PASS-01: the final step on the journey towards the optimal chemotherapy regimen for metastatic pancreatic adenocarcinoma?

Over a decade ago, the standard of care for metastatic pancreatic ductal adenocarcinoma (PDAC) shifted from single-agent gemcitabine (GEM) to multi-agent chemotherapy. In pivotal phase III randomized clinical trials (RCTs), both FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) demonstrated improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) compared with GEM (1-3). Since then, in the absence of head-to-head prospective comparisons between these two regimens, multiple retrospective studies and meta-analyses have sought to define the optimal first-line approach for metastatic PDAC (4-7), with largely inconclusive results.

Significant contributions to this discussion have emerged from recent clinical trials. The NAPOLI-3 trial, a global phase III RCT, compared NALIRIFOX with GnP as first-line therapy (8). The results favored NALIRIFOX in both OS and PFS, suggesting that GnP may be less effective than a fluoropyrimidine-based triplet regimen. More recently, the Japanese phase II/III GENERATE/JCOG1611 trial reported outcomes comparing first-line modified FFX (mFFX) with GnP (and S-IROX) in metastatic PDAC (9,10). PFS and ORR were comparable between treatment arms, and the study did not achieve its primary endpoint of demonstrating the superiority of mFFX over GnP. Although the GnP arm exhibited numerically longer OS, this observation should not be interpreted as definitive evidence of superiority, given the premature termination of the trial for futility.

Many Western clinicians remain skeptical of the GENERATE/JCOG1611 findings, given that the study enrolled only Asian patients and reported unusually long OS in the GnP arm. Figure 1 summarizes median OS (in months) across multiple phase II or III first-line RCTs evaluating GnP, NALIRIFOX, and FFX/mFFX in metastatic PDAC (1,2,8,9,11-35), and illustrates that the OS with GnP in GENERATE/JCOG1611 appears to be an outlier compared with other trials. Although the reasons underlying this apparent excess efficacy of GnP are not fully understood, it is plausible that Western and Eastern populations may respond differently to these regimens. Supporting this hypothesis, a prior meta-analysis of retrospective studies comparing first-line FFX versus GnP suggested a larger benefit with FFX among Western patients, whereas Asian patients appeared to derive greater benefit from GnP (36). One important consideration is that Asian patients may experience higher toxicity with FFX, potentially due to a higher prevalence of UGT1A1 polymorphisms affecting the metabolism of SN-38. In GENERATE/JCOG1611, patients were screened for UGT1A1 variants, and those harboring homozygous *6 or *28 alleles were excluded (9). Nevertheless, despite the use of an mFFX regimen (including lower irinotecan dosing and omission of bolus 5-FU), GENERATE/JCOG1611 reported higher rates of febrile neutropenia than PRODIGE 4/ACCORD 11 (8.8% vs. 5.4%) (1), underscoring the increased risk of FFX-related complications in Asian patients. Notably, subgroup analyses from NAPOLI-3 (37), together with findings from a recently published phase II RCT conducted in China comparing NALIRIFOX with GnP (38), suggest that NALIRIFOX may confer improved OS and PFS among Asian patients. This apparent benefit may be partly explained by improved intratumoral delivery of irinotecan through its nanoliposomal formulation, as well as optimized dosing of oxaliplatin within the NALIRIFOX regimen. Together, these factors may enhance therapeutic efficacy while maintaining a more manageable toxicity profile in this population.

Figure 1 Overall survival across multiple phase II or III first-line RCTs evaluating GnP, NALIRIFOX, and FFX/mFFX in the first-line treatment of metastatic PDAC. Phase II and III RCTs evaluating GnP, NALIRIFOX, and FFX or mFFX were identified through a PubMed search conducted on January 26, 2026. The search strategy was: (pancreas OR pancreatic) AND (cancer OR carcinoma OR adenocarcinoma) AND (metastatic OR metastasis OR metastases). Filters were applied for publication dates between Jan 1^st 2011 and Jan 26^th 2026 and for study types including randomized controlled trials and systematic reviews. Analyses were restricted to treatment arms comprising chemotherapy alone. The included studies correspond to references (1,2,8,9,11-35). FFX, FOLFIRINOX; GnP, gemcitabine plus nab-paclitaxel; mFFX, modified FOLFIRINOX; PDAC, pancreatic ductal adenocarcinoma; RCT, randomized clinical trial.

Therefore, whether FFX and GnP yield comparable outcomes in Western patients remained an open question. In September 2025, Knox et al. published in the Journal of Clinical Oncology the results of the Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial (11). In this phase II RCT, 160 patients with de novo metastatic pancreatic adenocarcinoma were randomized (1:1) to receive mFFX or GnP, administered according to institutional standards. Eligible patients were required to have measurable disease per RECIST 1.1 and at least one tumor lesion amenable to biopsy, with collection of ≥4 cores using an 18-gauge needle. Notably, patients with known or strongly suspected germline BRCA or PALB2 mutations were excluded. Patients were enrolled across six institutions in Canada and the United States between October 2020 and January 2024 (39). The primary endpoint was PFS in the intention-to-treat (ITT) population. Secondary endpoints included ORR, disease control rate (DCR), and OS in the ITT population, as well as duration of response (DoR) in the per-protocol population. The trial also incorporated predefined translational analyses of outcomes according to transcriptional subtype (basal-like vs. classical) and GATA6 expression assessed by in situ hybridization (ISH). Exploratory objectives included evaluation of biomarker-informed second-line therapy guided by monthly molecular tumor board (MTB) discussions (vs. empiric standard of care) and assessment of CA 19-9 response at 4 weeks after treatment initiation, with additional translational analyses ongoing at the time of publication.

Patient characteristics were generally well-balanced between arms; however, the GnP arm more frequently had factors associated with improved survival, such as Eastern Cooperative Oncology Group (ECOG) performance status 0 (58.8% vs. 41.3%), non-liver metastases (20.0% vs. 11.4%), KRAS wild-type tumors (13.9% vs. 4.0%), and tumors with classical gene expression pattern (77.2% vs. 67.8%). After a median follow-up of 8.3 months in the ITT population, median PFS was 4.0 months with mFFX and 5.3 months with GnP (HR =1.37; 95% CI: 0.97–1.92; P=0.07). Median OS was 8.5 months for mFFX versus 9.7 months for GnP (HR =1.57; 95% CI: 1.08–2.28; P=0.02). ORR was similar between groups (30% with GnP vs. 29% with mFFX), whereas DCR was higher with GnP (79.7% vs. 62.9%; P=0.03). Treatment with GnP was also associated with a longer median DoR (5.9 vs. 4.7 months; P=0.03) and a more favorable toxicity profile, including fewer hospital admissions due to treatment-related adverse events (7% vs. 20%).

RNA-based subgroup classification was available for 103 patients (64.4%), with 74% classified as classical. No significant differences in PFS or OS were observed between basal-like and classical subtypes overall. In basal-like tumors, mFFX was associated with numerically shorter PFS and lower ORR, with similar OS. In classical tumors, PFS and ORR were comparable between mFFX and GnP, but mFFX was associated with shorter OS. High GATA6 expression according to ISH correlated with the classical subtype and was associated with numerically longer PFS, without significant interaction with treatment regimen.

Overall, 75 patients (54%) received a second-line therapy, with no significant differences between study arms. Whole-genome sequencing (n=18), RNA profiling (n=5), and patient-derived organoids (PDOs; n=10) frequently informed second-line treatment selection, accounting for 42.8% of patients who received a second-line therapy. However, outcomes were similar between patients who received MTB-recommended versus standard second-line therapy, including median time on treatment (2.2 vs. 1.9 months) and OS from the start of second-line therapy (5.4 vs. 4.4 months; P=0.46). Finally, a >20% decrease in CA 19-9 at 4 weeks was associated with improved PFS (6.9 vs. 3.7 months; P=0.042). Conversely, a >20% increase in CA 19-9 at 4 weeks was associated with inferior PFS (3.1 vs. 6.7 months; P<0.001); notably, 22.7% of patients (n=10) with an early CA 19-9 rise subsequently achieved a partial response or stable disease lasting at least 4 months.

The authors should be commended for designing and conducting this important study, which represents the first RCT comparing mFFX and GnP as first-line therapy for metastatic PDAC in a Western population. Nevertheless, the results require careful scrutiny in light of the trial’s methodological constraints and the broader body of evidence. At first glance, the apparent OS advantage of GnP over mFFX in the ITT population is unexpected; however, this finding may largely reflect the study design and population. First, as an investigator-initiated trial, the planned sample size was reduced and, to increase the probability of detecting a treatment signal, the type I error assumption was relaxed (two-tailed P value =0.3). For context, the PASS-01 sample size (N=136) was nearly six-fold smaller than that of the NAPOLI-3 phase III trial. Moreover, imbalances in baseline prognostic characteristics between treatment arms, along with differences in the enrolled population, may have contributed to the observed superiority of GnP. As noted above, patients assigned to the GnP arm more frequently presented with factors associated with improved survival. In addition, patients with known or suspected germline BRCA or PALB2 mutations—estimated to account for 10–15% of metastatic PDAC and representing the subgroup most likely to benefit from platinum-based chemotherapy (40)—were excluded from PASS-01. Indeed, as can be observed in Figure 1, the OS results of the mFFX arm from PASS-01 are amongst the worst seen in RCTs. Additionally, the study included a greater representation of ethnic groups other than Caucasians, which—consistent with data from the GENERATE/JCOG1611 trial—could have favored outcomes with GnP. Notably, nearly 20% of patients in the mFFX arm were Asian. Finally, the inclusion of non-ductal histologies (e.g., mucinous adenocarcinoma and adenosquamous carcinoma) may have further influenced treatment outcomes (41).

In PASS-01, no significant differences in PFS or OS were observed between patients with basal-like and classical tumors, in contrast to prior findings, including those from the COMPASS trial (42,43). Another notable observation was the inferior OS among patients with classical tumors treated with mFFX compared with GnP, again diverging from prospective translational data—particularly from COMPASS—which suggested improved OS with mFFX in this subgroup. Conversely, among patients with basal-like tumors in PASS-01, OS appeared comparable between treatment arms. This also contrasts with COMPASS, where patients with basal-like tumors appeared to derive greater benefit from GnP than from mFFX. The reasons underlying these discrepancies remain uncertain. However, they may reflect limited statistical power—particularly for interaction analyses between transcriptional subtype and treatment—lack of adjustment for multiple hypothesis testing, and differences in eligibility criteria and baseline population characteristics across studies. Importantly, although the use of biomarker-driven therapies, such as KRAS inhibitors, may modify the natural history of the disease and attenuate prognostic differences between subtypes, their use in PASS-01 was minimal (1.4%). Finally, the exclusion of patients with known or suspected germline BRCA or PALB2 mutations may have further confounded comparisons by disproportionately affecting the classical subgroup.

Prior results from the Know Your Tumor (KYT) initiative suggested improved OS amongst patients whose tumors harbored potentially actionable alterations and who received matched therapies, compared with those treated with standard-of-care regimens (44). In contrast, PASS-01 did not demonstrate meaningful differences in either median time on second-line therapy or OS between patients managed with correlative-guided treatment selection and those treated according to routine clinician choice. Although the number of patients receiving molecularly informed second-line therapy in PASS-01 was relatively limited, it is important to note that actionability in this trial frequently relied on platforms beyond DNA-based genomic profiling, including RNA analyses and PDOs. These approaches were not incorporated in the KYT initiative and remain incompletely validated—particularly in the setting of refractory metastatic PDAC, where treatment windows are narrow and the clinical utility of such tools is not fully understood. Additionally, treatment selection was based on molecular profiling performed on biopsies obtained prior to initiation of systemic therapy. However, rebiopsy analyses from the COMPASS trial have demonstrated increased genomic instability at the time of progression on first-line treatment, including a higher burden of single nucleotide variants and structural variants relative to baseline metastatic samples (42). These observations suggest that molecular evolution under therapeutic pressure may limit the reliability of treatment decisions guided exclusively by pre-treatment tumor biopsies. Finally, given that only approximately half of patients with metastatic PDAC ultimately receive second-line therapy, the PASS-01 findings further reinforce the concept that biomarker-driven strategies and targeted therapies, when available, may need to be implemented earlier in the disease course in order to translate molecular insights into clinically meaningful benefit.

Taken together, the results of PRODIGE 4/ACCORD 11, MPACT, NAPOLI-3, GENERATE/JCOG1611, and PASS-01 do not definitively establish a single optimal first-line chemotherapy regimen for metastatic PDAC. Figure 2 presents reconstructed OS curves from the experimental and control polychemotherapy arms of these trials. Variability in outcomes observed with GnP and FFX/mFFX across studies likely reflects differences in study populations (Table 1), eligibility criteria, geographic enrollment (Western vs. Eastern cohorts), statistical design (including sample size), trial completion, and regimen delivery (particularly in the case of mFFX). In particular, there are important differences in baseline characteristics across trials, including a higher proportion of patients with a single metastatic site in GENERATE/JCOG1611 compared with MPACT and PASS-01, as well as a higher proportion of patients with ECOG performance status 0 in GENERATE/JCOG1611 compared with MPACT, which may have influenced OS outcomes. Emerging evidence from two randomized trials suggests that NALIRIFOX may be superior to GnP (8,38). However, whether conventional irinotecan confers survival outcomes comparable to its liposomal formulation remains uncertain. Many clinicians remain cautious about concluding that NALIRIFOX is superior to mFFX in the absence of a direct head-to-head comparison, especially given the broadly similar survival outcomes observed with NALIRIFOX in NAPOLI-3 and FFX in PRODIGE 4/ACCORD 11 (47,48). However, despite the absence of significant differences in median OS, indirect between-trial comparisons suggest that NALIRIFOX may be associated with improved longer-term survival (from approximately 18 months onward) compared with mFFX and a somewhat milder toxicity profile (49).

Figure 2 Reconstructed overall survival curves from the triplet and GnP regimens from PRODIGE 4/ACCORD 11, MPACT, NAPOLI-3, GENERATE/JCOG1611, and PASS-01 trials. Survival curves were truncated at the 32-month landmark. Survival curves were reconstructed using the method described by Guyot et al. (45). Data were digitally extracted using WebplotDigitizer from references (1,3,8,9,11). FFX, FOLFIRINOX; GnP, gemcitabine plus nab-paclitaxel; mFFX, modified FOLFIRINOX.

An important question is the clinical meaningfulness of the OS differences observed across these trials. More than a decade ago, the American Society of Clinical Oncology (ASCO) proposed a 4–5 month improvement in OS as a benchmark for clinically meaningful benefit in metastatic PDAC (50). In contrast, the PASS-01, NAPOLI-3, and GENERATE/JCOG1611 trials report median OS differences in the range of 1 to 3 months, falling below this threshold. These modest differences suggest that additional factors should inform first-line treatment selection. Although formal quality-of-life data are not yet available for PASS-01 or GENERATE/JCOG1611, exploratory analyses from NAPOLI-3 indicate that the OS benefit associated with NALIRIFOX was not accompanied by deterioration in quality of life (51). Importantly, given the relatively small OS differences seen in these trials, as well as variations in administration schedules and toxicity profiles among regimens (49), shared decision-making with patients is essential when selecting first-line therapy. Finally, treatment sequencing may have practical implications, as the lack of randomized evidence supporting GnP in the second-line setting may limit reimbursement of nab-paclitaxel after prior mFFX or NALIRIFOX in some settings, potentially restricting patient access to all active agents over the course of treatment.

That said, the survival results from PASS-01 provide additional support for the activity of GnP in this context, making it a reasonable option for patients without access to liposomal irinotecan or those who are not fit enough to receive FFX. Importantly, regardless of the selected first-line regimen, patients should be closely monitored to detect early signs of disease progression, thereby maximizing the opportunity to initiate potentially effective second-line therapies (11). Finally, with the advent of KRAS inhibitors in PDAC, combinations of these agents with established chemotherapy backbones are anticipated to further improve treatment outcomes (52). Ultimately, the optimal chemotherapy regimen may be the one that demonstrates the greatest efficacy and tolerability when used in combination with RAS-targeted therapies.

Despite the important contributions of the PASS-01 trial, several factors currently limit the feasibility of translating RNA-based analyses into routine clinical practice. Patients with metastatic PDAC are often clinically ill, requiring prompt initiation of systemic therapy. As a consequence, in real-world settings, treatment decisions will very frequently be made before transcriptomic results become available. Additionally, with current technologies, transcriptomic profiling is not feasible in approximately one quarter of patients, and this proportion may be even higher in populations with lower tumor burden or limited tissue availability. One potential surrogate that has shown correlation with transcriptional subtype is GATA6 RNA ISH, which is faster, less costly, and more widely accessible than full transcriptomic profiling. Nevertheless, in PASS-01, GATA6 ISH status was not associated with differences in chemotherapy response or PFS, limiting its immediate clinical utility as a predictive biomarker. Furthermore, single-cell RNA sequencing studies in metastatic PDAC have identified intermediate tumor cell populations co-expressing both classical and basal-like gene signatures within the same cells (53). These findings highlight the dynamic nature of tumor cell states and suggest that transcriptional programs may shift under therapeutic pressure, potentially limiting the clinical utility of a single baseline transcriptomic profile. Finally, emerging clinical data suggest that combining GEM and a fluoropyrimidine either concurrently (as explored in PACT-19) (29) or in alternating strategies (e.g., PRODIGE 37 and the SEQUENCE trial) (14,22) within multi-agent regimens may improve outcomes, potentially by increasing the likelihood that patients receive at least one highly active drug or combination. This empirical approach may, at present, offer a pragmatic alternative while the clinical integration of transcriptomic biomarkers continues to evolve.

In conclusion, PASS-01 represents an important investigator-initiated effort that signals a new direction in the management of metastatic PDAC. It is the first RCT to integrate a multi-omics framework into the first-line treatment strategy for this disease. Although its findings are not yet ready for immediate clinical implementation, the study provides a critical foundation for future biomarker-driven research and serves as a model for upcoming trials evaluating targeted approaches, including inhibitors of the MAP kinase pathway.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article has undergone external peer review.

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-26-0013/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-26-0013/coif). V.H.F.d.J. received honoraria from Knight Medical/BMS and Servier; received support for attending meetings and travel from Servier; and received payment for participation in Advisory Board from Servier. A.J. received institutional grants from Bayer and Servier; received honoraria from Novartis, Roche, Amgen, Servier, BMS, Astellas, MSD, AstraZeneca, Daiichi-Sankyo, Takeda, BeOne; received support for attending meetings and travel from Servier, IPSEN, Pfizer, Zodiac, AstraZeneca, Astellas, Daichii-Sankyo, Bayer, Amgen; and received payment for participation in Advisory Board from Bayer, Eli Lilly, Servier, BMS, MSD, Astellas, AstraZeneca, Takeda, BeOne. The authors have no other conflicts of interest to declare.

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