are discussed.

Conclusion

Given the central role of chemotherapy in pancreatic cancer treatment, ongoing clinical strategies that improve its efficacy are essential to achieving better outcomes for patients.

Background

Pancreatic cancer

Pancreatic cancer poses one of the biggest clinical challenges in oncology research. The 5-year survival rate for pancreatic cancer over the past two decades has shown only modest improvement, increasing from 5% in 2005 to 13% in 2026 [1, 2]. Pancreatic cancer is currently the third leading cause of cancer-related death in Europe and is estimated to surpass colorectal cancer to become the second most common cause of cancer-related death by 2040 [3, 4]. Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent histological subtype of pancreatic malignancy, accounting for around 90% of all pancreatic neoplasms [5, 6]. The extremely poor prognosis of PDAC patients can be attributed to several factors, which include lack of effective screening measures, asymptomatic early-stage disease, and high levels of chemoresistance [7–10].

Surgical resection followed by adjuvant chemotherapy provides the best survival outcome for patients with PDAC [11, 12]. However, owing to extreme difficulties in early detection of PDAC, only 20% of patients present with resectable disease [13]. Moreover, outcomes following surgical resection are still poor, with the rate of recurrence following surgery being as high 85%, and the 5-year survival rate of fully resected patients only reaching 15-25% [14–16]. The majority of patients with PDAC present with locally advanced or metastatic disease. For these patients, chemotherapy with or without a targeted agent is standard first-line treatment. With the development of novel anticancer agents, conventional chemotherapy is often overlooked, having the capability of curing patients with certain cancer types [17]. However, currently approved treatment modalities show limited efficacy in PDAC, highlighting the need to develop more novel therapies and/or develop additional strategies to enhance conventional chemotherapy regimens.

Standard-of-care chemotherapy for resectable and borderline-resectable pancreatic cancer

Neoadjuvant therapy (NAT) and adjuvant chemotherapy have demonstrated improvements in overall survival (OS) in both resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC), though only modest [18–22]. For RPC, upfront surgery followed by adjuvant chemotherapy remains the standard-of-care (SOC). Adjuvant chemotherapy regimens are guided by post-operative performance status, with modified FOLFIRINOX (mFOLFIRINOX) preferred for patients with high performance status, while gemcitabine + capecitabine, or gemcitabine alone, is used for those with lower performance status (Fig. 1) [23–25]. The PRODIGE-24 trial established mFOLFIRINOX as the preferred adjuvant regimen for high-performance status patients after demonstrating a significant OS and disease-free survival (DFS) benefit over gemcitabine [24, 26]. New combination strategies are also emerging for this disease setting. The phase III PACT-21 CASSANDRA trial compared neoadjuvant PAXG (gemcitabine, cisplatin, nab-paclitaxel, capecitabine) with mFOLFIRINOX in RPC and BRPC [27]. The PAXG regimen significantly improved event-free survival compared to mFOLFIRINOX (16 vs. 10.2 months, HR, 0.63 [95% CI, 0.47 to 0.84]; P = 0.0018). Accordingly, neoadjuvant PAXG may represent a potential standard comparator for future trials in this setting.

Fig. 1.

Current systemic treatment paradigm for PDAC. Approximately 15-20% of patients are eligible for upfront surgery. Adjuvant chemotherapy is the standard-of-care post-resection. Approximately 25-30% of patients present with borderline resectable / locally advanced disease and typically receive neoadjuvant chemotherapy followed by surgical resection. Approximately 50-55% of patients present with metastatic disease, with treatment selection based on performance status, age, comorbidities, and specific tumour characteristics. Current treatment outcomes remain sub-optimal, with most randomised trials reporting a median OS of less than one year with first-line regimens and approximately 6 months with second-line regimens. Given these limited outcomes, enrolment in clinical trials is encouraged at any stage of treatment for patients with PDAC, where available and appropriate. BRCA, breast cancer susceptibility gene; DDR-Mutant Pop., DNA damage response-mutant population; ECOG, Eastern Cooperative Oncology Group; 5-FU, 5-fluorouracil; 5-FU/LV, 5-fluorouracil and leucovorin; leucovorin–5-fluorouracil–irinotecan–oxaliplatin, mFOLFIRINOX (modified FOLFIRINOX); MSI-H, microsatellite instability-high; Nal-IRI, nanoliposomal irinotecan (Onivyde); NALIRIFOX, liposomal irinotecan (Onivyde)-5-fluorouracil-leucovorin-oxaliplatin; PALB2, partner and localiser of BRCA2.

To enhance drug delivery and minimise toxicity, albumin-bound paclitaxel (nab-paclitaxel, Abraxane®) was developed to work synergistically with gemcitabine [28, 29]. However, the APACT trial comparing nab-paclitaxel + gemcitabine vs. gemcitabine alone in patients with surgically resected pancreatic cancer did not meet its primary endpoint of independently assessed DFS [30]. Therefore, adjuvant mFOLFIRINOX and gemcitabine + capecitabine remain the preferred SOC adjuvant treatment options.

NAT, involving preoperative chemotherapy with or without radiation, has gained increasing acceptance, particularly for BRPC [31]. NAT aims to improve resectability and reduce recurrence risk by targeting micrometastatic disease [32, 33]. The PREOPANC-1 trial, and other studies, have demonstrated an OS benefit with neoadjuvant chemoradiotherapy compared to upfront surgery [21, 22]. Although several randomised trials have provided evidence that support the use of NAT in both RPC and BRPC (Table 1) [20, 22, 34], further evidence is needed before NAT becomes the SOC for all resectable cases [35]. The ongoing phase III Alliance A021806 trial is evaluating perioperative mFOLFIRINOX vs. the current SOC (upfront surgery + subsequent adjuvant mFOLFIRINOX) (Table 2) [36]. Uncertainty remains regarding the optimal NAT regimen, particularly in chemotherapy sequencing and agent selection. The ESPAC-5 trial compared immediate surgery to multiple neoadjuvant regimens and found that gemcitabine +capecitabine and FOLFIRINOX provided the best survival outcomes (Table 1) [22]. If ongoing trials continue to support these findings, NAT may become the preferred SOC for both RPC and BRPC.

Table 1.

Selected clinical trials of chemotherapy-based regimens in pancreatic cancer

					Efficacy Outcomes
Trial	Phase	Patient population	Intervention	Primary endpoint	ORRa (%)	mPFSb (months)	mOSc (months)	OSd Rate (year)	Result	AEe (≥ grade 3)
Burris et al. [47]	3	mPDAC (N = 126)	Gemcitabine vs. 5-FU	Clinical benefit response	5.4 vs. 0	2.33 vs. 0.92	5.65 vs. 4.41 (P = 0.0025)	18% vs. 2% (1-year)		Grade 3 & 4 Neutropenia (25.9% vs. 4.9%) Grade 3 or 4 Anaemia (9.7% vs. 0%)
National Cancer Institute of Canada Clinical Trials Group [48]	3	LAPC/mPDAC (N = 569)	Gemcitabine + Erlotinib vs. Gemcitabine	OS		3.75 vs. 3.55 (HR, 0.77, P < 0.004)	6.24 vs. 5.91 (HR, 0.82, P < 0.038)	23% vs. 17% (1-year)	Primary endpoint achieved	Neutropenia (24% vs. 27%) Thrombocytopenia (10% vs. 11%)
PRODIGE 4/ACCORD 11 [39]	3	mPDAC (N = 342)	FOLFIRINOX vs. Gemcitabine	QoLf	31.6 vs. 9.4	6.4 vs. 3.3 (HRg, 0.47, P < 0.001)	11.1 vs. 6.8 (HR, 0.57; P < 0.001)	43.2% vs. 31.4% (5-year) [26]		Neutropenia (45.7% vs. 21.0%) Febrile neutropenia (5.4% vs. 1.2%) Thrombocytopenia (9.1% vs. 3.6%) Diarrhoea (12.7% vs. 1.8%) Sensory neuropathy (9% vs. 0%)
Phase III, MPACT [37]	3	mPDAC (N = 861)	Nab-paclitaxel + Gemcitabine vs. Gemcitabine		23% vs. 7%	5.5 vs. 3.7 months (HR, 0.69, P < 0.001)	8.5 vs. 6.7 months (HR, 0.72; P < 0.001)	35% vs. 22% (1-year) 9% vs. 4% (2-year)		Neutropenia (38% vs. 27%) Fatigue (17% vs. 7%) Neuropathy (17% vs. 1%)
Phase III, CONKO-001 [19]	3	RPC (N = 368)	Adjuvant Gemcitabine vs. Observation			13.4 vs. 6.7 months (HR, 0.55, P < 0.001)	22.8 vs. 20.2 months (HR, 0.76; P = .01)	20.7% vs. 10.4% (5-year) 12.2 vs. 7.7% (10-year)
Phase III, PREOPANC [21, 49]	3	RPC & BRPC (N = 246)	Neoadjuvant Gemcitabine (3 cycles) + 36 Gy Radiotherapy (15 fractions during 2nd cycle) + subsequentSurgery + subsequent Gemcitabine (4 cycles) vs. Upfront Surgery followed by Adjuvant Gemcitabine (6 cycles)			8.1 vs. 7.7 months (HR, 0.69, P < 0.009)	15.7 vs. 14.3 months (HR, 0.73; P = 0.025)	27.7% vs. 16.5% (3-year) 20.5% vs. 6.5% (5-year)		52% vs. 41% (P = 0.096)
Phase III, RTOG 9704 [50]	3	RPC (N = 451, 388-PC)	Pre- and post-chemoradiation 5-FU vs. Pre- and post-chemoradiation Gemcitabine	OS			20.5 vs. 17.1 (HR, 0.84; P = 0.12)	22% vs. 18% (5-year)	Primary endpoint not achieved	Worst late nonhematologic (4.5% vs. 3.3%) Worst hematologic (16.8% vs. 19.2%) Worst overall toxicities (18.6% vs. 21%)
Phase III, JASPAC 01	3	RPC (N = 385)	Gemcitabine vs. S-1 as Adjuvant Chemotherapy	OS		11.3 vs. 22.9 (HR, 0.60; P < 0.0001)	25.5 vs. 46.5 (HR, 0.57; Pnon-inferiority<0·0001, P < 0·0001 for superiority)	38.8% vs. 59.7% (3-year) 24.4% vs. 44.1% (5-year)	Primary endpoint achieved	Leucopenia (39% vs. 9%) Neutropenia (72% vs. 13%) Stomatitis (0% vs. 3%) Diarrhoea (0% vs. 5%)
Phase III, ESPAC3	3	RPC (N = 1088)	5-FU + Folinic Acid vs. Gemcitabine	OS		14.1 vs. 14.3 (HR, 0.96; P = 0.53)	23 vs. 23.6 (HR, 0.94; P = 0.39)	78.5% vs. 48.1% (1-year) 80.1% vs. 49.1% (2-year)	Primary endpoint not achieved	14% vs. 7.5% (P < 0.001)
Phase III, ESPAC4 [25]	3	RPC (N = 732)	Gemcitabine + Capecitabine vs. Gemcitabine monotherapy			13.9 vs. 13.1 months (HR, 0.86, P = 0.082)	28.4 vs. 31.6 months (HR, 0.83; P = 0.031) [51]	84.1% vs. 80.5% (1-year) 53.8% vs. 52.1% (2-year) 32% vs. 25% (5-year) [25, 51]		Neutropenia (38% vs. 24%); diarrhoea (5% vs. 2%); Hand-foot syndrome (7% vs. 0%)
Phase II, ESPAC5 [22]	2	BRPC (N = 478)	Neoadjuvant Gemcitabine + Capecitabine vs. Neoadjuvant FOLFIRINOX vs. Neoadjuvant Capecitabine-based Chemoradiation vs. Upfront Surgery			59% for NATs combined vs. 33% for Upfront Surgery (HR, 0.53, P = 0.043)		76% for NAT groups combined vs. 39% for Upfront Surgery (1-year)		34% in NAT Groups vs. 7% in Upfront Surgery Group
NAPOLI-1 [40, 52]	3	mPDAC (N = 417)	Nanoliposomal Irinotecan + 5-FU + Folinic acid vs. 5-FU + Folinic Acid vs. Nanoliposomal Irinotecan Monotherapy	OS	19% vs. 1% vs. 6%	3.1 vs. 1.5 (Nanoliposomal Irinotecan + 5-FU + Folinic Acid vs. 5-FU + Folinic Acid; HR, 0.56, P = 0.0001); 2.7 vs. 1.6 (Nanoliposomal Irinotecan Monotherapy vs. 5-FU + Folinic Acid; HR, 0.81, P = 0.1)	6.1 vs. 4.2 (Nanoliposomal Irinotecan + 5-FU + Folinic Acid vs. 5-FU + Folinic Acid; HR, 0.67, P = 0.012); 4.9 vs. 4.2 (Nanoliposomal Irinotecan Monotherapy vs. 5-FU + Folinic Acid; HR, 0.99, P = 0.94)	26% vs. 16% (Nanoliposomal Irinotecan + 5-FU + Folinic Acid vs. 5-FU + Folinic Acid; 1-year)	Primary endpoint achieved	Neutropenia (27% vs. 15% vs. 1%) Diarrhoea (13% vs. 21% vs. 4%) Vomiting (11% vs. 14% vs. 3%) Fatigue (14% vs. 6% vs. 4%) [Nanoliposomal Irinotecan + 5-FU + Folinic Acid vs. Nanoliposomal Irinotecan Monotherapy vs. 5-FU + Folinic Acid
NAPOLI-3 [53]	3	mPDAC (N = 770)	NALIRIFOX vs. Nab-paclitaxel + Gemcitabine	OS	41.8 vs. 36.2 (P = 0.11	7.4 vs. 5.6 (HR, 0.69, P = 0.0001)	11.1 vs. 9.2 (HR, 0.83, P = 0.036)	45.6% vs. 39.5% (1-year) 26.2% vs. 19.3% (1.5-year)		87% vs. 86%
FOOTPATH [42]	2	mPDAC (N = 265)	Liposomal Irinotecan + 5-FU + Folinic Acid (NAPOLI) vs. Sequential NAPOLI + mFOLFOX6h vs. Gemcitabine + Nab-paclitaxel	PFS		3.1 (HR, 1.224, P = 0.2123) vs. 6 (HR, 0.864, P = 0.0720 vs. 4.3)	8.7 vs. 7.9 (HR, 1.178, P = 0.348) vs. 11 (HR, 0.879, P = 0.154)		Primary endpoint not achieved	Higher rates of neutropenia and peripheral neuropathy in NAPOLI Diarrhoea more frequent in sequential NAPOLI and mFOLFOX6 and Gemcitabine + Nab-paclitaxel
ALPACA [43]	2	mPDAC (N = 325)	Alternating treatment cycles of Gemcitabine + Nab- paclitaxel + Gemcitabine Monotherapy vs. Standard Continuous Gemcitabine + Nab- paclitaxel after a 3-month induction phase	OS		5.5 vs. 5.3 (HR, 0.767, P = 0.1017)	10.5 vs. 10.4 (HR, 0.903, P = 0.5551)		Primary endpoint not achieved	Peripheral neuropathy (all grades, 44.7% vs. 52.5%) Occurrence of infections (all grades, 29.4% vs. 47.5%)
O’Reilly et al. [54]	2	gBRCA/PALB2 + PDAC (N = 50)	Cisplatin + Gemcitabine + Veliparib vs. Cisplatin + Gemcitabine	RR		10.1 vs. 9.7 (P = 0.73)	15.5 vs. 16.4 (P = 0.6)	30.6% (2-year) 17.8% (3-year)	Primary endpoint not achieved	Neutropenia (48% vs. 30%) Thrombocytopenia (55% vs. 9%) Anemia (52% vs. 35%)
SWOG S1513 [55]	2	mPDAC (N = 123)	Veliparib + mFOLFIRIi vs. FOLFIRI	OS	18% vs. 20% (P = 0.99)	2.1 vs. 2.9 (HR, 1.39; P = 0.09)	5.4 vs. 6.5 (HR, 1.23; P = 0.28)		Primary endpoint not achieved	69% vs. 58%
Prep-02/JSAP-05 [56]	2/3	RPC (N = 364)	Neoadjuvant Gemcitabine + S1 + subsequent Upfront surgery + subsequent Adjuvant S1 vs. Upfront Surgery + subsequent Adjuvant S1	OS			36.7 vs. 26.6 (HR, 0.72; P = 0.015)		Primary endpoint achieved	Leukopenia or neutropenia (72.8%) in Neoadjuvant Gemcitabine + S1 + subsequent Upfront Surgery + subsequent Adjuvant S1 Group
PANACHE01-PRODIGE48 [57]	2	RPC (N = 153; 146 available for analysis)	Neoadjuvant mFOLFIRINOX or FOLFOX vs. Surgery + Standard Adjuvant Chemotherapy	OS				84.1% vs. 71.8% (1-year)	Primary endpoint achieved	56.7% vs. 57.4%

^aORR,Overall Response Rate; ^bmPFS, Median Progression Free Survival; ^cmOS, Median Overall Survival; ^dOS, Overall Survival; ^eAE, Adverse Events; ^fQoL, Quality of Life; ^gHR, Hazard Ratio; ^hmFOLFOX6, oxaliplatin, leucovorin (folinic acid), and fluorouracil (5-FU); ⁱmFOLFIRI, irinotecan, leucovorin, and 5-FU; ^bmPFS, Median Progession Free Survival; ^cmOS, Median Overall Survival; ^dOS, Overall Survival; ^eAE, Adverse Events; ^fQoL, Quality of Life; ^gHR, Hazard Ratio; ^hmFOLFOX6, oxaliplatin, leucovorin (folinic acid), and fluorouracil (5-FU); ⁱmFOLFIRI, irinotecan, leucovorin, and 5-FU

Table 2.

Recruiting and ongoing clinical trials of chemotherapy-based regimens in pancreatic cancer

Trial	Phase	Patient Population	Intervention	Primary Endpoint
ALLIANCE A021806 [36]	3	RPCa	Neoadjuvant mFOLFIRINOX + subsequent Adjuvant mFOLFIRINOX vs. Upfront Surgery + subsequent Adjuvant mFOLFIRINOX	OSb
NeoPancOne [244]	2	RPC	Measure GATA6 expression via biopsy + subsequent mFOLFIRINOX + subsequent Surgery + subsequent mFOLFIRINOX	DFSc in RPC treated with peri-operative mFOLFIRINOX according to baseline tumour GATA6 expression level
APOLLO EA2192 [125]	2	Resected pancreatic cancer and a pathogenic BRCA1, BRCA2, or PALB2 mutation	Olaparib vs. Curative-intent resection + subsequent placebo + subsequent ≥ three months of multi-agent chemotherapy	RFSd
PANCREAS [245]	2	RPC or BRPCe	Classical vs. basal transcriptional profiling.Classical subtype will be assigned to mFOLFIRINOX and basal-like tumours will be assigned to Gemcitabine + Nab-paclitaxel	Composite clinical response, CA19-9 decline, and performance status
PREOPANC-3 [246]	3	RPC	Neoadjuvant mFOLFIRINOX + subsequent Surgery + Adjuvant mFOLFIRINOX vs. Surgery + subsequent Adjuvant mFOLFIRINOX	OS
NCT05630183 [210]	2	mPDAC who have progressed on prior FOLFIRINOX	Botensilimab + Nab-paclitaxel + Gemcitabine vs. Nab-paclitaxel + Gemcitabine	Efficacy
CheMo4METPANC [211]	2	mPDAC	Gemcitabine + Nab-paclitaxel + Chemokine Motif Receptor 4 Inhibitor (Motixafortide) + Immune Checkpoint Blockade (Cemiplimab) vs. Gemcitabine + Nab-paclitaxel	PFSf
ARC-8 [247]	1	mPDAC	AB680 (CD73 Inhibitor) + Zimberelimab (PD-1 Inhibitor) +Nab-paclitaxel + Gemcitabine	Safety, tolerability, pharmacokinetic, pharmacodynamic and clinical activity
NCT06179160 [163]	1	mPDAC	INCB161734 monotherapy vs. INCB161734 combination therapies, including + mFOLFIRINOX or + Gemcitabine + Nab-paclitaxel	Safety
RMC-GI-102 (NCT06445062) [248]	1/2	KRASG12D Mutated mPDAC	Daraxonrasib + Gemcitabine + Nab-paclitaxel	Safety, tolerability, pharmacokinetics, and preliminary antitumour activity
NCT05382559 [249]	1	KRASG12D Mutated mPDAC	ASP3082 monotherapy or in combination with mFOLFIRINOX	Safety
NCT07409272 [250]	3	KRASG12D Mutated mPDAC	Setidegrasib + mFOLFIRINOX or NALIRIFOX	OS
NCT04794699 [251]	1	MTAP-deleted mPDAC	IDE397 (MAT2A Inhibitor) monotherapy or +chemotherapy or + ADCg	Safety, pharmacokinetics, pharmacodynamics
NCT06792435 [252]	2	CLDN18.2-postive mPDAC	XNW27011 (Topoisomerase Inhibitor-based ADC targeting CLDN18.2h)	Safety and efficacy
TWINPEAK Study [253]	1/2	mPDAC	Spevatamig (PT886, IgG1-based bispecific antibody targeting CLDN18.2 and CD47) monotherapy + Gemcitabine + Nab-paclitaxel	Safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy

^aRPC, Resectable Pancreatic Cancer; ^bOS, Overall Survival; ^cDFS, Disease Free Survival; ^dRFS, Relapse Free Survival; ^eBRPC, Borderline Resectable Pancreatic Cancer; ^fPFS, Progression Free Survival; ^gADC, Antibody-drug Conjugate; ^hCLD18.2, Claudin 18.2

Standard-of-care chemotherapy for locally advanced and metastatic pancreatic cancer

For unresectable or metastatic PDAC (mPDAC), SOC first-line options include mFOLFIRINOX, gemcitabine + nab-paclitaxel, or gemcitabine alone, depending on patient performance status [28, 37, 38]. In the mPDAC setting, the PRODIGE-4/ACCORD-11 trial confirmed the superior efficacy of FOLFIRINOX over gemcitabine, though with higher toxicity [39]. For those with lower performance status, gemcitabine + nab-paclitaxel remains the standard choice, as supported by the MPACT trial (Table 1) [38]. For patients who progress on gemcitabine-based therapy, nanoliposomal irinotecan + 5-FU/leucovorin (Onivyde® + 5-FU/LV) has emerged as the second-line SOC, based on the NAPOLI-1 trial (Fig. 1) [40]. The NAPOLI-3 trial further supported NALIRIFOX as an effective first-line alternative to gemcitabine + nab-paclitaxel for mPDAC, demonstrating superior OS, leading to its FDA approval in 2024 (Table 1) [41]. Given the toxicity burden of chemotherapy, treatment sequencing strategies have been explored in trials such as FOOTPATH and ALPACA, which tested alternating chemotherapy cycles to improve tolerability while maintaining efficacy [42, 43]. These studies suggest that sequential regimens may reduce toxicities without compromising survival outcomes. In fact, dose adjustments have been associated with improved survival in both the MPACT and NAPOLI 3 studies [44, 45].

Recently, tumour treating fields (TTFs; Optune Pax®), which use low-intensity electrical fields delivered via a portable, battery-powered device to disrupt cancer cell mitosis, have also been investigated in locally advanced PDAC (LAPC). The phase III PANOVA-3 trial demonstrated that the addition of TTFs to gemcitabine + nab-paclitaxel significantly improved OS compared to chemotherapy alone (16.2 vs. 14.2 months, HR, 0.82 [95% CI, 0.68 to 0.99]; P = 0.039), without increasing systemic toxicity. This device has since received FDA approval for the treatment of LAPC in combination with gemcitabine + nab-paclitaxel. Positive results have emerged from the phase II PANOVA-4 trial investigating TTFs in combination with atezolizumab + gemcitabine + nab-paclitaxel in mPDAC. The study met its pre-specified primary endpoint, demonstrating a statistically significant improvement in disease control rate (DCR) compared with historical controls from the phase III MPACT trial [46].

The SOC for PDAC continues to evolve, with mFOLFIRINOX remaining the standard adjuvant regimen for high-performance status patients, gemcitabine-based therapies preferred for those with lower performance status, and NAT gaining traction as a potential new SOC for resectable and borderline resectable disease. In mPDAC, mFOLFIRINOX + gemcitabine + nab-paclitaxel remain first-line SOC regimens, with NALIRIFOX emerging as an alternative for high-performance status patients. Overall, compared to other malignancies, PDAC patient response to SOC chemotherapy remains poor. Ongoing trials will continue to refine treatment sequencing and regimen selection to improve both efficacy and tolerability.

Current and emerging clinical strategies to enhance chemotherapeutic efficacy in pancreatic cancer

Therapeutic targeting of PDAC-specific hallmarks, as reviewed by Kane et al. [58], can enhance the efficacy of existing chemotherapy regimens. Current and investigational strategies include:

1. Overcoming the dense PDAC stroma with stromal-degrading agents to enhance chemotherapy delivery to tumour cells, as well as employing nanomedicine formulations of standard chemotherapy to improve drug penetration and retention.

2. Targeting specific genomic vulnerabilities of PDAC tumours - such as BRCA1/2 and KRAS^G12D mutations - using small-molecule inhibitors.

3. Converting the immunologically “cold” PDAC tumour into a more immunologically “hot” phenotype through chemoimmunotherapy and cancer vaccine approaches.

4. Combining electroporation with chemotherapy to achieve localised tumour cell killing while reducing systemic toxicity.

Stromal targeting therapies and nanomedicines

The desmoplastic stroma surrounding the pancreatic tumour, composed of cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), and immune-inflammatory cells, is a key driver of PDAC progression and chemoresistance [59]. This desmoplastic stromal reaction increases tumour interstitial fluid pressure, posing a major barrier to the efficient delivery of chemotherapeutics to tumour cells [60, 61]. Nanoparticles have gained traction in recent years as they exhibit high accumulation in tumour tissues through the enhanced permeation and retention (EPR) effect, improved distribution, and high drug loading capacity [62]. Nab-paclitaxel (Abraxane®) and liposomal irinotecan (Onivyde®) are currently the only nano-based drug delivery systems to receive FDA approval for use in PDAC (Fig. 2) [63]. Both nanosystems lower systemic toxicity by their improved pharmacokinetics and provide better therapeutic results compared to their conventional non-liposomal formulations [37, 40].

Fig. 2.

Current standard therapy and clinical chemotherapy enhancement strategies for pancreatic cancer. Conceptual wheel illustrating the current therapeutic landscape discussed in this review. Standard-of-care therapies for pancreatic cancer are arranged around the outer ring, whereas emerging chemotherapy enhancement strategies are positioned at the centre to emphasise their role in augmenting existing treatment modalities. (A) Currently FDA-approved chemotherapy nanomedicines, Abraxane® and Onivyde®, provide enhanced drug retention. These agents may be combined with stromal-targeting agents [e.g., Galunisertib or all-trans retinoic acid (ATRA)] to enhance tumour vascularity and facilitate chemotherapy delivery. (B) PDAC-specific genomic vulnerabilities include mutant KRAS and germline/somatic BRCA1/2 (g/sBRCA1/2) mutations. KRAS-directed therapeutic strategies in PDAC now include both mutation-selective inhibitors and multi-selective RAS(ON) inhibitors. Daraxonrasib (RMC-6236) induces formation of a ternary complex between active RAS-GTP and cyclophilin A (CypA), thereby inhibiting downstream RAS signalling, and is currently being evaluated in combination with standard-of-care chemotherapy. The addition of PARP inhibitors to adjuvant chemotherapy is a potential strategy for g/sBRCA1/2-mutant PDAC. (C) Pembrolizumab is the only current FDA approved immunotherapy for MSI-H or TMB-high (>10 mutations/Mb) PDAC. A promising chemoimmunotherapy regimen for mPDAC includes motixafortide (CXCR4 inhibitor) + pembrolizumab combined with Onivyde®, 5-FU and folinic acid. Adjuvant mRNA–lipoplex neoantigen vaccination (autogene cevumeran), followed by mFOLFIRINOX, shows durable responses in PDAC. (D) Standard-of-care chemotherapy for PDAC may be combined with electroporation - electrochemotherapy (ECT) or irreversible electroporation (IRE) - to enhance drug uptake and reduce systemic toxicity. Tumour treating fields (TTFields; Optune®) have also been evaluated in combination with gemcitabine + nab-paclitaxel in LAPC, with phase III data demonstrating a survival benefit and subsequent FDA approval for this indication. ChemoRT, chemoradiotherapy; CypA, cyclophilin A; dMMR, deficient mismatch repair; ECT, electrochemotherapy; g/sBRCA1/2, germline and somatic mutations in BRCA1/2; IRE, irreversible electroporation; LAPC, locally advanced pancreatic cancer; MSI-H, microsatellite instability-high; TMB, tumour mutational burden; TTFields, tumour treating fields.

A major component of the ECM, which is consistently increased in PDAC is hyaluronan [64], a hydrophilic glycosaminoglycan which modulates cell proliferation, adhesion, and migration by interacting with cell surface hyaluronan receptors such as CD44 and RHAMM [65]. Both preclinical and clinical data indicate that accumulation of hyaluronan correlates with drug resistance and poorer prognosis in PDAC patients [66–69]. This provided strong rationale for the development of PEGylated hyaluronidase 20 (PEGPH20) as a chemotherapy adjuvant [70, 71]. A phase II trial found that PEGPH20 potentiated the effects of nab-paclitaxel + gemcitabine, as shown by a near doubling of progression-free survival (PFS) and improved OS in patients with hyaluronan-high mPDAC (median PFS of 9.2 vs. 5.2 months, HR, 0.51 [95% CI, 0.26 to 1.00]; P = 0.048; median OS of 11.5 vs. 8.5 months, HR, 0.96 [95% CI, 0.57 to 1.61] [72]. However, disappointment was met at phase III (HALO301 trial), where PEGPH20 + nab-paclitaxel + gemcitabine reduced tumour burden but did not significantly improve PFS or OS compared to chemotherapy alone in patients with hyaluronan-high mPDAC (median PFS of 7.1 vs. 7.1 months, HR, 0.97 [95% CI, 0.75 to 1.26]; median OS of 11.2 vs. 11.5 months, HR, 1.00 [95% CI, 0.80 to 1.27]; P = 0.97) [73]. Such findings have reshaped our knowledge of the desmoplastic PDAC ECM as a chemotherapeutic barrier, with the relationship between stromal components and the overall tumour microenvironment (TME) perhaps being more complex than initially thought.

Signalling pathways involved in the establishment of the desmoplastic PDAC stroma, i.e., through activated pancreatic stellate cells (PSC)/CAF oncogenic activity, including Sonic Hedgehog (Shh) and transforming growth factor-β (TGF-β) signalling, have also been targeted in combination with SOC regimens [74, 75]. The Shh pathway is generally hyperactive in PDAC tumours and induces PSC activation via paracrine signalling with tumour cells within the stromal compartment, promoting and maintaining desmoplasia [76, 77]. However, the addition of Shh inhibitors to SOC chemotherapy in PDAC clinical trials has been largely unsatisfactory, and in certain instances, detrimental. The phase II trial involving the Smoothened inhibitor saridegib (IPI-926) in patients with mPDAC was halted due to a survival disadvantage being observed in the gemcitabine + IPI-926 arm [78], with similar results having been seen when IPI-926 was combined with the FOLFIRINOX regimen [79]. Shh inhibition may yet play a role in chemotherapy treatment strategies for PDAC, potentially requiring optimised dosing [80], fine-tuning of the tumour-restraining ECM balance [81], and/or the use of nano-mediated delivery systems to improve plasma solubility [82]. As such, clinical trials continue to evaluate Shh inhibition with chemotherapy in PDAC [83, 84].

The pleiotropic cytokine, TGF-β, can have either a tumour suppressive or tumour promoting role depending on the stage of PDAC [85]. TGF-β plays a critical role in the desmoplastic reaction by promoting activation and proliferation of PSCs, inducing the expression of fibrogenic targets such as α-SMA and type I collagen, and driving ECM protein deposition via both Smad and non-Smad signalling pathways [86, 87]. Galunisertib is a small molecule serine/threonine kinase inhibitor of the TGF-β receptor I (TGF-βRI), and has been evaluated in a phase II trial in patients with unresectable PDAC. The combination of galunisertib + gemcitabine improved the median survival compared to gemcitabine alone (8.9 vs. 7.1 months; HR, 0.79 [95% CI, 0.59 to 1.09]), with minimal added toxicity (Fig. 2) [75]. Another TGF-βRI kinase inhibitor, Vactosertib, is currently being evaluated in a phase I trial in combination with nal-IRI/5-FU/leucovorin in patients with mPDAC [88]. A newer generation human IgG2 anti-TGF-β-neutralizing antibody, NIS793, is currently being evaluated in a number of clinical trials with SOC chemotherapy in patients with resectable PDAC and mPDAC [89–92].

Rather than fully ablating CAFs, efforts have concentrated on reprogramming activated CAFs into quiescent fibroblasts. The lack of success in phase II trials of Shh pathway inhibition combined with chemotherapy may be due to the failure to consider CAF subpopulations that restrict, rather than promote, PDAC tumour progression [87, 93, 94]. The vitamin D receptor (VDR) presents itself as a chemo-enhancing target, acting as a genomic suppressor of PSC activation. This activated PSC/CAF normalisation strategy utilising calcipotriol has yet to demonstrate positive results clinically, with several clinical trials currently evaluating its efficacy in combination with first-line chemotherapeutics [95–98]. A recent pilot study assessing paricalcitol + nanoliposomal irinotecan + 5-FU/leucovorin in patients with advanced PDAC demonstrated that paricalcitol at 7 µg/kg/week is well tolerated and may enhance tumour vascularity [99]. Activated CAF reversal can also be achieved through administration of all-trans retinoic acid (ATRA), which has been shown to restore PSC quiescence via retinoic acid receptor-β–mediated downregulation of actomyosin contractility [100]. A single-arm phase I clinical trial evaluating gemcitabine + nab-paclitaxel in combination with ATRA in patients with locally advanced or mPDAC demonstrated that the three-drug regimen is safe and well tolerated [101]. A phase II clinical trial will now compare gemcitabine + nab-paclitaxel with and without ATRA [102].

Targeting PDAC-specific mutational vulnerabilities

PARP inhibitors

Germline mutational profiling has enabled personalised therapy selection in patients with advanced PDAC [103]. A meaningful subset of PDAC tumours is characterised by a homologous recombination deficiency (HRD). Tumour cells that are deficient in homologous recombination repair (HRR), such as BRCA1/2 and PALB2 mutants, display enhanced response to platinum-based chemotherapy and to inhibitors of the single-strand break repair protein poly(adenosine diphosphate-ribose) polymerase (PARP) [54, 104, 105]. Mutations in BRCA1, BRCA2 and PALB2 are detected in approximately 0.3-2.3%, 0.7-5.7%, and 3.1-3.7% of PDAC cases, respectively [106–109]. These HRD mutational profiles provide an actionable target, with PARP inhibitors being utilised to promote the accumulation of unrepaired DNA single-strand breaks (SSBs) and the stalling of DNA replication during S-phase, which leads to DNA double-strand breaks (DSBs) [110].

The phase III POLO trial led to the FDA approval of the first PARP inhibitor, olaparib, for maintenance therapy in patients with BRCA-mutated mPDAC whose disease has not progressed after ≥16 weeks of platinum-based chemotherapy [111]. Median PFS was significantly longer in the olaparib arm than in the placebo arm (7.4 vs. 3.8 months; HR, 0.53; [95% CI, 0.35 to 0.82]; P = 0.004). However, no statistically significant difference in median OS was observed. It is important to note that, despite the promising results from the phase III POLO trial, PDAC patients harbouring germline BRCA1/2 mutations exhibit a heterogeneous spectrum of responses to platinum-based chemotherapy and/or PARP inhibitor treatment [112]. Critically, for a germline variant to confer clinical vulnerability to platinum-based chemotherapy and PARP inhibitors, the tumour must typically undergo loss of heterozygosity (LOH) or a second somatic hit to fully abrogate HRR capacity [113, 114]. In mono-allelic mutations, retention of the wild-type allele may preserve residual HRR activity, and such tumours may not exhibit a fully homologous recombination-deficient phenotype despite the presence of a germline mutation. Consequently, classifying all BRCA/PALB2-mutated tumours as uniformly homologous recombination deficient (HRD+) may represent an oversimplification in biomarker-driven patient stratification. Integration of next-generation sequencing-based assessment of DNA damage repair (DDR) gene alterations with HRD scores may improve the identification of PDAC subgroups with differential sensitivity to platinum-based chemotherapy and PARP inhibitors [115, 116].

Targeting tumour heterogeneity with novel DDR-directed therapies may help overcome refractory disease or acquired resistance to platinum-based chemotherapy and/or PARP inhibitors. Moreover, the use of PDAC patient-derived xenograft (PDX) and ex vivo models that recapitulate the clinically observed spectrum of responses in germline BRCA1/2–mutant PDAC may enable more informative treatment decisions [117, 118].

A phase I/II clinical trial examined the combination of veliparib, a PARP inhibitor with weaker PARP-trapping activity than olaparib but a more favourable toxicity profile [119], + 5-FU + oxaliplatin (FOLFOX) in patients with mPDAC. The combination was well tolerated and achieved an overall response rate (ORR) of 26% in patients with mPDAC. The greatest activity was observed in patients with HR–DDR mutations who were platinum-naïve, with an ORR of 57% [120]. Although platinum agents may produce superior tumour responses in HRD-associated PDAC, they can be associated with significant dose-limiting toxicities [121]. Therefore, assessing the efficacy of PARP inhibitors in combination with reduced-dose platinum therapy to limit toxicity may be worthwhile. Combining PARP inhibitors with antimetabolite-based chemotherapy or topoisomerase I (Top1) inhibitors represents another potential therapeutic approach, exploiting complementary DNA damage and repair pathways while potentially improving the tolerability profile [122]. A phase II trial evaluated the efficacy of gemcitabine + cisplatin with or without veliparib in PDAC patients harbouring germline BRCA1/2 or PALB2 mutations [54]. Disappointingly, the addition of veliparib did not enhance the response rate in this setting. A phase I study evaluated the safety and tolerability of olaparib + irinotecan + cisplatin (Olaparib + IC), as well as olaparib + mitomycin C (Olaparib + ICM), in patients with advanced mPDAC [123]. The results indicated that olaparib + IC or ICM was associated with significant toxicity, and the risk–benefit profile of these combinations was deemed unacceptable for further study. The phase II SWOG S1513 trial examined the addition of veliparib to mFOLFIRI (Folinic acid + 5-FU + Irinotecan) vs. FOLFIRI alone for second-line treatment of mPDAC, where 9% of patients had HRD gene mutations, including germline BRCA1, BRCA2, ATM and somatic BRCA2, PALB2, ATM, CDK12 mutations. An additional 20% of patients had mutations in other DNA repair genes [55]. The combination arm did not demonstrate a significant improvement in median OS compared with the control arm (5.4 months vs. 6.5 months; HR, 1.23, P = 0.28). Moreover, the veliparib arm exhibited a higher incidence of grade 3/4 toxicities. Currently, a phase I/II trial is evaluating rucaparib + nal-IRI + 5-FU in metastatic gastrointestinal malignancies, including PDAC. Patients previously treated with platinum therapy demonstrated encouraging responses [124]. The study is now progressing to evaluate the combination’s efficacy in patients with mPDAC, both with and without BRCA1/2 or PALB2 alterations.

Further clinical trials are warranted to determine the utility of combining PARP inhibitors with chemotherapy as a treatment strategy in PDAC. The ongoing phase II APOLLO EA2192 trial aims to determine whether adding olaparib to standard adjuvant chemotherapy improves relapse-free survival in PDAC patients with germline or somatic BRCA1/2 or PALB2 mutations (Table 2) [125]. Although maintenance olaparib and rucaparib have demonstrated significant improvements in PFS in germline BRCA1/2 mutant and somatic BRCA1/2, PALB2 mutant PDAC, respectively, following platinum-based therapy disease stabilization, acquired resistance ultimately develops. Unfortunately, the addition of PARP inhibitors to platinum-based and/or antimetabolite chemotherapy has thus far demonstrated limited efficacy in PDAC. Accordingly, clinical efforts have shifted toward combining PARP inhibitors with immune checkpoint inhibitors (ICIs), supported by preclinical evidence that PARP inhibition upregulates PD-L1 expression via JAK2/STAT3 signalling in PDAC cells [126–128]. Combinations of PARP inhibitors with ATR inhibitors, which target complementary DDR pathways involved in SSB repair, are also under active clinical investigation [129–131].

KRAS inhibitors

Among the identified somatic alterations in PDAC, activating mutations in KRAS hotspot residues are the most common, occurring in approximately 90% of patients [132]. Mutational activation of KRAS typically occurs early in pancreatic cancer carcinogenesis, being crucial for the formation of pancreatic intraepithelial neoplasia lesions and progression to invasive PDAC [133]. KRAS-mutated PDAC is associated with worse OS when compared to wild-type KRAS PDAC tumours [133, 134]. KRAS has long been considered an “undruggable” target due to the absence of suitable binding sites for small-molecule inhibitors. This perception changed with the development of covalent inhibitors targeting the switch II pocket of mutant KRAS^G12C, which locks KRAS in its inactive GDP-bound conformation, suppressing downstream signalling, and halting cell proliferation [135, 136]. Two KRAS^G12C inhibitors, sotorasib and adagrasib, each received accelerated FDA approval for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) harbouring a KRAS^G12C mutation, which are found in 39% of NSCLC tumours [137, 138]. However, KRAS^G12C mutations are found in only a small subset of PDAC, occurring in approximately 1-2% of patients [139]. Modest single agent clinical activity of sotorasib was observed in chemo-refractory KRAS^G12C-mutant PDAC [140]. Thus, combining KRAS^G12C inhibitors with standard chemotherapy is hypothesised to augment anti-tumour response in PDAC. A phase Ib/II study will examine whether the addition of sotorasib to second-line chemotherapy regimens in KRAS^G12C-mutated PDAC will enhance anti-tumour efficacy and ORR [141]. Interestingly, a longitudinal study of liquid biopsy-based biomarkers in patients with resectable PDAC revealed that patients who received FOLFIRINOX + subsequent surgical resection had new KRAS mutations in their cell-free DNA compared to those before treatment [142]. Therefore, targeting KRAS may potentially have implications for managing chemoresistance. Indeed, sotorasib and adagrasib are now included in the National Comprehensive Cancer Network guidelines for treating locally advanced and mPDAC with KRAS^G12C mutations.

The KRAS^G12D mutation is the most common KRAS variant in PDAC, occurring in almost 40% of patients [143, 144]. Consequently, the development of selective inhibitors targeting KRAS^G12D has become a key focus in PDAC research. Mirati Therapeutics, now a subsidiary of Bristol Myers Squibb, developed MRTX1133, a highly potent and selective non-covalent inhibitor of KRAS^G12D. MRTX1133 binds reversibly to KRAS^G12D, permanently modifying the protein and potentially reducing the risk of resistance mechanisms associated with covalent inhibitors (Fig. 2). Despite promising preclinical efficacy [145], the clinical advancement of MRTX1133 has been hampered by its unfavourable pharmacokinetic properties, being recently terminated at phase I due to this issue [146]. HRS-4642, developed by Jiangsu Hengrui Pharmaceuticals, is a highly potent, non-covalent KRAS^G12D inhibitor formulated as a liposomal injection. This liposomal encapsulation allows the drug to selectively deposit and continuously accumulate in tumour tissues, providing favourable pharmacokinetic properties and reducing toxicity [147]. HRS-4642 was evaluated in combination with gemcitabine + nab-paclitaxel in treatment-naïve mPDAC, yielding an ORR of 60% and DCR of 93.3% [148].

Beyond mutation-selective inhibitors, recent research has focused on the development of pan-RAS or RAS(ON) inhibitors designed to target multiple RAS isoforms and mutations simultaneously. These agents function through a molecular glue-like mechanism, binding active GTP-bound RAS and the chaperone protein cyclophilin A (CypA) to form a ternary complex [149]. This resulting CypA–drug–RAS–GTP complex sterically blocks interactions between RAS and its downstream effector proteins, thereby suppressing RAS-dependent oncogenic signalling [150]. Revolution Medicines developed daraxonrasib (RMC-6236), an oral RAS(ON) multi-selective inhibitor that demonstrated significant clinical benefit in the phase III RASolute 302 trial [151]. In this pivotal phase III study, 500 patients with previously treated mPDAC were randomised to receive daraxonrasib (n = 248) or investigator’s choice of four standard chemotherapy regimens (n = 252), representing current global standards of care. The median OS in the RAS G12 population was 13.2 months with daraxonrasib vs. 6.6 months with chemotherapy (HR, 0.40 [95% CI, 0.30–0.53]; P < 0.0001). The phase III RASolute 303 trial will evaluate daraxonrasib alone, gemcitabine + nab-paclitaxel alone, and daraxonrasib + gemcitabine + nab-paclitaxel in the first-line treatment of mPDAC [152]. Additionally, the phase III RASolute 304 trial will evaluate whether daraxonrasib improves DFS compared to SOC observation following neoadjuvant and/or adjuvant chemotherapy in resected PDAC [153]. Zoldonrasib (RMC-9805) is another oral RAS(ON) inhibitor which is KRAS^G12D-specific, targeting the GTP-bound state through a molecular glue-like mechanism similar to that of daraxonrasib, but mechanistically distinct in that it directly targets the KRAS^G12D allele [154]. Preliminary results from its phase I study (NCT06040541) in patients with previously treated KRAS^G12D-mutant advanced PDAC demonstrated encouraging anti-tumour activity, with an ORR of 30% and a DCR of 80% [155]. Building on these findings, the trial was expanded to evaluate zoldonrasib + the RAS(ON) multi-selective inhibitor daraxonrasib. The combination demonstrated a manageable safety profile and encouraging preliminary efficacy, achieving an ORR of 50% and a DCR of 97% [156]. Importantly, KRAS isoform-selective inhibitors may offer a more favourable therapeutic index than pan-RAS inhibitors, potentially improving tolerability and facilitating combination with cytotoxic chemotherapy [157, 158]. The phase III RASolute 305 study is evaluating zoldonrasib + chemotherapy compared to placebo + chemotherapy in the first-line treatment of KRAS^G12D-mutated mPDAC [159]. Additionally, the safety and preliminary anti-tumour activity of zoldonrasib + SOC chemotherapy or with novel agents is being evaluated in gastrointestinal solid tumours, including PDAC [160]. In patients with first-line KRAS^G12D-mutant mPDAC, zoldonrasib + mFOLFIRINOX or gemcitabine + nab-paclitaxel demonstrated a manageable safety profile and encouraging preliminary efficacy, achieving ORRs of 82% and 61%, respectively [161]. INCB161734 is a novel, orally bioavailable KRAS^G12D-selective ON/OFF inhibitor developed by Incyte Corporation that achieves sustained suppression of downstream MAPK signalling independent of KRAS nucleotide state [162]. Preliminary data from its phase I dose-escalation and expansion study in patients with advanced or mPDAC demonstrated an ORR of 34%, while early combination studies with chemotherapy have demonstrated an encouraging safety profile [163]. The phase III DAWN-303 study will evaluate standard chemotherapy with or without INCB161734 in the first-line KRAS^G12D-mutated mPDAC setting [164]. GFH375 (VS-7375), currently being developed by GenFleet Therapeutics and Verastem Oncology, is another non-covalent KRAS^G12D dual ON/OFF inhibitor being investigated in KRAS^G12D-mutant PDAC. In a phase I/II monotherapy study, GFH375 in advanced pretreated KRAS^G12D-mutant PDAC demonstrated an ORR of 40.7% with a median PFS of 5.5 months and a 4-month PFS rate of 78.2% [165]. Additional RAS(ON) isoform-selective inhibitors are in the pipeline, including RMC-0708 and RMC-8839, which target the active state of KRAS^Q61H and KRAS^G13C, respectively.

Targeting upstream and downstream signalling pathways which are engaged by mutant KRAS has shown promise in PDAC, with targets including EGFR, SHP2, SOS1, MEK, mTOR, and CDK4/6 [166]. Trametinib, a selective and reversible small molecule inhibitor of MEK1/2 kinase activity, augmented the efficacy of nab-paclitaxel-based chemotherapy, demonstrating a trend towards an additive effect on tumour growth in subcutaneous PDAC xenograft models [235]. However, in a phase II study involving patients with untreated mPDAC, the combination of trametinib + gemcitabine demonstrated limited efficacy and did not improve OS [236]. Additionally, concomitant inhibition of focal adhesion kinase (FAK) with VS-4718 and MAPK kinase with avutometinib + gemcitabine + nab-paclitaxel, led to tumour regression, reduced liver metastasis, and improved survival in KRAS-driven PDAC mouse models [237]. PDAC stromal targeting with VS-4718 + RAF-MEK targeting with avutometinib improved anti-tumour immunity and priming of T cell responses in response to chemotherapy. Thus, indirect KRAS co-targeting may offer therapeutic potential when added to standard chemotherapy in PDAC. Preliminary results from the RAMP 205 trial evaluating avutometinib + defactinib, a FAK inhibitor, + gemcitabine + nab-paclitaxel in first-line mPDAC suggests synergistic activity with this combination [167]. Recently, compelling preclinical data demonstrated that pharmacological disruption of three independent nodes within KRAS signalling - downstream (RAF1), upstream (EGFR), and orthogonal (STAT3) - induces complete regression of orthotopic PDAC tumours. To pharmacologically replicate the genetic ablation of these pathways, researchers utilised a triple-combination regimen consisting of the irreversible EGFR inhibitor afatinib, the selective STAT3 proteolysis-targeting chimera (PROTAC) SD36, and the multi-selective RAS(ON) inhibitor daraxonrasib to systematically shut down primary RAS signalling and its bypass mechanisms. Notably, this simultaneous multi-node blockade successfully prevented the emergence of acquired therapeutic resistance for more than 200 days post-treatment. These findings underscore the therapeutic potential of rational multi-target combination strategies in this disease [168].

In addition to small-molecule inhibitors, RNA interference (RNAi) offers another means of suppressing KRAS expression. This approach employs double-stranded RNAs of 20–25 nucleotides, known as small interfering RNAs (siRNAs), to selectively inhibit the expression of mRNA from specific oncogenes [169]. In a phase I/IIa study, a miniature biodegradable polymeric matrix encapsulating anti-KRAS^G12D siRNA (siG12D), termed siG12D-LODER^TM, was implanted directly into LAPC tumours via a standard endoscopic ultrasound-guided biopsy procedure [170]. siG12D-LODER^TM was administered in combination with gemcitabine or mFOLFIRINOX. The results were encouraging, with the combination being well tolerated and stable disease observed in the majority of patients (10/12). siG12D-LODER^TM, which targets KRAS^G12D as well as other G12X mutations (e.g., G12C, G12V), was evaluated in a phase II study (PROTACT) in combination with chemotherapy for the treatment of LAPC [171]. In the modified intention-to-treat population, there was no significant difference in OS between patients treated with siG12D-LODER^TM + gemcitabine + nab-paclitaxel vs. those treated with gemcitabine + nab-paclitaxel alone (22.7 vs. 21.9 months, respectively [P > 0.05]). Among patients with KRAS^G12D/V mutations, the OS trended toward improvement in the siG12D-LODER^TM + gemcitabine + nab-paclitaxel arm, with an OS of 22.7 months vs. 13.4 months in the gemcitabine + nab-paclitaxel arm (HR, 0.59 [95% CI, 0.18–1.96]; P = 0.39].

However, poor delivery and off-target effects have limited the clinical application of RNAi-based KRAS targeting in PDAC to date. Selective protein degradation therefore represents another promising strategy for reducing KRAS^G12D in PDAC. PROTACs are heterobifunctional small molecules composed of two ligands connected by a linker: one that binds an E3 ubiquitin ligase and another that binds the target protein. By recruiting the target protein to the E3 ligase, PROTACs promote ubiquitination and subsequent degradation via the ubiquitin-proteasome system [172]. ASP3082, a potent and selective KRAS^G12D degrader, is currently being evaluated in a phase I study as monotherapy or in combination with cetuximab or chemotherapy in patients with previously treated locally advanced or metastatic KRAS^G12D-mutant solid tumours, including PDAC [173].

Immune modulation for chemo-enhancement

Another distinctive feature of PDAC treatment resistance is its immunological “cold” landscape. Particularly, the aforementioned desmoplastic TME and resulting hypoxia contribute to regulatory T cell-mediated suppression of CD8⁺ T cell activity [174]. Emerging strategies - including chemoimmunotherapy combinations, personalised mRNA neoantigen vaccines, and modulation of the patient’s microbiome - are opening new avenues to enhance treatment response in PDAC.

Chemoimmunotherapy

Immunotherapy, particularly ICI therapy targeting programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1), has shown marked efficacy and is the SOC for several malignancies, including melanoma, NSCLC, renal cell carcinoma, and refractory Hodgkin’s lymphoma [175–178]. Unfortunately, immune checkpoint blockade (ICB) monotherapy, using either anti-PD-1/PD-L1 antibodies or cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) antibodies, has shown limited clinical success in PDAC [179–181]. Based on the KEYNOTE-158 study, the anti–PD-1 antibody pembrolizumab (Keytruda) received FDA approval for the treatment of patients with advanced PDAC whose tumours exhibit deficient mismatch repair (dMMR) with high microsatellite instability (MSI-H), conferring increased immunogenicity, or a high tumour mutational burden (>10 mutations per megabase), and who have progressed following prior therapy [182, 183]. Despite being the only currently approved immunotherapy for PDAC, the clinical impact of pembrolizumab is limited due to the low incidence of dMMR in PDAC, which has been reported to range from 0.5–2% [184–188]. Effective immunotherapy for PDAC with proficient mismatch repair (pMMR), that is not MSI-H, remains an area of active clinical investigation. PDAC is frequently refractory to immunotherapy, largely due to its immunosuppressive TME, limited immune cell infiltration, and relatively low expression of tumour-specific neoantigens [189–191]. Consequently, considerable efforts have focused on converting the immunologically “cold” PDAC TME into a more responsive “hot” state.

Interestingly, in addition to their direct cytotoxic activity, certain chemotherapeutic agents exhibit immunomodulatory properties. These agents have been shown to sensitise the TME to immunotherapies by enhancing antigen presentation by dendritic cells (DCs), increasing CD8⁺ T cell activity, and promoting T cell infiltration into tumour sites [192–195]. These immunogenic effects are often dependent on chemo-induced production of apoptotic cells, which release damage-associated molecular patterns (DAMPs). These DAMPs are then engulfed and presented by DCs, triggering T lymphocyte-mediated immunologic cytotoxicity, a process known as immunogenic cell death [196, 197]. A meta-analysis revealed that combining chemotherapy with immunotherapy for PDAC significantly improves PFS and DCR compared to chemotherapy alone, without significantly increasing adverse events [198]. FOLFIRINOX initiates immunological effects, with one cycle of the regimen being found to promote the activation of CD4⁺ and CD8⁺ T cells, the proliferation of natural killer T cells, and the activation of antigen presenting cells (APCs) in PDAC patients [199]. Enhanced immune activation, evidenced by an increase in pro-inflammatory cytokines IL-18 and IL-15, along with a decrease in the expression of the immunosuppressive gene CXCL5, has also been observed following FOLFIRINOX delivery [199, 200].

Despite encouraging preclinical data and evidence of immune activation induced by FOLFIRINOX in patients, successful clinical outcomes with FOLFIRINOX-based regimens combined with immunotherapy in PDAC have remained limited. A randomised phase III trial (CISPD3-trial) investigated the efficacy and safety of sintilimab (anti-PD-1 mAb) + mFOLFIRINOX vs. mFOLFIRINOX alone in patients with metastatic or recurrent PDAC [259]. The median OS was similar between the sintilimab + mFOLFIRINOX arm vs. mFOLFIRINOX monotherapy arm (10.9 months vs. 10.8 months, respectively). Median PFS was similar between the sintilimab + mFOLFIRINOX and mFOLFIRINOX monotherapy arms (5.9 vs. 5.73 months), while ORR was higher with the combination (50% vs. 23.9%). A phase II trial evaluated the combined anti-tumour efficacy and safety of nivolumab (anti-PD-1 mAb) + mFOLFIRINOX in mPDAC. Compared to previously reported data, no meaningful increase in ORR, OS or PFS was observed with nivolumab + mFOLFIRINOX [201]. The phase II COMBAT/KEYNOTE-202 trial evaluated the safety and efficacy of motixafortide (CXCR4 inhibitor) + pembrolizumab + nanoliposomal irinotecan + fluorouracil + folinic acid in mPDAC. Clinical benefit was achieved, with a confirmed ORR of 13.2%, DCR of 63.2%, and median OS of 6.6 months in the intention-to-treat population [202].

A range of clinical trials has demonstrated the efficacy of combining immunotherapies, such as anti-PD-1 antibodies, anti-CTLA-4 antibodies, and anti-CD40 agonists, with gemcitabine-based chemotherapy in PDAC [203–206]. In a phase Ib study, the addition of the CD40 agonist sotigalimab to gemcitabine + nab-paclitaxel, with or without nivolumab, was well-tolerated and demonstrated promising tumour regression rates in patients with mPDAC [207]. In the phase II PRINCE trial, the combination of sotigalimab + nivolumab + chemotherapy did not show a significant improvement in the 1-year OS rate. However, survival following sotigalimab + chemotherapy was correlated with increased intratumoural CD4⁺ T cell infiltration and the presence of APCs [208]. Preliminary data from the phase Ib/II study evaluating gemcitabine + nab-paclitaxel + toripalimab, a novel anti-PD-1 antibody, in advanced PDAC are promising, with a 1-year OS rate of 69.1% and the chemoimmunotherapy combination demonstrating expected anti-tumour activity [209]. In parallel, a phase II trial will assess whether adding botensilimab to nab-paclitaxel + gemcitabine improves efficacy compared with chemotherapy alone in patients with mPDAC whose disease has progressed following prior FOLFIRINOX therapy [210]. The CheMo4METPANC pilot study evaluated the preliminary safety and radiologic response of motixafortide (a CXCR4 inhibitor) + cemiplimab (an anti–PD-1 antibody) + gemcitabine + nab-paclitaxel in treatment-naïve mPDAC (Table 2). Preliminary results from this chemoimmunotherapy combination were encouraging, demonstrating a durable partial response rate of 55% and a DCR of 82%, compared with historical partial response and DCRs of 23% and 48%, respectively, for gemcitabine + nab-paclitaxel [211]. Overall, chemoimmunotherapy strategies in PDAC have achieved only limited clinical efficacy to date. The future of immunotherapy for PDAC is trending towards rational triple-combination regimens incorporating PD-1/PDL-1 blockade, CXCR4 inhibition and chemotherapy. Additionally, neoantigen-based vaccines aimed at immune priming and stimulation have shown encouraging results in early-phase studies [212].

mRNA neoantigen vaccines

The abundance of neoantigens in PDAC and its poor response to ICIs [213] has led to the development of neoantigen-based mRNA vaccines [214]. Autogene cevumeran is an individualised neoantigen-based mRNA vaccine, containing up to 20 neoantigens in lipoplex nanoparticles. When combined with mFOLFIRINOX-based chemotherapy and a PD-L1 blocker (atezolizumab), autogene cevumeran induced strong T cell responses in PDAC patients, which correlated with delayed disease recurrence (Fig. 2) [215]. Critically, this vaccine-induced T cell response was durable at an extended 3.2-year median follow-up, with responders having prolonged recurrence-free survival compared with non-responders without vaccine-induced T cells [212]. Such encouraging results have led to a phase II randomised study (IMCODE 003) evaluating the efficacy and safety of autogene cevumeran + atezolizumab+ mFOLFIRINOX vs. mFOLFIRINOX alone in treatment-naïve resected PDAC patients [216].

Electroporation

Electroporation employs high-voltage electrical pulses to increase cell membrane permeability [217] and can be either reversible, with transient membrane disruption, or irreversible, with sustained pore formation leading to loss of barrier integrity [218]. Electrochemotherapy (ECT) combines reversible electroporation (RE) with chemotherapy, using low-intensity electrical pulses (<1500 V/cm) to transiently increase cell membrane permeability and thereby enhance the intracellular uptake of non- or poorly permeant chemotherapeutic agents [219]. ECT has been shown to enhance the cytotoxicity of chemotherapy while reducing the dose required for intravenous administration [220–222]. This treatment strategy has generated interest in PDAC because it avoids thermal injury to peri-pancreatic vessels and surrounding gastrointestinal structures. However, ECT has rarely been implemented in mPDAC and has instead been primarily applied in BRPC or LAPC. Notably, a substantial proportion of patients with LAPC die without developing metastatic disease, with mortality often attributable to complications arising from locally destructive tumour growth [223]. In this context, electroporation offers a less invasive alternative to surgical resection for local tumour control in LAPC and, when combined with chemotherapy, may improve survival outcomes [224].

To date, a limited number of phase I/II clinical trials have evaluated the safety and efficacy of ECT in LAPC [225–228]. A clinical phase I/II study assessed the effectiveness of ECT + bleomycin in patients with LAPC who had achieved stable disease or a partial response following chemotherapy with gemcitabine + oxaliplatin or FOLFIRINOX. In this cohort, ECT achieved a local DCR of 56% at 6 months post-treatment and a median OS of 11.5 months. Notably, multiple single-needle insertions using variable geometry to improve tumour coverage were associated with enhanced local disease control and OS [228].

Irreversible electroporation (IRE), commercially known as NanoKnife® (AngioDynamics, Inc., Latham, New York), is a non-thermal ablation modality that delivers short (50–100 μs), high-voltage (1500–3000 V/cm) electrical pulses to induce permanent, lethal nanopore formation in the cell membrane, thereby disrupting cellular homeostasis and triggering apoptosis [229–231]. IRE has shown promising outcomes when used alone, in combination with chemotherapy, or as an adjunct to surgery in LAPC [232–236]. LAPC patients treated with IRE in combination with chemotherapy, including gemcitabine- or FOLFIRINOX-based regimens, demonstrated improved OS, higher cancer-specific survival, and longer PFS compared with chemotherapy alone [237]. Consistently, another study reported that the addition of IRE to chemotherapy significantly improved survival outcomes in LAPC relative to chemotherapy alone. Moreover, when compared with neoadjuvant chemotherapy + subsequent surgical resection, the combination of chemotherapy + IRE achieved comparable OS and PFS in LAPC patients with minimal vascular invasion [238]. Similar to ECT, IRE induces the formation of nanoscale membrane pores, increasing cellular permeability to macromolecules, including chemotherapeutic agents (Fig. 2) [239]. In addition, the non-thermal nature of IRE offers a key advantage in highly vascular organs such as the pancreas, where thermal ablation may be compromised by the “heat-sink” effect, leading to incomplete tumour destruction [240]. Together, these mechanisms may underlie the observed synergy between IRE and chemotherapy compared with chemotherapy alone.

Both ECT and IRE represent promising approaches to enhance chemotherapy response in LAPC, although further investigation is required to define their role in PDAC [241]. However, variability in reported complication rates across studies remains a concern, likely reflecting a lack of standardisation in treatment protocols and/or differences in tumour size among patient populations [242, 243]. Accordingly, additional clinical studies are needed to establish ECT and IRE as viable treatment modalities for PDAC, either as standalone therapies or in combination with standard chemotherapy.

Emerging targets for chemotherapy enhancement in PDAC

In recent years, efforts have focused on surface proteins that are amplified and associated with chemotherapy resistance in PDAC. These proteins provide opportunities for tumour-specific targeting and the enhancement of chemosensitivity. Key emerging targets in PDAC include, KRAS, methylthioadenosine phosphorylase (MTAP), EGFR, claudin 18.2 (CLDN18.2) and WEE1.

KRAS

The genomic landscape of PDAC is well-established and characterised by four key driver mutations. In addition to activating mutations in KRAS, occurring in up to 90% of PDACs, inactivating alterations in tumour suppressor genes, including cyclin-dependent kinase inhibitor 2A (CDKN2A), p53 (TP53), and SMAD family member 4 (SMAD4) occur in 90%, 75%, and 50% of PDAC tumours, respectively [254]. Critically, mutant KRAS plays a central role at every step of PDAC progression, initiating a cascade of oncogenic events which alter several key hallmarks of PDAC tumour biology and TME [58].

As discussed in the KRAS Inhibitors section, recent clinical breakthroughs have positioned mutant KRAS as a critical and rapidly evolving therapeutic target for PDAC. This has fuelled the development of allele-specific inhibitors, pan-RAS inhibitors, PROTAC degraders, and KRAS-targeted mutation-specific vaccines [255]. Following the recent landmark RASolute 302 trial, with daraxonrasib demonstrating a near doubling of median OS compared to standard chemotherapy, it is highly anticipated that RAS(ON) KRAS inhibitors will gain approval as a single agent in the first-line metastatic setting [151]. KRAS inhibitors may also have a place in the adjuvant and neoadjuvant setting for RPC/BRPC. Biomarker-selected NAT is likely to play an important role, one being the Purity Independent Subtyping of Tumors (PurIST) classifier to differentiate basal and classical subtypes [256, 257]. Emerging preclinical data suggest that classical PDAC cells are acutely resistant to KRAS inhibition [145]. PDAC tumour cells can shift from classical to basal-like states during chemotherapy treatment [258], thus combining KRAS inhibitors with cytotoxic chemotherapy may successfully target both of these cell states, amplifying the cytotoxicity against PDAC tumour cells. Indeed, durability of responses to single-agent inhibitors remains in question. Clinical trials that combine KRAS-targeted agents with chemotherapy backbones are actively ongoing in PDAC (Table 2). Indeed, encouraging preliminary data from the phase I zoldonrasib +daraxonrasib combination trial (NCT06040541) support the initiation of the phase III RASolute 309 trial, which will evaluate zoldonrasib +daraxonrasib vs. gemcitabine + nab-paclitaxel as first-line therapy for KRAS^G12D-mutated mPDAC.

Methylthioadenosine phosphorylase (MTAP)

Inactivation of CDKN2A by homozygous deletion occurs in up to 40% of PDAC cases. Owing to the close genomic proximity of MTAP and CDKN2A on chromosome 9p21, MTAP is frequently co-deleted with homozygous loss of CDKN2A [259], with MTAP loss reported in approximately 22% to 38% of PDAC cases [260–262]. MTAP is the rate-limiting enzyme in the methionine salvage pathway, catalysing the conversion of 2-methylthioadenosine (MTA) into methionine and adenine. Consequently, MTAP loss leads to MTA accumulation, generating tumour-selective metabolic vulnerabilities that have prompted the development of therapies targeting MTA-sensitive pathways [263]. Specifically, MTA accumulation induces partial inhibition of protein arginine methyltransferase 5 (PRMT5), a key enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine (SAM) to arginine residues on histone and non-histone proteins [264]. Thus, MTAP-deficient cells exhibit increased dependence on residual PRMT5 activity, enabling synthetic lethality with PRMT5 inhibition [265].

MTA-cooperative PRMT5 inhibitors in preclinical and clinical development include BMS-986504 (navlimetostat), anvumetostat (formerly AMG 193), AZD3470, and TNG908. The ongoing phase II/III MountainTAP-30 trial is evaluating the addition of BMS-986504 to nab-paclitaxel + gemcitabine in first-line mPDAC with homozygous MTAP deletion [266]. In parallel, Amgen is advancing anvumetostat in the phase Ib MTAPESTRY 103 trial, which is evaluating its combination with SOC chemotherapy in PDAC patients with homozygous MTAP deletion [267]. MTAP-deficient tumours may also be therapeutically targeted via inhibition of methionine adenosyltransferase 2α (MAT2A), the predominant enzyme catalysing SAM biosynthesis from methionine, and several MAT2A inhibitors are currently under clinical investigation [262] (Table 2).

TNG908 was initially selected as a lead MTAP-selective PRMT5 inhibitor by Tango Therapeutics; however, development efforts have since shifted toward next-generation compounds TNG462 and TNG456, which demonstrate improved potency and selectivity [268, 269]. The ongoing phase I/II TNG462-C102 study is evaluating TNG462 + SOC chemotherapy in PDAC [270]. Preliminary data from an ongoing phase I/II trial by Tango Therapeutics evaluating the PRMT5 inhibitor vopimetostat + the RAS(ON) inhibitor daraxonrasib in patients with MTAP-deleted, RAS-mutant mPDAC have shown encouraging early clinical activity. In a limited cohort, the combination achieved an ORR of 92%, with a 6-month PFS rate of 90% [271].

Epidermal growth factor receptor (EGFR)

EGFR, a transmembrane tyrosine kinase receptor, is overexpressed in approximately 30–89% of PDAC cases and is associated with lymph node metastasis and poor survival outcomes [272, 273]. The tyrosine kinase inhibitor erlotinib (Tarceva®) was approved for the treatment of advanced PDAC in 2005, following results from the NCIC-CTG phase III trial, which demonstrated a modest but statistically significant improvement in survival with the addition of erlotinib to gemcitabine (6.24 months vs. 5.91 months) [274].

More recently, EGFR monoclonal antibodies have been investigated in PDAC to block ligand binding and prevent EGFR activation. The phase III NOTABLE III trial evaluated the anti-EGFR monoclonal antibody nimotuzumab + gemcitabine in KRAS-wild-type LAPC or mPDAC. Nimotuzumab significantly improved median OS compared to placebo (10.9 months vs. 8.5 months; HR, 0.66; P = 0.08), suggesting a new therapeutic option for KRAS wild-type PDAC [275]. Due to the limited activity of Tarceva® + gemcitabine in PDAC, investigational approaches include combining EGFR inhibitors with MEK inhibitors and BCL-xL degraders [276].

Claudin 18.2 (CLDN18.2)

CLDN18.2, a tight junction protein, is expressed in up to 60% of PDACs and associated metastases [277]. However, the association between CLDN18.2 expression and patient survival remains inconsistent across studies, some identifying it as an independent favourable prognostic marker while others report no correlation or even suggest worse outcomes [278–280]. Despite these mixed findings, CLDN18.2 remains a promising target for monoclonal antibody therapy due to its tumour-selective expression and limited nonspecific binding.

Zolbetuximab (IMAB362) is a monoclonal antibody targeting CLDN18.2, which mediates its effects through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Zolbetuximab, when combined with chemotherapy, has shown promise in phase II trials for advanced gastric and gastroesophageal junction cancers, demonstrating a favourable safety profile and significantly prolonging survival [281]. However, the phase II GLEAM trial evaluating zolbetuximab + nab-paclitaxel + gemcitabine as first-line therapy for CLDN18.2-positive mPDAC did not meet its primary endpoint of OS [282]. Nevertheless, exploratory biomarker analyses suggested that elevated circulating IL-18 levels may be associated with clinical benefit from zolbetuximab in patients with CLDN18.2-positive mPDAC [283]. A forthcoming phase I/II trial will evaluate the bispecific antibody PT886, which targets both CLDN18.2 and CD47, in combination with chemotherapy and/or pembrolizumab in patients with gastric, gastroesophageal adenocarcinomas, and PDAC [284]. Recently, the anti-CLDN18.2 antibody-drug conjugate (ADC) IBI343 has demonstrated promising safety and efficacy in CLDN18.2-positive PDAC. IBI343 is conjugated to the cytotoxic payload exatecan, a Top1 inhibitor, which is released upon lysosomal processing following binding to CLDN18.2-positive cells, thereby inducing tumour DNA damage and promoting apoptosis. This phase II trial is currently ongoing [285]. Currently, there are no FDA approved CLDN18.2-targeted therapies for PDAC, but the aforementioned ongoing early-phase studies may guide their clinical implementation (Table 2). Indeed, further investigation is required to gain a clearer understanding of the expression pattern and clinicopathological relevance of CLDN18.2 in PDAC [286, 287].

WEE1 (WEE1 G2 checkpoint kinase)

The TP53 tumour suppressor gene is mutated in approximately 70% of PDAC tumours, often resulting in defects in G1/S checkpoint regulation [288]. Consequently, DNA-damaged cells with TP53 mutations heavily rely on the G2/M checkpoint for survival. WEE1, a tyrosine kinase, plays a critical role in the G2/M checkpoint by preventing premature mitosis through inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1). As a result, WEE1 represents a potential therapeutic target to enhance the sensitivity of PDAC to chemotherapy and radiotherapy [289].

The highly selective WEE1 inhibitor AZD1775 (adavosertib, formerly MK-1775) has been investigated in various cancers, including PDAC, leveraging the concept of synthetic lethality. A phase I dose-escalation trial of adavosertib + gemcitabine + radiation in patients with previously untreated LAPC demonstrated that the combination was well tolerated and resulted in significantly higher OS compared to chemoradiotherapy alone [290]. The orally available, selective WEE1 inhibitor azenosertib (Zn-c3, developed by Zentalis) will be evaluated in a phase II trial in combination with gemcitabine for second-line advanced PDAC treatment [291].

Precision chemotherapy

Chemo-induced toxicities vary widely, and currently there are no validated biomarkers that reliably predict efficacy of chemotherapeutic agents. Given that chemotherapy remains the backbone of the PDAC treatment paradigm (Fig. 1), the development of transcriptomic classification approaches to guide selection between gemcitabine-based and FOLFIRINOX-based regimens represents a critical unmet need. Traditional transcriptomic classifications define PDAC into two main subtypes, classical and basal-like [292]. Basal-like tumours are consistently associated with poorer survival and increased chemoresistance [293–296]. However, recent single-cell and longitudinal studies suggest that these subtypes are not fixed, but instead exist along a reversible and dynamic continuum influenced by therapeutic pressure [297–299]. This pronounced intratumoural heterogeneity contributes to highly variable treatment responses [300]. Together, these findings highlight the need for integrated predictive models that incorporate transcriptomic, genomic, and tumour microenvironmental features to enable truly precision-guided chemotherapy in PDAC.

Chanez et al. [301] discuss the development of predictive transcriptomic signatures for personalised chemotherapy in PDAC and the challenges that remain for clinical implementation. Emerging evidence from three such signatures, GemPred, GemCore and Pancreas-View, show potential in this setting as they continue to be validated in independent cohorts. GemPred was the first transcriptomic signature developed in PDAC, using RNA-seq data patient-derived primary cultures and xenografts to generate predictive scores for gemcitabine sensitivity, before validating these data in retrospectively resected tumours [302]. In validation cohorts, GemPred+ patients derived a greater survival benefit from adjuvant gemcitabine, though the signature has no clear prognostic value outside of this [26, 303]. This was unsurprising given its development in a resected cohort, limiting its utility in more advanced and metastatic disease. GemCore was created to directly address this limitation, specifically targeting smaller biopsy samples and fine-needle aspirations in patients with advanced PDAC [304]. GemCore retained predictive value for first-line gemcitabine, with GemCore+ patients demonstrating better survival than GemCore- patients in both primary and metastatic biopsies. More recently, Pancreas-View has emerged as the most comprehensive transcriptomic platform yet, combining multiple drug-specific signatures to predict sensitivity to gemcitabine as well as each component of FOLFIRINOX, with the addition of AI-based integration of stromal and immune-related features [305]. Retrospective validation of Pancreas-View obtained promising results, with treatment matched to predicted sensitivity correlating with better survival in both primary and metastatic diseases [306]. The platform also identified a multi-drug-resistant subgroup with poor outcomes. Pancreas-View represents the most advanced of these platforms and is currently being tested prospectively in ongoing trials, however, these signatures in general are limited to real-world barriers in PDAC management such inadequate tumour RNA from small biopsies, contamination by normal or non-tumour tissues, the vast intratumoural heterogeneity seen in PDAC, and the need for faster standardised workflows prior to routine clinical implementation. Despite this, Pancreas-View remains promising in this setting, with potential for generating a shift in PDAC chemotherapy regimen choice to biomarker-guided selection, enabling treatment de-escalation, improved first-line matching and early identification of multi-drug resistant tumours.

Conclusions

Chemotherapy remains the mainstay of PDAC treatment; however, despite ongoing refinements in chemotherapeutic regimens, its role continues to evolve but remains limited in terms of durable clinical benefit. Targeted and immune-based therapies have thus far provided minimal survival benefit for the majority of patients. Accordingly, strategies aimed at enhancing the efficacy of currently available chemotherapies represent an important therapeutic avenue in PDAC.

Therapeutic strategies directed at PDAC-specific resistance mechanisms, including stromal desmoplasia, actionable genomic alterations (such as BRCA1/2 and PALB2 mutations), and modulation of the TME, have demonstrated emerging promise. KRAS-directed therapies, particularly multi-selective RAS(ON) inhibition, and MTAP-directed synthetic lethal strategies represent two significant emerging directions in PDAC drug development, with early clinical studies suggesting meaningful translational potential. Although not discussed in detail here, drug repurposing through the use of existing FDA-approved drugs may also contribute to enhancing chemotherapy efficacy and overcoming resistance in this challenging malignancy. By leveraging well-characterised, clinically approved drugs, these approaches offer the potential for more rapid and streamlined translation into clinical practice. Furthermore, given the intensity of chemotherapy regimens in PDAC, adjunctive local ablative strategies, such as electroporation and regional hyperthermia, may improve therapeutic efficacy while minimising systemic toxicity. The emergence of mRNA cancer vaccines also shows promise, particularly in overcoming the immunologically “cold” nature of PDAC tumours. While ICIs have shifted treatment paradigms and significantly improved OS in several solid malignancies, their use as a monotherapy in PDAC has been largely disappointing. Consequently, research efforts have focused on rational combination strategies, particularly the integration of ICIs with chemotherapy, which has suggested early signals of improved and potentially more durable responses in selected settings. This evolving therapeutic landscape is reflected in the expanding portfolio of chemoimmunotherapy-based clinical trials in PDAC. Although survival outcomes are gradually improving, further strategies to enhance responses to SOC chemotherapy will be critical to sustain and accelerate this progress.

Abbreviations

ADC

Antibody-drug conjugate

APCs

Antigen-presenting cells

ATRA

All-trans retinoic acid

BRPC

Borderline resectable pancreatic cancer

CAFs

Cancer-associated fibroblasts

CDK1

Cyclin-dependent kinase 1

CDKN2A

Cyclin-dependent kinase inhibitor 2A

CLDN18.2

Claudin 18.2

CTLA-4

Cytotoxic T-lymphocyte antigen-4

CypA

Cyclophilin A

DAMPs

Damage-associated molecular patterns

DCs

Dendritic cells

DCR

Disease control rate

DDR

DNA damage repair

DFS

Disease-free survival

dMMR

Deficient mismatch repair

DSBs

Double-strand breaks

ECM

Extracellular matrix

ECT

Electrochemotherapy

EPR

Enhanced permeation and retention

FAK

Focal adhesion kinase

FOLFOX

5-fluorouracil and oxaliplatin

HRD

Homologous recombination deficiency

HRR

Homologous recombination repair

ICB

Immune checkpoint blockade

ICI

Immune checkpoint inhibitor

IRE

Irreversible electroporation

LAPC

locally advanced PDAC

LOH

Loss of heterozygosity

mFOLFIRI

Folinic acid + 5-fluorouracil + irinotecan

mFOLFIRINOX

Modified FOLFIRINOX

mPDAC

Metastatic pancreatic ductal adenocarcinoma

MSI-H

High microsatellite instability

MAT2A

Methionine adenosyltransferase 2α

MTA

2-methylthioadenosine

MTAP

Methylthioadenosine phosphorylase

NALIRIFOX

Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin (Onivyde®)

Nab-paclitaxel

Albumin-bound paclitaxel (Abraxane®)

NAT

Neoadjuvant therapy

NSCLC

Non-small cell lung cancer

ORR

Overall response rate

OS

Overall survival

PARP

Poly(adenosine diphosphate–ribose) polymerase

PD-1

Programmed cell death protein 1

PD-L1

Programmed cell death ligand 1

PDAC

Pancreatic ductal adenocarcinoma

PDX

Patient-derived xenograft

PEGPH20

PEGylated hyaluronidase 20

PFS

Progression-free survival

PROTAC

Proteolysis-targeting chimera

PRMT5

Protein arginine methyltransferase 5

PSC

Pancreatic stellate cells

PurIST

Purity Independent Subtyping of Tumors

pMMR

Proficient mismatch repair

RE

Reversible electroporation

RNAi

RNA interference

RPC

Resectable pancreatic cancer

Shh

Sonic hedgehog

siRNAs

Small interfering RNAs

SOC

Standard-of-care

SSBs

Single-strand breaks

SAM

S-adenosylmethionine

SMAD4

SMAD family member 4

TGF-β

Transforming growth factor-β

TGF-βRI

Transforming growth factor-β receptor I

TME

Tumour microenvironment

TP53 (p53)

Tumour protein p53

TTFs

Tumour treating fields

Top1

Topoisomerase I

VDR

Vitamin D receptor

Author contributions

DH: Writing – review & editing, Writing – original draft, Conceptualization. LEK: Writing – review & editing, Conceptualization. APM: Writing – review & editing, Conceptualization. SGM: Writing – review & editing, Conceptualization.

Funding

This work was funded through a PhD scholarship from Musgrave Group, Ireland, and Breakthrough Cancer Research, Ireland (Registered Charity No: 20077945; DH; Grant ID: MBPhD-0122); a Research Ireland Postdoctoral Fellowship (LEK; grant number GOIPD/2024/331); and Viatris Ireland (SGM).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.