In the adjuvant setting, the PRODIGE 24 trial demonstrated that modified FOLFIRINOX (mFFX) yielded a median OS of 53.5 vs. 35.5 months (HR 0.68; P = 0.001) versus gemcitabine, establishing mFFX as the preferred adjuvant regimen for fit patients [11]. In the metastatic setting, both mFFX and gemcitabine + nab-paclitaxel achieve median OS of ~11–12 months with no definitive head-to-head superiority [7, 8].

The JCOG1611 (GENERATE) trial found GEM/nab-P was not inferior to mFFX (median OS 17.1 vs. 14.0 months; HR 1.31), supporting its use as a preferred first-line option in Asian populations [9]. PASS-01 further found that basal-like PDAC subtype was associated with worse outcomes on mFFX, while classical subtype trended toward benefit — underscoring the need for transcriptomic stratification [10].

NALIRIFOX (liposomal irinotecan, 5-FU, leucovorin, oxaliplatin) demonstrated superiority over GEM/nab-P in the NAPOLI-3 phase III trial (median OS 11.1 vs. 9.2 months; HR 0.83), with a distinct toxicity profile — lower hematologic toxicity but higher rates of severe diarrhea [7]. NALIRIFOX is now an additional first-line standard.

In second-line, nanoliposomal irinotecan + 5-FU/leucovorin (nal-IRI + 5-FU/LV) remains the only approved regimen following gemcitabine-based therapy, with median OS of ~6.2 months in the NAPOLI-1 trial [4].

MRTX1133 is a non-covalent, selective KRAS G12D inhibitor that binds the switch II pocket in both active and inactive states. Critically, it reprograms the tumor microenvironment — increasing intratumoral CD8+ T cells, decreasing myeloid infiltration, and reprogramming cancer-associated fibroblasts (CAFs) — with synergistic tumor eradication when combined with immune checkpoint blockade [6, 14].

RMC-9805 represents a mechanistically distinct approach: a covalent, oral, RAS(ON) G12D-selective tri-complex inhibitor that targets the active, GTP-bound state of KRAS G12D by forming a ternary complex with cyclophilin A [35].

For the ~50% of PDAC patients with non-G12D KRAS mutations, pan-RAS inhibitors offer broader coverage. RMC-6236, a RAS(ON) multi-selective inhibitor, is active against multiple KRAS mutant isoforms and is being evaluated in combination with RMC-9805 in clinical trials.

Daraxonrasib (BI 1701963), a SOS1 inhibitor that blocks KRAS activation by preventing nucleotide exchange, is in phase I/II trials with MEK inhibitors. SHP2 inhibitors (TNO155, RMC-4630) target upstream KRAS activation and are being explored in combination with KRAS inhibitors to prevent adaptive resistance [2, 4].

For the small G12C+ PDAC subset (~2–3%), sotorasib and adagrasib remain options, often combined with anti-EGFR antibodies given the rapid feedback reactivation seen in CRC-like contexts.

Resistance to KRAS G12D inhibitors in PDAC is multifactorial. AGER-dependent macropinocytosis drives resistance by facilitating albumin internalization and glutathione synthesis, inhibiting apoptosis [15]. Secondary KRAS mutations, bypass signaling through PI3K/AKT and FGFR pathways, and CAF-mediated FGF1 secretion that reactivates MAPK signaling represent additional resistance nodes.

Combination strategies targeting FAK (to reprogram CAFs) alongside RAF/MEK inhibition (avutometinib) have shown preclinical efficacy in overcoming stromal-mediated resistance [16].

Olaparib received FDA approval in December 2019 as maintenance therapy for germline BRCA1/2-mutant metastatic PDAC following at least 16 weeks of platinum-based first-line chemotherapy without progression, based on the POLO trial (median PFS 7.4 vs. 3.8 months; HR 0.53) [17, 18]. Real-world data from 114 Italian patients confirmed a significant OS benefit with olaparib exposure (HR 0.568; P = 0.02) [19].

Rucaparib has also been evaluated; however, acquired BRCA/PALB2 reversion mutations — detected in 16.6% of patients progressing on rucaparib — were associated with rapid resistance and poor post-progression outcomes [20].

Talazoparib, a more potent PARP trapper, showed superior efficacy in HRD PDAC models including ATM-, BRCA1-, BRCA2-, and PALB2-deficient genotypes, providing rationale for a talazoparib-based PAD regimen (PARP + ATR + DNA-PK inhibition) in clinical development [22].

Next-generation PARP1-selective inhibitors such as saruparib (AZD5305) demonstrated superior preclinical complete response rates (75% vs. 37% for olaparib) and significantly longer PFS in patient-derived xenograft models, with a favorable safety profile that may facilitate combination with ATR inhibitors (ceralasertib) [21]. The ongoing SWOG S2001 trial is evaluating olaparib + pembrolizumab versus olaparib alone as maintenance therapy in gBRCA1/2-mutant PDAC [23].

NTRK fusions (<1% of PDAC) are targetable with tumor-agnostic TRK inhibitors larotrectinib and entrectinib, which have demonstrated ORRs exceeding 50% in NTRK fusion-positive solid tumors [29]. Next-generation TRK inhibitors like repotrectinib address resistance to first-generation agents.

RET fusions (~1%) respond to selective inhibitors selpercatinib and pralsetinib with ORRs >50% across tumor types [4]. FGFR2 fusions (~0.8%) show durable responses to pemigatinib, the FDA-approved FGFR1–3 inhibitor.

NRG1 fusions, an emerging target in KRAS wild-type PDAC, activate HER2/HER3 signaling and are targetable with zenocutuzumab (a bispecific antibody; ORR 42% in fusion-positive cancers) [4].

CDK4/6 inhibitors address the ~50% of PDAC with CDKN2A loss, though single-agent efficacy is limited by compensatory ERK/PI3K upregulation. Preclinical CRISPR screens identified synergistic combinations with ERK inhibitors (ulixertinib + palbociclib; NCT03454035), CDK2 inhibitors, and SRC family kinase inhibitors [31].

For the 1–2% of PDAC that is MSI-H/dMMR, pembrolizumab shows exceptional responses (ORR 75% in the Mayo Clinic series; median PFS not reached) [32]. For the vast majority of MSS PDAC tumors, checkpoint inhibitors as monotherapy have failed to demonstrate benefit [34].

PRMT5 inhibitors exploit the synthetic lethality created by MTAP deletion (co-deleted with CDKN2A in ~50% of PDAC). MTAP-deleted cells accumulate MTA, which selectively inhibits PRMT5 and creates dependency on residual PRMT5 activity [4].

Metabolic targeting — exploiting KRAS-driven macropinocytosis, autophagy, and glycolytic reprogramming — represents an orthogonal vulnerability. Autophagy inhibitors (hydroxychloroquine) and glutaminase inhibitors are in clinical evaluation [35].

Both MRTX1133 and RMC-9805 have demonstrated TME reprogramming in preclinical models — increasing CD8+ T cell infiltration, reducing immunosuppressive myeloid cells, and upregulating FAS-mediated tumor cell killing — providing a strong mechanistic rationale for combination with anti-PD-1 therapy. RMC-9805 + anti-PD-1 produced complete responses in immunocompetent PDAC models that are refractory to immunotherapy alone [13, 14].